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Biomedical subjects

Andrew Lam

Publications and source records attributed to Andrew Lam.

10 recordsLinked to original sources
PubMed2006

Transforming growth factor-beta receptor type 1 (TGFbetaRI) kinase activity but not p38 activation is required for TGFbetaRI-induced myofibroblast differentiation and profibrotic gene expression.

Transforming growth factor-beta (TGFbeta) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGFbeta also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGFbetaRI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGFbetaRI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGFbeta-induced SMAD signaling, myofibroblast transformation, and collagen gel contraction. Furthermore, we extended our findings to a rat bleomycin-induced lung fibrosis model, demonstrating a significant decrease in the number of myofibroblasts at fibroblastic foci in animals treated with SD-208 but not those treated with SD-282. SD-208 also reduced collagen deposition in this in vivo model. Microarray analysis of human lung fibroblasts identified molecular fingerprints of these processes and showed that SD-208 had global effects on reversing TGFbeta-induced genes involved in fibrosis, inflammation, cell proliferation, cytoskeletal organization, and apoptosis. These studies also revealed that although the p38 pathway may not be needed for appearance or disappearance of the myofibroblast, it can mediate a subset of inflammatory and fibrogenic events of the myofibroblast during the process of tissue repair and fibrosis. Our findings suggest that inhibitors such as SD-208 may be therapeutically useful in human interstitial lung diseases and pulmonary fibrosis.

Activin Receptors, Type I↗
PubMed2006

Cardiovascular risk factors and events in glaucoma patients with peripapillary focal arteriolar narrowing.

PURPOSE: To evaluate cardiovascular risk factors and events in glaucoma patients with and without peripapillary focal arteriolar narrowing of retinal vessels. METHODS: We examined the fundus photographs of 325 consecutive glaucoma patients for evidence of focal arteriolar narrowing of retinal vessels adjacent to the optic disc. Cases and controls were matched for age, race, sex and mean deviation on Humphrey visual field. Medical information regarding cardiovascular risk factors and events was collected from patients' primary care physicians, and this information was confirmed by questionnaires sent to the patients themselves. RESULTS: A total of 58 pairs of cases and controls were matched. The prevalence of hypertension and diabetes was exactly equal in both groups, 65.5% and 27.6%, respectively. Similarly, the prevalences of myocardial infarction, cardiac surgery, angioplasty, family history of heart disease and smoking were nearly identical in both groups. There was no significant difference in the prevalence of strokes or transient ischaemic attacks. The prevalence of hypercholesterolemia and mortality was greater in the case group (mean differences of 8.6, p = 0.42 and 5.2, p = 0.25, respectively), however, these differences were not statistically significant. CONCLUSION: There is no significant relationship between peripapillary focal arteriolar narrowing of retinal vessels and cardiovascular risk factors or events in patients with glaucoma. Proximal narrowing does not appear to be a marker of systemic vascular disease.

Aged↗
PubMed2005

Measurement of scleral thickness in uveal effusion syndrome.

PURPOSE: To measure scleral thickness in patients with and without uveal effusion syndrome using ultrasound biomicroscopy (UBM) and magnetic resonance imaging (MRI). DESIGN: Prospective case-control study. METHODS: UBM was used to measure scleral thickness in five subjects with uveal effusion syndrome and five matched controls. We also used MRI to measure scleral thickness in three subjects. RESULTS: The mean thicknesses for eyes with uveal effusion syndrome versus control eyes were 0.65 +/- 0.08 mm and 0.55 +/- 0.05 mm, respectively (mean difference 0.10, P value = .13). MRI measurements of three subjects showed abnormally thick sclera but were imprecise. CONCLUSIONS: UBM can be used to measure scleral thickness, and our results support the finding that patients with uveal effusion syndrome have abnormally thick sclera. Compared with MRI, UBM may be a more accurate and precise method of measuring scleral thickness. UBM can be a useful adjunctive test in the management of uveal effusion syndrome.

Aged↗
PubMed2005

Laser Doppler flowmetry in asymmetric glaucoma.

PURPOSE: To evaluate the relationship between extent of glaucoma damage and optic nerve blood flow, we investigated optic nerve head bloodflow in patients with asymmetric glaucoma damage between their two eyes and also in glaucomatous eyes with asymmetric damage inferiorly versus superiorly. METHODS: From our institutional practice, 16 subjects with asymmetric glaucoma damage between their two eyes and 25 eyes of 20 patients with asymmetric damage superiorly versus inferiorly were included in the study. Determinations of relative optic nerve head blood flow, velocity, and volume were obtained with laser Doppler flowmetry in the superotemporal and inferotemporal neuroretinalrim and in the cup. Means of flow (Flow(3)), velocity (Vel(3)), and volume (Vol(3))were calculated from these three measurement sites, and eyes or hemidisks with greater glaucomatous damage were compared to eyes or hemidisks with less damage. RESULTS: For subjects with asymmetric glaucoma damage between eyes, Flow(3) and Vel(3) were significantly lower in the eyes with worse glaucoma damage(mean difference = 2.09, p = 0.005, and mean difference = 0.05, p = 0.002,respectively). When comparing optic disks displaying within-eye asymmetry, the hemidisk with greater damage showed significantly lower blood velocity than the hemidisk with less damage (mean difference = 0.05, p = 0.013); however,no difference in blood flow or volume was detected. CONCLUSIONS: This study provides additional evidence that impaired optic nerve circulation is associated with the extent of glaucomatous pathology.

Adult↗
PubMed2004

B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation.

The natriuretic peptides, including human B-type natriuretic peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-beta (TGF-beta) is associated with profibrotic processes in heart failure, we tested whether BNP could inhibit TGF-beta-induced effects on primary human cardiac fibroblasts. BNP inhibited TGF-beta-induced cell proliferation as well as the production of collagen 1 and fibronectin proteins as measured by Western blot analysis. cDNA microarray analysis was performed on RNA from cardiac fibroblasts incubated in the presence or absence of TGF-beta and BNP for 24 and 48 hours. TGF-beta, but not BNP, treatment resulted in a significant change in the RNA profile. BNP treatment resulted in a remarkable reduction in TGF-beta effects; 88% and 85% of all TGF-beta-regulated mRNAs were affected at 24 and 48 hours, respectively. BNP opposed TGF-beta-regulated genes related to fibrosis (collagen 1, fibronectin, CTGF, PAI-1, and TIMP3), myofibroblast conversion (alpha-smooth muscle actin 2 and nonmuscle myosin heavy chain), proliferation (PDGFA, IGF1, FGF18, and IGFBP10), and inflammation (COX2, IL6, TNFalpha-induced protein 6, and TNF superfamily, member 4). Lastly, BNP stimulated the extracellular signal-related kinase pathway via cyclic guanosine monophosphate-dependent protein kinase signaling, and two mitogen-activated protein kinase kinase inhibitors, U0126 and PD98059, reversed BNP inhibition of TGF-beta-induced collagen-1 expression. These findings demonstrate that BNP has a direct effect on cardiac fibroblasts to inhibit fibrotic responses via extracellular signal-related kinase signaling, suggesting that BNP functions as an antifibrotic factor in the heart to prevent cardiac remodeling in pathological conditions.

Adolescent↗
PubMed2003

Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies.

BACKGROUND: The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. METHODS: Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. RESULTS: The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy. CONCLUSIONS: These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.

Administration, Oral↗
PubMed2002

Visual field loss in patients with glaucoma who have asymmetric peripapillary focal arteriolar narrowing.

OBJECTIVE: To evaluate the relationship between peripapillary focal arteriolar narrowing and visual field defects. METHODS: From our institutional practice, we identified 31 patients with glaucoma who had peripapillary focal arteriolar narrowing in only one eye and compared visual field data between the two eyes. Mean deviation (MD) and corrected pattern standard deviation (CPSD) were recorded using Humphrey visual field testing at the time proximal narrowing was apparent on the fundus photograph. Visual field data from subsets of patients with mild and severe narrowing were also compared. RESULTS: The MD and CPSD were significantly worse in eyes with peripapillary focal arteriolar narrowing. The eyes with narrowing exhibited a mean MD of -8.77 +/- 8.27 dB and a mean CPSD of 5.01 +/- 3.42 dB. Eyes without narrowing displayed a mean MD of -4.52 +/- 6.64 dB and a mean CPSD of 3.01 +/- 2.68 dB (P =.003 for both). There was no significant difference in severity of the visual field defect between eyes with mild and severe arteriolar narrowing. CONCLUSION: To our knowledge, this is the first study to show that the presence of peripapillary focal arteriolar narrowing is related to the severity of visual field loss in patients with glaucoma.

Aged↗
PubMedDate not supplied

Photodynamic therapy in young patients.

BACKGROUND AND OBJECTIVE: To present a consecutive case series of patients 50 years or younger who underwent photodynamic therapy (PDT) for choroidal neovascularization (CNV) from etiologies other than age-related macular degeneration. PATIENTS AND METHODS: Retrospective chart review of 35 consecutive eyes of 34 patients. RESULTS: Visual acuity remained stable or improved in 20 of 35 eyes. Thirteen eyes with myopic degeneration had pre-treatment and post-treatment mean visual acuities of 20/100 and 20/200, respectively. Eight eyes with idiopathic CNV had an improvement of mean visual acuity from 20/200 to 20/125. Six eyes with ocular histoplasmosis displayed a stable mean visual acuity of 20/50. Of 3 eyes with angioid streaks, visual acuity remained stable in 2 eyes and declined in 1 eye. Five eyes with other etiologies all had improved vision. CONCLUSION: Although the current literature shows evidence that PDT is beneficial in treating CNV secondary to myopic degeneration, the evidence for etiologies such as idiopathic causes, ocular histoplasmosis, and angioid streaks is optimistic but remains unproven. Our study suggests that PDT may be beneficial in stabilizing and improving vision when treating CNV from these etiologies.

Adult↗
PubMedDate not supplied

Uveal metastases from breast carcinoma in three male patients.

The authors present a case series of three male patients with uveal metastases originating from breast carcinoma. The mean age at discovery of uveal metastases and the mean interval from diagnosis of primary breast carcinoma were 49.7 and 2.3 years, respectively. The analogous data in women are 56 and 5.4 years, respectively. In this series, all three patients were affected bilaterally and four of six eyes (67%) had multifocal tumors. In women, metastases are bilateral in 38% and multifocal in 48%. Compared with women, metastases in men may occur sooner and with a higher incidence of bilateral and multifocal tumors.

Adult↗