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Biomedical subjects

G K Lam

Publications and source records attributed to G K Lam.

At least 19 recordsLinked to original sources
PubMed2001

Inhaled nitric oxide for primary pulmonary hypertension in pregnancy.

BACKGROUND: Primary pulmonary hypertension is a rare and dangerous entity in pregnancy. Previous studies have found a 35-50% maternal mortality rate in the peripartum period. To date, most reports have described treatment of these patients with diuretics, digoxin, and calcium-channel blockers. CASE: We describe the successful treatment of a primigravida with severe primary pulmonary hypertension. We used elective intubation before labor, inhaled nitric oxide therapy, and assisted vaginal delivery with epidural anesthesia that resulted in a viable infant and survival of the mother. CONCLUSION: Nitric oxide can be used to successfully treat primary pulmonary hypertension in pregnancy.

Administration, Inhalation↗
PubMed1999

The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder.

BACKGROUND: Information-transducing heterotrimeric G proteins have been implicated previously in the mechanism of action of mood stabilizers and in the pathophysiology of mood disorders. Mononuclear leukocytes of patients with unipolar and bipolar depression have been characterized by reduced measures of the stimulatory and inhibitory G proteins. In this study, patients with seasonal affective disorder (SAD) were measured for mononuclear leukocyte G protein levels while depressed during the winter, following light therapy, and in remission during the summer. METHODS: Twenty-six patients with SAD and 28 healthy subjects were assessed in the study. The immunoreactivities of Gs alpha, Gi alpha, and Gbeta subunit proteins were determined by Western blot analysis of mononuclear leukocyte membranes with selective polyclonal antibodies for the various G subunit proteins, followed by densitometric quantitation using an image analysis system. RESULTS: Untreated patients with SAD and winter, atypical-type depression showed significantly reduced mononuclear leukocyte immunoreactive levels of Gs alpha and Gi alpha proteins, similar to previous observations in patients with nonseasonal major depression. The reduced G protein levels were normalized with 2 weeks of light therapy. The same patients while in remission during the summer had G protein levels that were similar to those of healthy subjects. CONCLUSIONS: G protein-immunoreactive measures in patients with SAD are suggested as a state marker for winter depression, which is normalized by light treatment and during the summer. We speculate that light may exert its effects via normalization of transducin (Gt protein) levels, which are thought to be reduced in winter depression.

Adult↗
PubMed1999

Range modulation in proton therapy--an optimization technique for clinical and experimental applications.

A fast optimization algorithm for range modulation in clinical and experimental applications of proton therapy is described. The method is versatile towards the number of parameters provided for range modulation, i.e. the trade-off between accuracy and simplicity of the latter can be chosen freely. The approach is, therefore, adaptable to most operating proton therapy facilities. It requires only a few basic measurements as input data and results in a depth dose uniformity of better than 2%. A typical calculation takes less than 90 s on a DEC VAXstation 3100, FORTRAN. The method has been extensively tested at the TRIUMF Proton Therapy Facility in Vancouver, BC.

Algorithms↗
PubMed1998

Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder.

Seasonal variations in mood and behavior (seasonality) and seasonal affective disorder (SAD) have been attributed to seasonal fluctuations in brain serotonin (5-HT). the short (s), as opposed to the long (l), allele of the 5-HT transporter linked polymorphism (5-HTTLPR) has been associated with neuroticism and depression. We hypothesized that this short allele would also be associated with SAD and with higher levels of seasonality. Ninety-seven SAD patients and 71 non-seasonal healthy controls with low seasonality levels were genotyped for 5-HTTLPR and compared statistically. Patients with SAD were less likely to have the l/l genotype (27.8% vs 47.9%; P < 0.01) and more likely to have the s allele (44.8% vs 32.4%; P < 0.02) as compared to controls. The three 5-HTTLPR genotypes were also differentially distributed in patients and controls (P < 0.03). The SAD patients with the l/l genotype had a lower mean seasonality score than did patients with the other two genotypes (mean +/- s.d. = 15.3 +/- 2.8 vs 17.1 +/- 3.4 respectively; P < 0.02). The 5-HTTLPR short allele contributes to the trait of seasonality and is a risk factor for SAD, providing further evidence for a relationship between genetic variation in the 5-HT transporter (5-HTT) and behavior.

Affect↗
PubMed1997

Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors.

HIV-1-infected long-term nonprogressors are a heterogeneous group of individuals with regard to immunologic and virologic markers of HIV-1 disease. CC chemokine receptor 5 (CCR5) has recently been identified as an important coreceptor for HIV-1 entry into CD4+ T cells. A mutant allele of CCR5 confers a high degree of resistance to HIV-1 infection in homozygous individuals and partial protection against HIV disease progression in heterozygotes. The frequency of CCR5 heterozygotes is increased among HIV-1- infected long-term nonprogressors compared with progressors; however, the host defense mechanisms responsible for nonprogression in CCR5 heterozygotes are unknown. We hypothesized that nonprogressors who were heterozygous for the mutant CCR5 gene might define a subgroup of nonprogressors with higher CD4+ T cell counts and lower viral load compared with CCR5 wild-type nonprogressors. However, in a cohort of 33 HIV-1-infected long-term nonprogressors, those who were heterozygous for the mutant CCR5 gene were indistinguishable from CCR5 wild-type nonprogressors with regard to all measured immunologic and virologic parameters. Although epidemiologic data support a role for the mutant CCR5 allele in the determination of the state of long-term nonprogression in some HIV-1- infected individuals, it is not the only determinant. Furthermore, long-term nonprogressors with the wild-type CCR5 genotype are indistinguishable from heterozygotes from an immunologic and virologic standpoint.

Adult↗
PubMed1997

Studies on lymphoid tissue from HIV-infected individuals: implications for the design of therapeutic strategies.

Lymphoid tissue is a major reservoir of human immunodeficiency virus (HIV) infection in vivo. In addition, the lymphoid microenvironment provides a replicative advantage to the virus in that it provides a milieu of activated target cells that allows for efficient virus spread. The process of mobilization and activation of immune competent cells directed against the virus paradoxically contributes to the propagation of virus replication. Disruption of the lymphoid microenvironment during the progression of HIV disease is a poorly understood process, which may be of considerable importance pathogenically. Studies of lymph node biopsy samples taken 8 weeks apart from individuals who did not undergo any change in their therapeutic regimen (i.e., patients who either remained untreated or remained on their ongoing nucleoside analogue reverse transcriptase inhibitor monotherapy regimen) revealed little change in histopathology or viral load over the 8-week period. These results with successive lymph node biopsy samples taken from different sites indicate that an isolated lymph node biopsy accurately reflects the pathologic process associated with HIV infection and that this process diffusely involves the lymphoid system. Treatment with reverse transcriptase inhibitor monotherapy of patients in relatively early stage HIV disease had no detectable impact on the viral load in lymphoid tissue, suggesting the need to investigate more potent antiretroviral regimens during this stage of disease. Among patients with moderately advanced HIV disease, switching to combination therapy from a monotherapy regimen resulted in decreased viral replication in lymph nodes; this effect was associated with decreases in plasma viremia. Despite the fact that measures of viral replication decreased significantly, the net frequency of HIV-infected cells in peripheral blood and lymph nodes remained unchanged. Potent antiretroviral drug combinations may be capable of profound and long-term downregulation of plasma viremia. It will be essential to monitor the status of viral trapping, viral burden, and viral replication within lymphoid tissue during treatment with such drugs to determine accurately their true potential for impact on these key features of HIV pathogenesis.

Anti-HIV Agents↗
PubMed1997

A general cavity theory.

A cavity theory is used to relate the dose deposited in the cavity (sensitive volume of the detector) to that in the surrounding medium which may be of different atomic number or composition. Burlin proposed a general cavity theory to include all cavity sizes. The Burlin theory ignores all secondary-electron scattering effects which results in large discrepancies in dose to the cavity compared with the experimental results in high atomic number media. Kearsley proposed a new general cavity theory which includes secondary-electron scattering at the cavity boundary. The Kearsley theory showed excellent agreement with experimental results for 60Co y-rays but poor correlation for 10 MV x-rays. The Kearsley theory has numerous parameters and the magnitude of the input parameters is arbitrary; therefore the dose to the cavity depends on the choice of parameters. We have developed a new cavity theory which includes secondary-electron backscattering from the medium into the cavity. The strengths of this proposed theory are that it contains few parameters and a methodical way of determining the magnitude of the parameters experimentally. the proposed theory gives better agreement with experimental results in lithium fluoride thermoluminescence dosimeters for 60Co y-rays and 10 MV x-rays in aluminium, copper and lead than do the Burlin and Kearsley cavity theories.

Gamma Rays↗
PubMed1996

Proton dose monitoring with PET: quantitative studies in Lucite.

The feasibility of using PET for proton dose monitoring is examined here in detail. First experimental studies in a Lucite phantom have been performed at the medical TRIUMF proton beamline for proton energies of 62 MeV and 110 MeV. The proton dose delivered to the phantom ranged from 16 Gy up to 317 Gy. The induced activity was analysed 20-40 min after the irradiation with a PET scanner. The obtained depth activity profiles were compared to our calculation based on a model using available isotope production cross-section data. Both the observed absolute count rates and the activity profiles were found to agree very well with this model. Effects such as proton range straggling, inelastic nuclear interactions and the energy spectrum of the emitted positrons were studied in detail and found to change the activities by 5-10%. The lateral deposition of dose in the phantom could be very well localized by the induced activity. However, the spatial correlation between dose depth profiles and depth activity profiles was found to be poor, hence the extraction of isodose profiles from activity profiles seems to be very difficult.

Carbon↗
PubMed1996

Measurements of relative biological effectiveness of the 70 MeV proton beam at TRIUMF using Chinese hamster V79 cells and the high-precision cell sorter assay.

Measurements of relative biological effectiveness (RBE) have been made on the range-modulated 70 MeV proton beam at TRIUMF using a precise cell sorting survival assay. In this study, Chinese hamster V79-WNRE cells were suspended in medium containing liquid gelatin at 37 degrees C in irradiation tubes and the gel was allowed to solidify by cooling to 4 degrees C. Complete cell survival responses were measured at 11 positions with 2 mm spacing within a proton stopping peak width of approximately 2 cm. Survival responses after proton irradiation were compared with responses to 60Co gamma rays measured at the same time, and RBE values were determined as a function of both dose and depth. Above doses of 4 Gy, the average RBE for these cells throughout the modulated proton stopping distribution was 1.21 +/- 0.05, measured at a survival of 1%. However, we also observed that, within the spread-out Bragg peak, the RBE increased with increasing depth, from approximately 1.2 at the proximal part to > 1.3 at the distal part of the peak. At the distal edge of the stopping distribution, the RBE value increased significantly, to an extent that may be of concern when this region of the treatment volume is close to sensitive tissues. Below 4 Gy, the RBE value was also dependent on radiation dose, increasing significantly to values of approximately 1.37 and 1.56 at 2 and 1 Gy, respectively. Our results illustrate that the use of a single RBE value in different irradiation protocols can be an oversimplification, and argues for the use of "proton gray doses" rather than "gamma-ray equivalent grays."

Animals↗
PubMed1996

Immune reaction induced by X-rays and pions and its stimulation by schizophyllan (SPG).

Female C57BL/6 mice aged 6-8 weeks with transplanted Lewis lung cancer cells were used to investigate the anti-tumour effects and immune reactions in tumour tissue induced by X-ray and pion irradiation and their modification by schizophyllan (SPG). The effect of SPG on the rate of lung metastasis and the survival time of the mice was also studied using the same tumour system. These studies showed that in this tumour system the "practical' relative biological effectiveness (RBE) of pions was 1.33 in the dose ranges used (3 Gy x 4 = P3; 6 Gy x 4 = P6). SPG increased the suppression of tumour growth associated with moderate doses of radiation: X-rays (4 Gy x 4 = X4) or P3. SPG also decreased the number of lung metastases and prolonged the life span of the mice, these effects being independent of radiation. The addition of SPG to radiation increased both the macrophage infiltration and T-lymphocyte infiltration in the local tumour and the lung nodules. There did not appear to be any major differential effect of SPG on the pion-treated mice compared with those treated with X-rays.

Adjuvants, Immunologic↗
PubMed1996

Early skin response to fractionated doses of pions for determining therapeutic gain factors.

This study concerns the biological effectiveness of fractionated doses of pions on early skin reactions near the implanted tumor, to evaluate the therapeutic gain factors of pions. The C3H mouse limbs bearing microscopical SCCVII tumors were irradiated with pions (9.6-38.4 Gy) or x-rays (14.4-50.4 Gy) in 2-7 fractions. Nicotinamide (500 mg/kg) and carbogen (a mixture of 95% O2 + 5% CO2), as hypoxic radiosensitizers, were administered prior to the x-rays, to confirm the presence of hypoxic cells in the skin. The mean skin scores and number of damaged nails assessed. The ratios of x-ray/pion doses needed for giving comparable skin reactions were 1.3-1.5. Nicotinamide and carbogen enhanced the skin reactions. When the ratios were compared with those of tumor cure, the pions showed no therapeutic gains. One of the possible causes was that the presence of hypoxic cells in the skin may have reduced the therapeutic gain.

Animals↗
PubMed1995

The definition of damage interaction in International Commission of Radiation Units and Measurement Report 30.

There is some clarification required in the present definition of synergism and antagonism as published in report No 30 by the International Commission on Radiation Units and Measurements for quantitative concepts in radiobiology. In the report, damage interaction appears to be defined relative to additive action rather than to independent action. While the concept of independent action is completely independent of the action mechanism of radiations, it is shown that the concept of additive action requires that isoeffective doses of two different radiations be 'mechanistically equivalent' so that one can 'switch' from one response curve to another at the corresponding effect level. This makes the meaningful use of additive action strongly dependent on a supporting model. At present, most of the current models of radiation action cannot accommodate additive action. The report also states that, due to population selection, cell killing may be greater than that due to independent action if the survivor of one radiation is sensitive to the other radiation. An in-depth study indicates that the analysis is more complicated, depending on whether or not the population is known to be mixed. Lastly, an amended definition of damage interaction for the report is proposed.

Animals↗
PubMed1995

Biological effectiveness of fractionated dose of pions in microscopic SCCVII tumors: comparison between tumor control dose and tumor growth time assays.

The relative biological effectiveness (RBE) of fractionated pions for tumor growth time (TGT) assay changes with the endpoints, so it is essential to determine the RBE for tumor control dose (TCD) assay. For this purpose, the TCD50 of fractionated pions was compared with that of photons, and the RBEs for TGT and TCD assays were concurrently compared as a function of the effect level. A "convenient" RBE (cRBE) was substituted for the RBE when the comparison was made between similar fractionation schedules with different dose per fraction. SCCVII tumors (2 x 10(4) or 2 x 10(5) cells) were implanted into the feet of C3H mice and irradiated starting from 2 days after implantation at a total dose range of either 9.6-38.4 Gy pions (2.4-6.4 Gy per fraction) or 14.4-50.4 Gy photons (3.6-7.2 Gy per fraction) in 2-10 fractions over 5-6 days. The cRBE and the RBE at the iso-effective level of 30 days TGT were 1.53-1.60 for 2.4-4.8 Gy pions and 1.50 for 4-fractionated pions, respectively: there were only small differences within these schedules used. However, the cRBE values decreased from 1.60 to 1.15 with increasing TGT from 30 to 75 days. In contrast, the cRBE values for TCD50 increased from 1.08 to 1.40 (95% confidence limits [CL]; 1.18-1.63) with increasing evaluation time from 60 to 100 days: pions significantly inhibited late tumor appearance. The TCD50 at 100 days was 28.7 Gy (CL; 25.0-32.5 Gy) for pions and 40.3 Gy (CL; 36.3-44.2 Gy) for photons. In conclusion, the RBE for TCD50 was not predictable from the RBE for TGT assay. The cRBE value of 1.4 for microscopic tumor control was in close agreement with the reported values for skin reaction.

Animals↗
PubMed1994

A general formulation of the concept of independent action for the combined effects of agents.

Analysis schemes for the classification of synergism and antagonism for mixed agents operate on the discrepancies between observed and calculated results. As such they cannot be confirmed by experiments and therefore have to be tested in terms of mathematical and logical self-consistency. The concept of independent action is close to the literal meaning of the term "non-interaction". Since this concept does not depend on the mechanisms of actions nor on the type of effect scale used, it is suitable as one of the basic criterion for the definition of synergism and antagonism. A general mathematical framework of independent action is presented in this paper based on the concept of "relative effect" as used in the literature. The different equations for independent action currently used in various areas are shown to be manifestations of a general formula under different sets of boundary conditions, which are the natural limiting values of the effects of the corresponding system observed at low and at high doses of the agents. The framework can be generalized to the combined action of n-agents as well as to the interaction of an agent with itself. In addition, the differential form of the formula for independent action is derived. This framework of systematic definitions and derived equations enable a more in-depth study of the implications of the concept of independent action and its relation to other concepts of non-interaction.

Animals↗
PubMed1994

The response of Chinese hamster V79-379A cells exposed to negative pi-mesons: evidence that increased radioresistance is dependent on linear energy transfer.

Chinese hamster V79-379A cells exhibit low-dose hypersensitivity to 250 kVp X rays followed by an increased radioresistant response over the dose range 0.5-1 Gy. This phenomenon is not seen with neutrons (Marples and Joiner, Radiat. Res. 133, 41-51, 1993). It was therefore postulated the induction of radioresistance might develop as a response to a cellular event(s) which predominates after low- and not high-LET radiation. To test this hypothesis, we measured the survival response of V79-379A cells exposed to pions. Clonogenic survival was assessed for cells irradiated in the Bragg peak (35 keV/microns) and plateau region (10-20 keV/microns) of the beam, using an automated microscope (DMIPS cell analyzer). As expected, peak pions were found to be more effective per unit of dose at killing cells than plateau pions. The survival curve for cells irradiated in the plateau of the pion beam was found to incorporate a region of low-dose hypersensitivity and increased radioresistance, the effective D0 was dose-dependent, ranging from 3.5-5. This was not seen with peak pions, where the effective D0 was, on average, constant reflecting a single-exponential survival curve. Fitting the data with an induced repair model indicates that the phenomenon of increased radioresistance is almost certainly dependent on LET.

Animals↗
PubMed1993

The differential aspects of the linear isobole in the study of combined action of agents.

Although the isobologram is presently the most widely used method of analysis for combined effects of agents, there are several different interpretations of the linear isobole in regard to its use as a criterion of interaction. An investigation of the differential aspects of the linear isobole relation may cast some light in this regard. By conceptual extension of the present single effect level (i.e. effect-point) relation of the linear isobole to an effect-neighbourhood relation in which the linear isobole holds over a small continuous range of effect levels, the mathematical differential of the linear isobole can be developed and investigated. This differential aspect provides some useful insights into the implication and interpretation of the linear isobole relation when used as a general criterion in agent interaction studies. It can also serve as the mathematical basis for the formulation of analytic schemes in which the linear isobole relation is applicable over a continuous range of effect levels.

Drug Interactions↗
PubMed1992

The study of combined action of agents using differential geometry of dose-effect surfaces.

Although graphic surfaces have been used routinely in the study of combined action of agents, they are mainly used for display purposes. In this paper, it is shown that useful mechanistic information can be obtained from an analytical study of these surfaces using the tools of differential geometry. From the analysis of some simple dose-effect surfaces, it is proposed that the intrinsic curvature, referred to in differential geometry as the Gaussian curvature, of a dose-effect surface can be used as a general criterion for the classification of interaction between different agents. This is analogous to the interpretation of the line curvature of a dose-effect curve as an indication of self-interaction between doses for an agent. In this framework, the dose-effect surface would have basic uniform fabric with zero curvature in the absence of interaction, tentatively referred to as null-interaction. Pictorially speaking, this fabric is distorted locally or globally like the stretching and shrinking of a rubber sheet by the presence of interaction mechanisms between different agents. Since self-interaction with dilution dummies does not generate intrinsic curvature, this criterion of null-interaction would describe the interaction between two truly different agents. It is shown that many of the published interaction mechanisms give rise to dose-effect surfaces with characteristic curvatures. This possible correlation between the intrinsic geometric curvature of dose-effect surfaces and the biophysical mechanism of interaction presents an interesting philosophical viewpoint for the study of combined action of agents.

Dose-Response Relationship, Drug↗