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Biomedical subjects

A M Peters

Publications and source records attributed to A M Peters.

At least 37 records · Page 2Linked to original sources
PubMed2001

Cerebral activation during a simple force production task: changes in the time course of the haemodynamic response.

An event-related paradigm was used to investigate the fMRI signal from the primary motor cortex (M1) and the supplementary motor area (SMA) during isolated isometric wrist extension at five different force levels. There was only a weak trend towards increased area of activation with increased force output, but there was a force-related increase in percentage change of signal within voxels in M1 (Kendall Tc = 0.48, p < 0.01), which may indicate control of force output by variation of neural firing rate. In SMA there was a correlation between peak force output and time-to-peak of the haemodynamic response in SMA (Kendall Tc = 0.74, p < 0.0001). This unexpected finding of a task-related change in the shape of the haemodynamic response within a single brain area requires further investigation. It may indicate a slower rise time at lower perfusion rates, or may be the result of inhibitory processes in motor control.

Adult↗
PubMed2001

The effect of irradiation on the biodistribution of radiolabeled pegylated liposomes.

PURPOSE: The effect of total-body irradiation (TBI) on the biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) was evaluated in tumor-bearing nude mice as part of an ongoing effort to develop liposome-targeted radiosensitizers. METHODS AND MATERIALS: Mice received TBI (2 Gy or 5 Gy) according to two protocols: (1) to test the effect of radiation delivered 30 min before liposome injection on the time course of IDLPL biodistribution to tumor and normal tissues over 96 h; (2) to test the effect of radiation at times ranging from 72 h to 1 h before liposome injection on tumor and normal tissue uptake of IDLPL at 24 h. Tumor and tissue/organ levels of liposome uptake were measured by dissection and quantitation in a gamma counter. RESULTS: For most tissues (tumor, liver, kidney, lung, skin, heart, and central nervous system), irradiation did not alter IDLPL biodistribution. Splenic uptake appeared to be increased by TBI, but further analysis revealed that this effect was due to reduced splenic weight in irradiated mice. IDLPL uptake was increased in the small intestine, stomach, musculoskeletal system, female reproductive tract, and adrenal glands in irradiated mice. CONCLUSION: These findings suggest that concomitant administration of liposomal radiosensitizers during radical radiotherapy is likely to be safe. However, caution should be exercised in situations in which significant volumes of small intestine or hemopoietic tissue will be irradiated.

Animals↗
PubMed2001

The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.

Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a newly appreciated risk factor for lymphomas.

Adult↗
PubMed2001

Single-fraction irradiation has no effect on uptake of radiolabeled pegylated liposomes in a tumor xenograft model.

PURPOSE: These studies were performed with the intention of examining the effect of single-fraction doses of radiotherapy (RT) on the tumor deposition of radiolabeled pegylated liposomes in an animal xenograft tumor model. METHODS AND MATERIALS: Human KB head-and-neck xenograft tumors were established in female nude mice. The effect of single fraction tumor RT doses (5, 10, 15, and 20 Gy) on the tumor uptake of intravenously administered (111)In-DTPA-labeled pegylated liposomes (IDLPL) was examined using two protocols: (1) to test the effect of RT delivered 30 min before liposome injection on the time course of tumor uptake over a 96-h period; (2) to test the effect of RT at times ranging from 72-h to 1-h before liposome injection on the levels of liposome uptake at 24 h. Tumor and normal tissue/organ (blood, liver, spleen, lung, and kidney) liposome uptake was determined by dissection and quantitation in a gamma counter. RESULTS: There was no demonstrable effect of RT on tumor uptake of IDLPL (p > 0.1 for all comparisons). Reassuringly, neither was there an effect of RT on the pharmacokinetics and biodistribution of radiolabeled liposomes to normal tissues. CONCLUSIONS: Single fraction doses of RT appear to have no effect on tumor or normal tissue biodistribution and pharmacokinetics of radiolabeled pegylated liposomes in this animal model.

Animals↗
PubMed2001

Comparison between terminal slope rate constant and "slope/intercept" as measures of glomerular filtration rate using the single-compartment simplification.

Several whole-body variables are available for indexing glomerular filtration rate (GFR), including extracellular fluid volume (ECF volume, ECV), which has the advantage that GFR based only on the terminal exponential, alpha 2, of the chromium-51 ethylene diamine tetraacetic acid (51Cr-EDTA) plasma clearance curve is a measure already indexed for ECV. This slope-only method, however, is open to the theoretical criticism of a lack of robustness not present in the more conventional slope/intercept method, which generates GFR in absolute units before indexation to body surface area (BSA). To further evaluate the slope-only method, a large database of routine three-sample GFR measurements, based on 51Cr-EDTA, was analysed with the aim of comparing GFR/BSA with GFR/ECV, identifying the main sources of error in their respective measurements and explaining why they might be discrepant. The database was subdivided into 304 patients (group A) in whom the correlation coefficient of the fit to the three data points was greater than 0.99 and 31 patients in whom it was less than 0.99 (noisy data; group B). There was modest agreement between GFR/BSA and GFR/ECV in group A (r = 0.77; mean ratio 1.01 +/- 0.21). The difference between them correlated significantly with BSA (r = 0.52; P < 0.001), as would be expected given that small individuals have a relatively high BSA. Subdividing group A into four subgroups stratified according to BSA led to a slight improvement in the correlation between GFR/BSA and GFR/ECV. Because an error in alpha 2 is balanced by an opposing error in the intercept (which leads to a change in distribution volume in the opposite direction), and therefore impacts on both GFR/BSA and GFR/ECV, whereas an error in administered dose affects only GFR/BSA, it is possible to evaluate such errors by examining the respective relationships of GFR/BSA and GFR/ECV with indexed ECV. In group A, GFR/BSA correlated positively with ECV/1.73 m2, not surprisingly as ECV/BSA is effectively the ratio GFR/BSA to GFR/ECV, while GFR/ECV correlated negatively with ECV/1.73 m2. This implies that errors other than alpha 2, probably principally in administered dose, were as important as errors in alpha 2. This conclusion was supported by disappearance of the positive correlation between GFR/BSA and ECV/BSA in group B, brought about by the greater errors in alpha 2 in this group. This study suggests that, because of the effects of errors in the slope/intercept method that do not affect alpha 2, GFR based on slope only is at least as robust as that based on slope/intercept.

Adolescent↗
PubMed2001

Phase II study of pegylated liposomal doxorubicin (Caelyx) as induction chemotherapy for patients with squamous cell cancer of the head and neck.

A phase II trial of pegylated liposomal doxorubicin (Caelyx) as induction chemotherapy was conducted in 20 patients with treatment-naïve squamous cell cancer of the head and neck (SCCHN). 10 patients received two cycles of Caelyx (40 mg/m(2)) every 3 weeks before starting radical radiotherapy (RT). Subsequently, consecutive groups of 3 patients received a third escalating dose of Caelyx (10, 15 and 20 mg/m(2)) 3 days before RT. 9 of 18 (50%, 95% confidence intervals (CI): 26-74%) evaluable patients responded to Caelyx, with 11 responses in 26 (42%, 95% CI: 24-62%) evaluable sites (three complete responses (12%), eight partial responses (31%)). There was no grade 3/4 haematological, mucosal or cardiac toxicity. Nausea and vomiting were minimal. There were no drug-related RT delays. Local RT-induced toxicity was not increased. Caelyx has significant activity against SCCHN and warrants further investigation in this disease. In view of its tumour targeting properties and activity at moderate doses, it may be useful in concomitant chemoradiotherapy strategies for SCCHN.

Aged↗
PubMed2001

Filler syllables: what is their status in emerging grammar?

Although it has long been observed that some children incorporate unglossable syllables into their early utterances, it has been difficult to integrate these 'fillers' into theories of language acquisition. Because they straddle boundaries between phonology and morphosyntax, and between pragmatics and lexicon, they do not fit neatly into linguists' notions about 'modules' of language. Fillers have been reported in quite an array of languages, and yet they seem to be more common among learners of some languages than others. Even when language is held constant, children seem to vary immensely as to whether they produce fillers at all. With more researchers reporting fillers in more languages, it seems time to (1) review what we now know about fillers; (2) propose a reasonably unified set of criteria for identifying them; and (3) suggest an approach that will promote their further study.

Child Language↗
PubMed2001

Phase I-II study of pegylated liposomal cisplatin (SPI-077) in patients with inoperable head and neck cancer.

BACKGROUND: Concomitant chemoradiotherapy (CCRT) for squamous cancers of the head and neck (SCCHN) improves survival but increases toxicity. Pegylated liposomes localise to solid cancers and may deliver radiosensitizing agents preferentially to tumour tissue, potentially improving the therapeutic ratio of CCRT. PATIENTS AND METHODS: A phase I-II trial of pegylated liposome encapsulated cisplatin (SPI-077) was conducted in 18 patients with treatment-naive locally advanced, inoperable SCCHN. The first 10 patients received 2 cycles of 200 mg/m2, and the next 8 received 260 mg/m2, every 3 weeks before commencing radical radiotherapy (RT). RESULTS: Only 2 of 18 (11%) patients had partial responses to SPI-077 with 2 responses in 29 (6.9%) evaluable sites. SPI-077 was tolerated well with no haematological, renal, hepatic or neurological toxicities. Nausea and vomiting were minimal. There were no drug-related delays in the delivery of RT. RT-induced mucosal and cutaneous toxicity were not significantly increased. CONCLUSIONS: SPI-077 is essentially inactive against SCCHN and, in its present formulation, does not merit further evaluation as induction chemotherapy or as part of a CCRT approach.

Aged↗
PubMed2001

Detection of pelvic lymph node metastases in gynecologic malignancy: a comparison of CT, MR imaging, and positron emission tomography.

OBJECTIVE: Accurate assessment of lymph node status before treatment is critical in the treatment of gynecologic cancers because the 5-year survival and treatment of women is influenced by lymph node involvement. The aims of this study were to investigate the ability of X-ray CT, MR imaging, and (18)F-FDG positron emission tomography (PET) to detect pelvic lymph node metastases by comparing imaging with histopathologic findings after lymph node dissection. MATERIALS AND METHODS: Eighteen patients with gynecologic cancers were studied by all three imaging methods before surgery. The images were initially reviewed with routine diagnostic conditions and then, subsequently, by two observers who were unaware of the clinical and histopathologic findings of the patients. The nodal sites were split into upper (aortic to common iliac bifurcations) and lower (common iliac bifurcations to inguinal ligament) iliac chains. All observers' results were statistically analyzed with specificity, sensitivity, positive and negative predictive values, Fisher's exact test (individual observers) or chi-square test (combined observers), and Cohen's kappa test. RESULTS: Eight of 18 patients had lymph node metastases at histology. Findings of all three modalities agreed in full in only one patient. CT correctly revealed 10 node-negative patients, whereas MR imaging was correct in eight of these patients. (18)F-FDG PET correctly depicted one patient with lymph nodes negative for tumor. CT was the most specific imaging modality (97.0%), with MR imaging and PET rendering values of 90.7% and 77.3%, respectively, but sensitivity of all modalities was low (CT, 48.1%; MR imaging, 53.7%; PET, 24.5%). Observer agreement for each modality was good; kappa values among all observers were 0.88 for CT, 0.85 for MR imaging, and 0.72 for PET. CONCLUSION: CT is the most specific modality for detecting lymph nodes positive for tumor in gynecologic cancers, whereas MR imaging is the most sensitive. The poor results of PET in the pelvis are attributed to urinary (18)F-FDG in the ureters or bladder, which may mask or imitate lymph node metastases.

Adult↗
PubMed2001

Evaluation of pulmonary alveolar epithelial integrity by the detection of restriction to diffusion of hydrophilic solutes of different molecular sizes.

The rate of transfer of a hydrophilic solute from the alveoli to pulmonary blood following inhalation as an aerosol depends on the molecular size of the solute and the permeability of the alveolar epithelium. The value of this measurement for assessing damage to the epithelium in lung disease is compromised by cigarette smoking, which accelerates clearance by unknown mechanisms. The rates of clearance of (99m)Tc-labelled diethylenetriaminepenta-acetic acid (DTPA) (molecular mass 492 Da) and (113m)In-labelled biotinylated DTPA (B-DTPA) (molecular mass 1215 Da) were monitored simultaneously by dynamic gamma-radiation camera imaging following simultaneous inhalation, and compared between eight normal non-smoking subjects and nine habitual cigarette smokers. The clearance rates of DTPA were 0.95 (S.D. 0.39)%/min in non-smokers and 4.13 (1.06) %/min in smokers. These were about twice the clearance rates of B-DTPA, which in the corresponding groups were 0.41 (0.26) and 2.12 (0.72)%/min respectively. The ratio of the B-DTPA/DTPA clearance rates was, in all subjects, less than the ratio (0.74) of the cube roots of the molecular masses of the solutes, assumed to correspond to the ratio of their free diffusion coefficients in water, and was not significantly different between smokers and non-smokers. As alveolar permeability increased, the ratio of clearance rates in the entire population showed a significant trend to increase in a non-linear fashion towards the value corresponding to the ratio of the free diffusion coefficients. We conclude that the diffusion of at least the larger of these two solutes through the pulmonary alveolar epithelium is restricted (i.e. associated with a reflection coefficient greater than zero). Cigarette smoking, however, does not appear to cause a loss of this restriction, and may increase solute clearance by other mechanisms, such as reducing fluid volume within the alveolus, thereby raising the local radiotracer concentration, or increasing the number of pores available for solute exchange without affecting pore size. Conversely, if restriction was lost in lung disease, the ratio of the clearance rates of two solutes of dissimilar sizes could be used to detect disease in smokers as well as non-smokers.

Aerosols↗
PubMed2001

Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes.

The biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) were studied in 17 patients with locally advanced cancers. The patients received 65-107 MBq of IDLPL, and nuclear medicine whole body gamma camera imaging was used to study liposome biodistribution. The t(1/2beta) of IDLPL was 76.1 h. Positive tumor images were obtained in 15 of 17 studies (4 of 5 breast, 5 of 5 head and neck, 3 of 4 bronchus, 2 of 2 glioma, and 1 of 1 cervix cancer). The levels of tumor liposome uptake estimated from regions of interest on gamma camera images were approximately 0.5-3.5% of the injected dose at 72 h. The greatest levels of uptake were seen in the patients with head and neck cancers [33.0 +/- 15.8% ID/kg (percentage of injected dose/kg)]. The uptake in the lung tumors was at an intermediate level (18.3 +/- 5.7% ID/kg), and the breast cancers showed relatively low levels of uptake (5.3 +/- 2.6% ID/kg). These liposome uptake values mirrored the estimated tumor volumes of the various tumor types (36.2 +/- 18.0 cm3 for squamous cell cancer of the head and neck, 114.5 +/- 42.0 cm3 for lung tumors, and 234.7 +/- 101.4 cm3 for breast tumors). In addition, significant localization of the liposomes was seen in the tissues of the reticuloendothelial system (liver, spleen, and bone marrow). One patient with extensive mucocutaneous AIDS-related Kaposi sarcoma was also studied according to a modified protocol, and prominent deposition of the radiolabeled liposomes was demonstrated in these lesions. An additional two patients with resectable head and neck cancer received 26 MBq of IDLPL 48 h before undergoing surgical excision of their tumors. Samples of the tumor, adjacent normal mucosa, muscle, fat, skin, and salivary tissue were obtained at operation. The levels of tumor uptake were 8.8 and 15.9% ID/kg, respectively, with tumor uptake exceeding that in normal mucosa by a mean ratio of 2.3:1, in skin by 3.6:1, in salivary gland by 5.6:1, in muscle by 8.3:1, and in fat by 10.8:1. These data strongly support the development of pegylated liposomal agents for the treatment of solid tumors, particularly those of the head and neck.

Adult↗
PubMed2001

Differences in lymph drainage between swollen and non-swollen regions in arms with breast-cancer-related lymphoedema.

Recent research indicates that the pathophysiology of breast-cancer-related lymphoedema (BCRL) is more complex than simple axillary lymphatic obstruction as a result of the cancer treatment. Uneven distribution of swelling (involvement of the mid-arm region is common, but the hand is often spared) is puzzling. Our aim was to test the hypothesis that local differences in lymphatic drainage contribute to the regionality of the oedema. Using lymphoscintigraphy, we measured the removal rate constant, k (representing local lymph flow per unit distribution volume, VD), for 99mTc-labelled human immunoglobulin G in the oedematous proximal forearm, and in the hand (finger web) in women in whom the hand was unaffected. Tracer was injected subcutaneously, and the depot plus the rest of the arm was monitored with a gamma-radiation camera for up to 6 h. VD was assessed from image width. Contralateral arms served as controls. k was 25% lower in oedematous forearm tissue than in the control arm (BCRL, -0.070+/-0.026% x min(-1); control, -0.093+/-0.028% x min(-1); mean+/-S.D.; P=0.012) and VD was greater. In the non-oedematous hand of the BCRL arm, k was 18% higher than in the control hand (BCRL, -0.110+/-0.027% x min(-1); control, -0.095+/-0.028% x min(-1); P=0.057) and 59% higher than forearm k on the BCRL side (P=0.0014). VD did not differ between the hands. Images of the BCRL arm following hand injection showed diffuse activity in the superficial tissues, sometimes extending almost to the shoulder. A possible interpretation is that the hand is spared in some patients because local lymph flow is increased and diverted along collateral dermal routes. The results support the hypothesis that regional differences in surviving lymphatic function contribute to the distribution of swelling.

Aged↗
PubMed2000

Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis.

OBJECTIVE: To verify the hypothesis that in rheumatoid arthritis (RA), tumor necrosis factor alpha (TNFalpha) plays a critical role in regulating leukocyte trafficking and chemokine levels. METHODS: Ten patients with longstanding RA received a single 10 mg/kg infusion of anti-TNFalpha monoclonal antibody (cA2). The articular localization of autologous granulocytes, separated in vitro and labeled with 111In, was studied by analysis of gamma-camera images both before and 2 weeks after treatment. At the same sequential time points, synovial biopsy samples were assessed for infiltrating CD3+ T cells, CD22+ B cells, and CD68+ macrophages. Synovial tissue expression of the chemokines interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, Groalpha, and RANTES was also determined. Serum IL-8 and MCP-1 concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: Anti-TNFalpha therapy in RA significantly reduced 111In-labeled granulocyte migration into affected joints. There was a simultaneous and significant reduction in the numbers of infiltrating synovial CD3+ T cells, CD22+ B cells, and CD68+ macrophages and in the expression of IL-8 and MCP-1, with a trend toward a reduction in serum concentrations of these chemokines. CONCLUSION: TNFalpha blockade reduces synovial expression of the chemokines IL-8 and MCP-1 and diminishes inflammatory cell migration into RA joints.

Aged↗
PubMed2000

Influence of tumour size on uptake of(111)ln-DTPA-labelled pegylated liposomes in a human tumour xenograft model.

The relationship between tumour size and uptake of(111)In-DTPA-labelled pegylated liposomes has been examined in a human head and neck cancer xenograft model in nude mice. The mean tumour uptake of(111)In-labelled pegylated liposomes at 24 hours was 7.2 +/- 6.6% ID/g. Liposome uptake for tumours < 0.1 g, 0.1-1.0 g and > 1.0 g was 15.1 +/- 10.8, 5.9 +/- 2.2 and 3.0 +/- 1.3% ID/g, respectively. An inverse correlation between tumour weight and liposome uptake was observed by both Spearman's rank correlation test (r(s)= - 0.573, P< 0.001) and Pearson's correlation coefficient (r(s)= - 0.555, P< 0.001). For 18 tumours with macroscopic central necrosis, the ratio of uptake in the tumour rim relative to the necrotic tumour core was 11.2 +/- 6.4. Measurement of tumour vascular volume for tumours of various sizes revealed an inverse correlation between tumour weight and tumour vascular volume (Spearman's rank correlation test, r(s)= - 0.598, P< 0.001), consistent with poor or heterogeneous vascularization of larger tumours. These data have important implications for the clinical application of pegylated liposome targeted strategies for solid cancers which are discussed in detail.

Animals↗