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K D Miller

Publications and source records attributed to K D Miller.

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

Variability and information in a neural code of the cat lateral geniculate nucleus.

A central theme in neural coding concerns the role of response variability and noise in determining the information transmission of neurons. This issue was investigated in single cells of the lateral geniculate nucleus of barbiturate-anesthetized cats by quantifying the degree of precision in and the information transmission properties of individual spike train responses to full field, binary (bright or dark), flashing stimuli. We found that neuronal responses could be highly reproducible in their spike timing (approximately 1-2 ms standard deviation) and spike count (approximately 0.3 ratio of variance/mean, compared with 1.0 expected for a Poisson process). This degree of precision only became apparent when an adequate length of the stimulus sequence was specified to determine the neural response, emphasizing that the variables relevant to a cell's response must be controlled to observe the cell's intrinsic response precision. Responses could carry as much as 3.5 bits/spike of information about the stimulus, a rate that was within a factor of two of the limit the spike train could transmit. Moreover, there appeared to be little sign of redundancy in coding: on average, longer response sequences carried at least as much information about the stimulus as would be obtained by adding together the information carried by shorter response sequences considered independently. There also was no direct evidence found for synergy between response sequences. These results could largely, but not entirely, be explained by a simple model of the response in which one filters the stimulus by the cell's impulse response kernel, thresholds the result at a fairly high level, and incorporates a postspike refractory period.

Algorithms↗
PubMed2001

Fertility after unilateral cryptorchidism. Paternity, time to conception, pretreatment testicular location and size, hormone and sperm parameters.

OBJECTIVE: To further evaluate whether fertility is decreased among a cohort of men with previous unilateral cryptorchidism as compared with a control group of men. SUBJECTS AND METHODS: Formerly unilateral cryptorchid men who had undergone orchiopexy between the years of 1955 and 1975 at the Children's Hospital of Pittsburgh and a control group of men who were matched for age of an unrelated surgery at the same institution were evaluated by review of medical records and by completion of a questionnaire. 359 previously cryptorchid men were identified as having attempted paternity. Of these men, 320 had information concerning preoperative testicular location and 163 for preoperative testicular size. 106 of these men had levels of testosterone, inhibin B, FSH, and LH measured, while 95 of the men had semen analyses. RESULTS: Among men who had attempted paternity, there was no statistical difference in success of paternity between the previously unilateral group (89.7%) and the control group (93.7%). There was no difference in the mean time to conception (7.1 +/- 0.7 months for the unilateral group vs. 6.9 +/- 2.3 for the control group). Within the unilateral group in regard to success at paternity, no difference was found compared with the age of orchiopexy, preoperative testicular location, or preoperative testicular size. Inhibin B levels were lower among the unilateral group. FSH, LH, testosterone, sperm density, motility and morphology were not different, but considerable variation was noted within the cryptorchid group. CONCLUSIONS: In this continued evaluation of a cohort of previously cryptorchid men who had undergone unilateral orchiopexy, paternity does not appear to be significantly compromised after unilateral cryptorchidism. Unilateral cryptorchidism appears to be one of several factors contributing to infertility, similar to those found in the general population. No correlation was found between success at paternity and the age of orchiopexy, preoperative testicular size or preoperative testicular location. Inhibin B levels were lower while FSH, LH, T and sperm parameters did not differ.

Adult↗
PubMed2001

Study of interlaboratory reliability and reproducibility of estrogen and progesterone receptor assays in Europe. Documentation of poor reliability and identification of insufficient microwave antigen retrieval time as a major contributory element of unreliable assays.

Immunohistochemical assays for estrogen receptors (ERs) and progesterone receptors (PRs) have not been surveyed for technical validity. In the present study, the reliability of the immunohistochemical assay for ER and PR was evaluated using data from 105 laboratories participating in external quality assessment (EQA) during a 2-year period. Technical variables associated with reliable immunostaining were analyzed. The efficiency of the antigen retrieval step was identified as the single most important contributory factor influencing the overall reproducibility of the assays. Reliable assays were found in 24 (36%) of 66 laboratories participating in continual EQA, including the majority of centers known to have clinically validated results. Inadequate assay sensitivity, with subsequent weak staining, was the main cause of poor and variable results by laboratories using microwave antigen retrieval; too short a heating time was identified as the principal contributory factor. Extension of the heating time resulted in significant improvement regardless of all other variables in the immunohistochemical protocol. Continual participation in EQA is an effective means for identifying and ameliorating variables that influence the reliability of immunohistochemical assays for predictive markers, thereby assisting in technical validation and standardization.

Antigens↗
PubMed2001

Adenosine deaminase levels in nontuberculous lymphocytic pleural effusions.

OBJECTIVES: Adenosine deaminase (ADA) can aid in the diagnosis of tuberculous pleural effusions, but false-positive findings from lymphocytic effusions have been reported. We studied the ADA levels in a variety of nontuberculous lymphocytic effusions and analyzed the relationships between ADA and conventional hematologic and biochemical parameters. METHODS: One hundred six lymphocytic pleural fluid samples (lymphocyte count > 50%) were analyzed. These included post-coronary artery bypass grafting (CABG) effusions (n = 45), malignant effusions (n = 27), miscellaneous exudative effusions (n = 10), and transudative effusions (n = 24). ADA levels were determined using the Giusti method. In 22 randomly selected cases, ADA was measured again on the same sample 6 weeks later. RESULTS: The ADA level reached the diagnostic cutoff for tuberculosis (40 U/L) in only three cases (2.8%): two lymphomas and one complicated parapneumonic effusion. There was no significant correlation between effusion ADA levels and the total leukocyte (r = 0.08), differential lymphocyte (r = 0.18) or monocyte (r = - 0.18) counts. ADA levels were significantly lower in the transudative effusions (7.2 +/- 3.5 U/L) than in post-CABG (16.6 +/- 7.2 U/L), malignant (15.3 +/- 11.2 U/L), and other exudative (15.4 +/- 13.1 U/L) effusions (p < 0.001). ADA measurements were consistent when assayed 6 weeks apart (r = 0.95; p < 0.00001; coefficient of variation, 14%). CONCLUSIONS: ADA levels in nontuberculous lymphocytic effusions seldom exceeded the diagnostic cutoff for TB. Effusion ADA levels cannot be predicted from total or differential leukocyte counts. Post-CABG pleural fluids had ADA levels similar to other nontuberculous lymphocytic effusions. ADA is stable in effusion fluids, and its measurement is reproducible.

Adenosine Deaminase↗
PubMed2001

Selection bias in clinical trials.

All research is subject to bias that may systematically distort results. Though over 50 types of bias in analytical research have been identified and many classification schemes proposed, this review focuses on the special problem of selection bias in clinical trials. We demonstrate the systematic nature of selection bias in clinical research. We describe the common sources of selection bias in clinical trials including the (inappropriate) use of historical controls, stage migration, inclusion/exclusion criteria, the use of multiple subset analyses, and investigator bias. We then move from the general to the specific, using the recent experience of high dose chemotherapy for breast cancer as an illustrative example. Finally, we suggest means to avoid falling into the many selection bias traps that often confront clinical researchers.

Journal Article↗
PubMed2001

Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer.

A phase II trial evaluated the effectiveness and toxicity of combination paclitaxel (Taxol), gemcitabine (Gemzar), and trastuzumab (Herceptin) as first-line therapy for patients with newly diagnosed HER2-overexpressing metastatic breast cancer. To date, 27 patients have received paclitaxel at 175 mg/m2 over 3 hours on day 1, plus gemcitabine at 1,200 mg/m2 on days 1 and 8, plus trastuzumab at a 4-mg/kg loading dose on day 1, followed by 2 mg/kg weekly. Treatment cycles were repeated every 21 days. Responding or stable patients who had received six cycles of combination therapy continued single-agent trastuzumab weekly until disease progression. Treatment was generally well tolerated with grade 4 toxicity limited to myelosuppression. In all, 12 patients have achieved a partial remission and 1 patient had progressive disease; 14 patients continue treatment and have not yet been evaluated for response. Combination treatment with paclitaxel, gemcitabine, and trastuzumab is well tolerated and appears to be highly active. Accrual will continue to a total enrollment of 46 patients.

Adult↗
PubMed2000

Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy.

BACKGROUND: HAART has been associated with metabolic abnormalities (hyperlipidemia, insulin resistance, alterations in cortisol metabolism) and fat redistribution. SETTING: A prospective study of 26 Caucasian men (median age 43.5 years) with HIV-1 viral loads < 500 copies/ml for 12 months while on highly active antiretroviral therapy (HAART) who interrupted treatment for a median of 7.0 weeks (range 4.9-10.3 weeks). Seventeen (65.4%) patients reported at least one fat redistribution symptom at baseline. METHOD: Serum lipids, glucose and insulin levels during an oral glucose tolerance test, 24-h urinary free cortisol and 17-hydroxycorticosteroids, and anthropometric parameters were measured before HAART cessation and prior to its reinstitution. RESULTS: When baseline values were compared with those obtained after HAART interruption (means +/- SD), there was a significant decrease in total cholesterol (194+/-47.3 versus 159+/-29.3 mg/dl; P < 0.0001), low density lipoprotein (LDL) cholesterol (114+/-32.6 versus 96+/-24.7 mg/dl; P = 0.0013), triglycerides (261+/-244.3 versus 185+/-165.4 mg/dl; P = 0.008), and 24-hour urinary 17-hydroxycorticosteroids (15+/-7.9 versus 5+/-2.5 mg/24 h, P < 0.0001) and a significant increase in 24-hour urinary free cortisol (45+/-34.1 versus 62+/-32.2 microg/24 h; P = 0.016). There were no significant changes in glucose or insulin levels or in anthropometric measurements. CONCLUSIONS: A relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and triglyceride levels. No changes were observed in insulin resistance profiles or anthropometric measurements, perhaps because of the brief duration of HAART interruption. These results suggest that hyperlipidemia and alterations in corticosteroid metabolism in the setting of HAART are a direct drug effect that reverses with drug withdrawal. However, glucose metabolism and fat redistribution do not change over the short term.

Adult↗
PubMed2000

Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases.

BACKGROUND: An association between use of zidovudine and didanosine and a rare but life-threatening syndrome of hepatic steatosis, lactic acidosis, and myopathy has been reported. OBJECTIVE: To describe the syndrome of hepatic steatosis, lactic acidosis, and myopathy in four patients taking stavudine. DESIGN: Case series. SETTING: A community hospital in Washington, D.C., and National Institutes of Health Clinical Center, Bethesda, Maryland. PATIENTS: Two men and two women with HIV-1 infection who were taking stavudine presented with lactic acidosis and elevated levels of aminotransferases. All patients required intensive care. MEASUREMENTS: Levels of lactic acid, alanine aminotransferase, aspartate aminotransferase, amylase, and lipase; computed tomography of the abdomen; liver biopsy (two patients); and muscle biopsy (two patients). RESULTS: Histologic findings consistent with mitochondrial injury confirmed the diagnosis of hepatic or muscle abnormality. CONCLUSION: Because hepatic steatosis may be life-threatening, physicians should consider it as a possible cause of elevated hepatic aminotransferase levels among patients taking stavudine.

Acidosis, Lactic↗
PubMed2000

Phase II study of the multitargeted antifolate LY231514 (ALIMTA, MTA, pemetrexed disodium) in patients with advanced pancreatic cancer.

PURPOSE: To determine the safety and activity of LY231514 (ALIMTA, MTA, pemetrexed disodium, Eli Lilly and Co., Indianapolis, IN) in chemotherapy-naïve patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with unresectable or metastatic pancreatic cancer received LY231514 600 mg/m2 as a 10-minute infusion every three weeks. RESULTS: Forty-two patients were enrolled in this phase II trial. The median age was 60.3 (range 37-77) years; 79% had metastatic disease. Neutropenia was common (40% of patients > or = grade 3) but infectious complications were rare. Significant anemia or thrombocytopenia occurred in < 20% of patients. Non-hematologic toxicities included grade 2 or 3 skin reaction which was ameliorated by dexamethasone. Elevations of bilirubin or transaminases were infrequent (< 25% of patients) and did not require dose reductions or treatment delays. Thirty-five patients received two cycles of therapy and were evaluable for response. One complete (duration 16.2 months) and one partial (duration 6.9 months) were observed resulting in an objective response rate of 5.7% for evaluable patients. In addition, 17 patients (40%) had stable disease that lasted > or = 6 months in 5 patients. The median survival was 6.5 months, with 28% of patients alive at one year. CONCLUSIONS: LY231514 is a well-tolerated agent with minimal objective antitumor activity in pancreatic cancer. The median and one year survival times, which may be important indicators in phase II trials of new agents, are of interest. Combination trials of LY231514 in pancreatic cancer are planned.

Adenocarcinoma↗
PubMed2000

Competitive Hebbian learning through spike-timing-dependent synaptic plasticity.

Hebbian models of development and learning require both activity-dependent synaptic plasticity and a mechanism that induces competition between different synapses. One form of experimentally observed long-term synaptic plasticity, which we call spike-timing-dependent plasticity (STDP), depends on the relative timing of pre- and postsynaptic action potentials. In modeling studies, we find that this form of synaptic modification can automatically balance synaptic strengths to make postsynaptic firing irregular but more sensitive to presynaptic spike timing. It has been argued that neurons in vivo operate in such a balanced regime. Synapses modifiable by STDP compete for control of the timing of postsynaptic action potentials. Inputs that fire the postsynaptic neuron with short latency or that act in correlated groups are able to compete most successfully and develop strong synapses, while synapses of longer-latency or less-effective inputs are weakened.

Action Potentials↗
PubMed2000

The diagnosis of low-grade peripheral B-cell neoplasms in bone marrow trephines.

The aim of this study was to establish how effective is the use of immunohistochemistry on formalin-fixed bone marrow in diagnosing low-grade B-cell neoplasms. We investigated a series of 41 consecutive patients with bone marrow involvement for whom no other diagnostic tissues were available. The sections were stained with the following antibodies: CD3, CD20, CD79a, CD5, CD10, CD23, anti-cyclin D1 and kappa and lambda light chains. Antigen retrieval was performed using either a microwave oven or a pressure cooker. Labelling was performed with an avidin-biotin-peroxidase labelling system. A final diagnosis was reached in 37 out of 41 cases (90%): B-chronic lymphocytic leukaemia (15 cases), follicular lymphoma (10 cases), mantle-cell lymphoma (eight cases) and lymphoplasmacytoid lymphoma/immunocytoma (four cases). In the remaining four cases, a generic diagnosis of low-grade B-cell neoplasm was made. The immunophenotyping of formalin-fixed marrow is a useful technique for diagnosing most of the low-grade B-cell neoplasms.

Antigens, CD↗
PubMed2000

Reliability of immunohistochemical demonstration of oestrogen receptors in routine practice: interlaboratory variance in the sensitivity of detection and evaluation of scoring systems.

AIMS: To investigate interlaboratory variance in the immunohistochemical (IHC) detection of oestrogen receptors so as to determine the rate of false negatives, which could adversely influence the decision to give adjuvant tamoxifen treatment. METHODS: To ensure that similar results are obtained by different institutions, 200 laboratories from 26 countries have joined the UK national external quality assessment scheme for immunocytochemistry (NEQAS-ICC). Histological sections from breast cancers having low, medium, and high levels of oestrogen receptor expression were sent to each of the laboratories for immunohistochemical staining. The results obtained were evaluated for the sensitivity of detection, first by estimating threshold values of 1% and 10% of stained tumour cells, and second by the Quick score method, by a panel of four assessors judging individual sections independently on a single blind basis. The results were also evaluated using participants' own threshold values. RESULTS: Over 80% of laboratories were able to demonstrate oestrogen receptor positivity on the medium and high expressing tumours, but only 37% of laboratories scored adequately on the low expressing tumour. Approximately one third of laboratories failed to register any positive staining in this tumour, while one third showed only minimal positivity. CONCLUSIONS: There is considerable interlaboratory variability, especially in relation to the detection of breast cancers with low oestrogen receptor positivity, with a false negative rate of between 30% and 60%. This variability appears to be caused by minor differences in methodology that may be rectified by fine adjustment of overall technique.

Biomarkers, Tumor↗
PubMed2000

Immunohistochemical demonstration of oestrogen and progesterone receptors: correlation of standards achieved on in house tumours with that achieved on external quality assessment material in over 150 laboratories from 26 countries.

AIMS: To investigate the sensitivity of immunohistochemical (IHC) assays for oestrogen receptors (ER) and progesterone receptors (PR) achieved by laboratories on breast tumours fixed and processed in their own department, and to compare this with the degree of sensitivity they achieve on tumours circulated as part of an external quality assessment (EQA) programme. METHODS: On 10 occasions between April 1994 and June 1998, histological sections from breast cancers showing various degrees of expression of ER and PR were circulated for IHC staining to laboratories participating in the UK national external quality assessment scheme for immunocytochemistry (UK NEQAS-ICC). The staining of these tumours, in addition to that of tumours fixed and processed in the participants own laboratories (in house tumours), was assessed by a panel of four assessors, using the established UK NEQAS-ICC scoring system. For a selected assessment run, the degree of expression of participants in house tumours was evaluated by means of the semiquantitative quick score method. RESULTS: Although the scores awarded for the staining of in house tumours were generally higher than those awarded for the staining of UK NEQAS tumours, there was also a significant positive correlation between the two sets of scores. Using the quick score method of evaluation for one of the assessment runs, 47% of in house tumours were classified as having a high degree of ER expression. Of the remaining cases, a significant proportion initially classified as having only low or medium expression of ER were found to have higher expression when stained by the organising laboratory. The UK NEQAS-ICC centre's routine assay for hormonal receptors was found to be 90-100% efficient in achieving optimal demonstration of breast tumours from over 150 different laboratories. CONCLUSIONS: The significant positive correlation between the results obtained on the UK NEQAS tumours and the in house tumours provides evidence for the view that results achieved on EQA material are accurate indicators of in house laboratory performance. Although most laboratories adequately detected tumours with high receptor expression, a large proportion of in house tumours classified initially by participants' staining as being of low or medium ER expression had a higher degree of expression when stained by the UK NEQAS-ICC centre. The efficiency of the organising centre's routine IHC method for ER and PR in optimally demonstrating participants in house breast tumours shows that variations in fixation and tissue preparation are not limiting factors preventing a different laboratory achieving optimal demonstration.

Breast Neoplasms↗
PubMed2000

Frequency of oestrogen and progesterone receptor positivity by immunohistochemical analysis in 7016 breast carcinomas: correlation with patient age, assay sensitivity, threshold value, and mammographic screening.

AIMS: A routine immunohistochemical (IHC) assay is now commonly used for determining the oestrogen receptor (ER) and progesterone receptor (PR) status of women with breast cancer. To date, no large studies have been conducted that report the expected frequency of receptor positivity in relation to patient age and sensitivity of the IHC assay. Data on 7016 breast carcinomas from 71 laboratories were analysed to determine the frequency of receptor positivity and investigate possible causes of the observed variation in detection rates. METHODS: Members of UK NEQAS-ICC (UK National External Quality Assessment Scheme for Immunocytochemistry) provided data on the receptor status of cases routinely assayed in their departments over a period of two to 26 months between June 1996 and September 1998. Data on 7016 breast carcinomas were stratified according to patient age and receptor status. Frequency of receptor positivity was correlated with IHC assay sensitivity, the threshold value used to determine receptor positivity, and the presence or absence of mammographic screening in the hospitals or clinics served by the laboratories. RESULTS: The highest proportion of receptor positive cases occurred in patients in the age ranges > 65 years for ER and 41-50 years for PR. There was a significant positive correlation between frequency of receptor positivity and the sensitivity of the IHC assay, for both ER (rs = 0.346; p = 0.019; two tailed) and PR (rs = 0.561; p = 0.003; two tailed). The mean frequency of receptor positivity for laboratories using the same 10% threshold value was 77% for ER (95% confidence interval (CI), 74% to 80%) in laboratories with high sensitivity and 72% (95% CI, 68% to 76%) for those with low assay sensitivity (p = 0.025). For PR, the mean frequency of receptor positivity for laboratories using the same 10% threshold value and having high assay sensitivity was 63% (95% CI, 57% to 69%), and 51% (95% CI, 38% to 65%) for laboratories with assays of low sensitivity (p = 0.022). The mean frequency of ER positivity for laboratories serving hospitals and clinics where mammographic screening does and does not take place was 73.4% and 75.7%, respectively (p = 0.302; two tailed). CONCLUSIONS: Of the parameters investigated, patient age and IHC assay sensitivity were found to be the main variables influencing the frequency of receptor positivity. We recommend the range of receptor values obtained by laboratories achieving high assay sensitivity as a useful guide against which all laboratories can gauge their own results.

Adult↗
PubMed2000

Neural mechanisms of orientation selectivity in the visual cortex.

The origin of orientation selectivity in the responses of simple cells in cat visual cortex serves as a model problem for understanding cortical circuitry and computation. The feed-forward model posits that this selectivity arises simply from the arrangement of thalamic inputs to a simple cell. Much evidence, including a number of recent intracellular studies, supports a primary role of the thalamic inputs in determining simple cell response properties, including orientation tuning. This mechanism alone, however, cannot explain the invariance of orientation tuning to changes in stimulus contrast. Simple cells receive push-pull inhibition: ON inhibition in OFF subregions and vice versa. Addition of such inhibition to the feed-forward model can account for this contrast invariance, provided the inhibition is sufficiently strong. The predictions of "normalization" and "feedback" models are reviewed and compared with the predictions of this modified feed-forward model and with experimental results. The modified feed-forward and the feedback models ascribe fundamentally different functions to cortical processing.

Animals↗
PubMed2000

Breast cancer in vivo: contrast enhancement with thermoacoustic CT at 434 MHz-feasibility study.

The authors performed thermoacoustic computed tomography (CT) with 434-MHz radio waves in five patients with documented breast cancer. Three of the patients underwent imaging before chemotherapy was initiated and two at the conclusion of their primary chemotherapy. In the former three patients, thermoacoustic CT demonstrated contrast enhancement in the region of the tumor. In the latter two patients, no contrast enhancement was seen, and pathologic examination after surgical resection of the area of original tumor confirmed complete remission of disease.

Acoustics↗
PubMed2000

Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial.

PURPOSE: Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis. PATIENTS AND METHODS: This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects. RESULTS: Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed. CONCLUSION: The soy product did not alleviate hot flashes in breast cancer survivors.

Adolescent↗