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K D Miller

Publications and source records attributed to K D Miller.

At least 73 records · Page 4Linked to original sources
PubMed1999

Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy.

Multidrug antiretroviral regimens that include human immunodeficiency virus-1 (HIV-1) protease inhibitors are associated with distinct lipodystrophy, hypertriglyceridemia, hyperinsulinemia, and deposition of visceral abdominal adipose tissue. To determine whether these findings are related to abnormalities of adrenal function, we compared the hypothalamic-pituitary-adrenal axes of HIV-positive patients who had evidence of protease inhibitor-associated lipodystrophy (PIAL), control volunteers (CON), and patients with Cushing's syndrome (CS). To elucidate the metabolic consequences of the observed lipodystrophy, we measured basal serum lipids and compared glucose and insulin concentrations during an oral glucose tolerance test. Spontaneous plasma cortisol showed normal diurnal variation in PIAL. Cortisol levels were similar in CON and PIAL, and levels in these groups were less than those in CS at all times of the night or day (P < 0.005). Ovine CRH-stimulated morning plasma cortisol levels were similar in PIAL and CON. ACTH was significantly greater in PIAL than CON (P < 0.05) at 0, 15, and 30 min after CRH stimulation. Urinary free cortisol in PIAL (mean +/- SD, 76 +/- 51 nmol/day) was significant lower than those in CON (165 +/- 64 nmol/day; P < 0.001) and CS (1715 +/- 1203 nmol/day; P < 0.001). However, 17-hydroxycorticosteroid excretion was significantly greater in PIAL (43 +/- 23 micromol/day) than in CON (17 +/- 8 micromol/day; P < 0.001), although lower than that in CS (74 +/- 47 micromol/day; P < 0.01). Scatchard analysis revealed normal glucocorticoid receptor number and affinity in PIAL. Serum triglycerides were significantly greater in PIAL (6.57 +/- 5.63 mmol/L) than in CS (1.78 +/- 0.83 mmol/L; P < 0.001) or CON (1.36 +/- 0.84 mmol/L; P < 0.001). Although triglyceride levels were significantly correlated with body mass index for CON and CS, these were not correlated for PIAL. During an oral glucose tolerance test, similar glucose and insulin values were found in PIAL and CS that were greater (P < 0.05) than CON values at 30, 60, 90, and 120 min. We conclude that the lipodystrophy associated with use of HIV-1 protease inhibitors is a syndrome of increased intraabdominal adiposity with concomitant dyslipidemia and insulin resistance, but without total body weight gain and is distinct from any known form of hypercortisolism. Although urinary cortisol disposition seems to be altered in HIV-infected patients who are being treated with multidrug regimens that include protease inhibitors, the decreased free cortisol and increased 17-hydroxycorticosteroid excretion appear to be unlikely explanations for the observed lipodystrophy. The cause remains to be elucidated.

Adrenocorticotropic Hormone↗
PubMed1999

Taxanes in the treatment of breast cancer: a prodigy comes of age.

The taxanes, paclitaxel and docetaxel, are among the most promising new agents in the treatment of breast cancer. Responses are routinely seen in > 30% of patients with metastatic disease, including those who have previously received anthracyclines. Combination therapy has increased response rates but as yet has not improved the overall survival of patients with metastatic disease. Improved survival with the addition of paclitaxel to standard adjuvant therapy reported in a recently completed trial suggests the true impact of the taxanes has not yet been realized.

Antibiotics, Antineoplastic↗
PubMed1999

Metastatic breast cancer: the role of chemotherapy.

Treatment of metastatic breast cancer remains in flux. A flurry of new chemotherapeutic agents with activity against this disease has been identified in recent years, yet breast cancer remains a cause of significant morbidity and mortality. The taxanes in particular appear to hold promise for improved outcome and, in fact, are the treatment of choice for salvage therapy. Using the taxanes in high-dose regimens, with stem cell transplantation, in alternative schedules, and in combination regimens, including with biologic treatments, is the focus of future potential advances. Continued investigative energy and the discovery of novel drugs and therapeutic approaches for addition to established techniques hopefully will improve outcomes in the next generation of treatment strategies for metastatic breast cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Correlation-based development of ocularly matched orientation and ocular dominance maps: determination of required input activities.

We extend previous models for separate development of ocular dominance and orientation selectivity in cortical layer 4 by exploring conditions permitting combined organization of both properties. These conditions are expressed in terms of functions describing the degree of correlation in the firing of two inputs from the lateral geniculate nucleus (LGN), as a function of their retinotopic separation and their "type" (ON center or OFF center and left eye or right eye). The development of ocular dominance requires that the correlations of an input with other inputs of the same eye be stronger than or equal to its correlations with inputs of the opposite eye and strictly stronger at small retinotopic separations. This must be true after summing correlations with inputs of both center types. The development of orientation-selective simple cells requires that (1) an input's correlations with other inputs of the same center type be stronger than its correlations with inputs of the opposite center type at small retinotopic separation; and (2) this relationship reverse at larger retinotopic separations within an arbor radius (the radius over which LGN cells can project to a common cortical point). This must be true after summing correlations with inputs serving both eyes. For orientations to become matched in the two eyes, correlated activity within the receptive fields must be maximized by specific between-eye alignments of ON and OFF subregions. Thus the correlations between the eyes must differ depending on center type, and this difference must vary with retinotopic separation within an arbor radius. These principles are satisfied by a wide class of correlation functions. Combined development of ocularly matched orientation maps and ocular dominance maps can be achieved either simultaneously or sequentially. In the latter case, the model can produce a correlation between the locations of orientation map singularities and local ocular dominance peaks similar to that observed physiologically. The model's main prediction is that the above correlations should exist among inputs to cortical layer 4 simple cells before vision. In addition, mature simple cells are predicted to have certain relationships between the locations of the ON and OFF subregions of the left and right eyes' receptive fields.

Animals↗
PubMed1998

Contrast-invariant orientation tuning in cat visual cortex: thalamocortical input tuning and correlation-based intracortical connectivity.

The origin of orientation selectivity in visual cortical responses is a central problem for understanding cerebral cortical circuitry. In cats, many experiments suggest that orientation selectivity arises from the arrangement of lateral geniculate nucleus (LGN) afferents to layer 4 simple cells. However, this explanation is not sufficient to account for the contrast invariance of orientation tuning. To understand contrast invariance, we first characterize the input to cat simple cells generated by the oriented arrangement of LGN afferents. We demonstrate that it has two components: a spatial-phase-specific component (i.e., one that depends on receptive field spatial phase), which is tuned for orientation, and a phase-nonspecific component, which is untuned. Both components grow with contrast. Second, we show that a correlation-based intracortical circuit, in which connectivity between cell pairs is determined by the correlation of their LGN inputs, is sufficient to achieve well tuned, contrast-invariant orientation tuning. This circuit generates both spatially opponent, "antiphase" inhibition ("push-pull"), and spatially matched, "same-phase" excitation. The inhibition, if sufficiently strong, suppresses the untuned input component and sharpens responses to the tuned component at all contrasts. The excitation amplifies tuned responses. This circuit agrees with experimental evidence showing spatial opponency between, and similar orientation tuning of, the excitatory and inhibitory inputs received by a simple cell. Orientation tuning is primarily input driven, accounting for the observed invariance of tuning width after removal of intracortical synaptic input, as well as for the dependence of orientation tuning on stimulus spatial frequency. The model differs from previous push-pull models in requiring dominant rather than balanced inhibition and in predicting that a population of layer 4 inhibitory neurons should respond in a contrast-dependent manner to stimuli of all orientations, although their tuning width may be similar to that of excitatory neurons. The model demonstrates that fundamental response properties of cortical layer 4 can be explained by circuitry expected to develop under correlation-based rules of synaptic plasticity, and shows how such circuitry allows the cortex to distinguish stimulus intensity from stimulus form.

Animals↗
PubMed1998

Equivalence of a sprouting-and-retraction model and correlation-based plasticity models of neural development.

A simple model of correlation-based synaptic plasticity via axonal sprouting and retraction (Elliott, Howarth, & Shadbolt, 1996a) is shown to be equivalent to the class of correlation-based models (Miller, Keller, & Stryker, 1989), although these were formulated in terms of weight modification of anatomically fixed synapses. Both models maximize the same measure of synaptic correlation, subject to certain constraints on connectivity. Thus, the analyses of the correlation-based models suffice to characterize the behavior of the sprouting-and-retraction model. More detailed models are needed for theoretical distinctions to be drawn between plasticity via sprouting and retraction, weight modification, or a combination. The model of Elliott et al. involves stochastic search through allowed weight patterns for those that improve correlations. That of Miller et al. instead follows dynamical equations that determine continuous changes of the weights that improve correlations. The identity of these two approaches is shown to depend on the use of subtractive constraint enforcement in the models of Miller et al. More generally, to model the idea that neural development acts to maximize some measure of correlation subject to a constraint on the summed synaptic weight, the constraint must be enforced subtractively in a dynamical model.

Animals↗
PubMed1998

Visceral abdominal-fat accumulation associated with use of indinavir.

BACKGROUND: After the addition of the protease inhibitor indinavir to combination drug regimens for HIV-1 infection, some patients have experienced an increase in abdominal girth with symptoms of abdominal fullness, distension, or bloating. We aimed to find out whether this collection of symptoms was associated with changes in abdominal fat and whether such changes were associated with indinavir use. METHODS: Abdominal computed tomography was used in ten HIV-1-positive patients who had such abdominal symptoms to measure total adipose tissue (TAT) and visceral adipose tissue (VAT) at the umbilicus (L4 vertebral level). The VAT:TAT ratio in the ten cases was compared with that in ten HIV-1-infected patients who had been using indinavir without abdominal symptoms for at least 6 months and ten HIV-1-infected patients who were not using indinavir. FINDINGS: The mean VAT:TAT ratios for the three groups-non-users, symptom-free indinavir users, and symptomatic indinavir users-were 0.40 (SD 0.15), 0.59 (0.18), and 0.70 (0.20), respectively (p=0.004). The VAT:TAT ratio correlated with duration of indinavir use (r=0.47, p=0.01). The mean areas of VAT for the three groups were 106 cm2 (SD 72), 141 cm2 (65) and 202 cm2 (93), respectively (p=0.03). The mean body-mass index of the groups was similar, and patients in the two indinavir groups did not gain a significant amount of weight after starting the drug. Serum triglyceride values increased after starting indinavir and correlated with VAT:TAT ratios. INTERPRETATION: Our data suggest that some HIV-1-infected patients on indinavir treatment accumulate intra-abdominal fat that may cause abdominal symptoms. Recent evidence suggests that other HIV-1 protease inhibitors may be associated with changes in body-fat distribution. Larger studies of protease-inhibitor treatment are needed to investigate this association further and to investigate metabolic or endocrine mechanisms that may underlie this phenomenon.

Abdomen↗
PubMed1998

The role of glycosylation in flavonol-induced pollen germination.

Flavonols are small (C15) plant-specific molecules that are required for petunia and maize pollen to germinate. They exist in two chemical forms: the aglycone or glycosyl conjugates. Flavonol-deficient pollen is biochemically complemented by flavonol aglycones but not by the glycosylated forms that accumulate in wild type (WT) pollen. Coincident with the biochemical induction of germination, the added flavonol aglycone is rapidly converted to a galactoside and then to a glucosyl galactoside (diglycoside) that is identical to the compound present in WT pollen. A flavonol 3-O-galactosyltransferase (F3GalTase) activity has been identified that controls the formation of glycosylated flavonols in pollen. Importantly, this enzyme also catalyzes the reverse reaction, i.e. the production of the flavonol aglycone from the galactoside and UDP (Fig. 1). F3GalTase/RevGalTase therefore has the potential to control the level of the bioactive flavonol species and as a result, pollen germination.

Flavonoids↗
PubMed1997

Crystalluria and urinary tract abnormalities associated with indinavir.

BACKGROUND: Indinavir, a protease inhibitor widely used to treat patients with HIV infection, has been associated with nephrolithiasis. Distinctive urinary crystals and a spectrum of urologic disorders were noted in patients receiving indinavir. OBJECTIVE: To determine the composition of urinary crystals and the frequency of asymptomatic crystalluria and urinary tract symptoms in patients receiving indinavir. PATIENTS: Patients with HIV infection who were enrolled in studies conducted at the National Institutes of Health. MEASUREMENTS: Microscopic urinalysis, high-performance liquid chromatography (HPLC) and mass spectrometry of urinary crystals and stones, and clinical evaluation of patients with urologic symptoms. RESULTS: Of 240 patients receiving indinavir, 142 provided urine specimens for analysis. Twenty-nine (20%) had crystals consisting of plate-like rectangles and fan-shaped or starburst forms. Mass spectrometry and HPLC confirmed that these crystals were composed of indinavir. Of 40 patients who were not receiving indinavir, none had similar crystals (P < 0.001). Nineteen of the 240 patients receiving indinavir (8%) developed urologic symptoms. Of these, 7 (3%) had nephrolithiasis and the other 12 (5%) had previously undescribed syndromes: crystalluria associated with dysuria and crystalluria associated with back or flank pain. Four of the patients with the latter syndrome had radiographic evidence of intrarenal sludging. CONCLUSIONS: Indinavir forms characteristic crystals in the urine. This crystalluria may be associated with dysuria and urinary frequency, with flank or back pain associated with intrarenal sludging, and with the classic syndrome of renal colic.

Adult↗
PubMed1997

Physiological gain leads to high ISI variability in a simple model of a cortical regular spiking cell.

To understand the interspike interval (ISI) variability displayed by visual cortical neurons (Softky & Koch, 1993), it is critical to examine the dynamics of their neuronal integration, as well as the variability in their synaptic input current. Most previous models have focused on the latter factor. We match a simple integrate-and-fire model to the experimentally measured integrative properties of cortical regular spiking cells (McCormick, Connors, Lighthall, & Prince, 1985). After setting RC parameters, the post-spike voltage reset is set to match experimental measurements of neuronal gain (obtained from in vitro plots of firing frequency versus injected current). Examination of the resulting model leads to an intuitive picture of neuronal integration that unifies the seemingly contradictory 1/square root of N and random walk pictures that have previously been proposed. When ISIs are dominated by postspike recovery, 1/square root of N arguments hold and spiking is regular; after the "memory" of the last spike becomes negligible, spike threshold crossing is caused by input variance around a steady state and spiking is Poisson. In integrate-and-fire neurons matched to cortical cell physiology, steady-state behavior is predominant, and ISIs are highly variable at all physiological firing rates and for a wide range of inhibitory and excitatory inputs.

Animals↗
PubMed1997

Development of spatiotemporal receptive fields of simple cells: I. Model formulation.

A model for the development of spatiotemporal receptive fields of simple cells in the visual cortex is proposed. The model is based on the 1990 hypothesis of Saul and Humphrey that the convergence of four types of input onto a cortical cell, viz. non-lagged ON and OFF inputs and lagged ON and OFF inputs, underlies the spatial and temporal structure of the receptive fields. It therefore explains both orientation and direction selectivity of simple cells. The response properties of the four types of input are described by the product of linear spatial and temporal response functions. Extending the 1994 model of one of the authors (K.D. Miller), we describe the development of spatiotemporal receptive fields as a Hebbian learning process taking into account not only spatial but also temporal correlations between the different inputs. We derive the correlation functions that drive the development both for the period before and after eye-opening and demonstrate how the joint development of orientation and direction selectivity can be understood in the framework of correlation-based learning. Our investigation is split into two parts that are presented in two papers. In the first, the model for the response properties and for the development of direction-selective receptive fields is presented. In the second paper we present simulation results that are compared with experimental data, and also provide a first analysis of our model.

Animals↗
PubMed1997

Development of spatiotemporal receptive fields of simple cells: II. Simulation and analysis.

In part I of this article a correlation based model for the developmental process of spatiotemporal receptive fields has been introduced. In this model the development is described as an activity-dependent competition between four types of input from the lateral geniculate nucleus onto a cortical cell, viz. non-lagged ON and OFF and lagged ON and OFF inputs. In the present paper simulation results and a first analysis are presented for this model. We study the developmental process both before and after eye-opening and compare the results with experimental data from reverse correlation measurements. The outcome of the developmental process is determined mainly by the spatial and the temporal correlations between the different inputs. In particular, if the mean correlation between non-lagged and lagged inputs is weak, receptive fields with a widely varying degree of direction selectivity emerge. However, spatiotemporal receptive fields may show rotation of their preferred orientation as a function of response delay. Even if the mean correlation between two types of temporal input is not weak, direction-selective receptive fields may emerge because of an intracortical interaction between different cortical maps. In an environment of moving lines or gratings, direction-selective receptive fields develop only if the distribution of the directions of motion presented during development shows some anisotropy. In this case, a continuous map of preferred direction is also shown to develop.

Algorithms↗
PubMed1997

Primitive neuroectodermal tumors arising in testicular germ cell neoplasms.

Twenty-nine young men (mean age 29 years) had primitive neuroectodermal tumors (PNETs) arising in germ cell tumors (GCTs). Nine patients had PNETs confined to the testis, eight patients had PNETs in the testis and at metastatic sites, and 12 patients had PNETs identified only at extratesticular sites. Immunohistochemistry was of use in the further classification of these PNETs as neuroblastoma, medulloepithelioma, peripheral neuroepithelioma, or ependymoblastoma. The histologic pattern of PNETs in the testis (neuroblastoma or medulloepithelioma) did not predict which tumors metastasized. PNETs localized to the testis did not affect prognosis. Eight patients with no PNETs outside the testis were free of disease 1 month to 10 years after diagnosis. PNETs in extratesticular sites were an adverse prognostic factor. Nineteen patients with extratesticular PNETs had adequate clinical follow-up. Thirteen are dead of disease from 4 months to 5 1/2 years (mean 26 months) after diagnosis, four are alive with disease 6 months to 2 years after diagnosis, and two have no evidence of disease with short follow-up (6 and 17 months). Mean survival was longer (34 months) for patients whose extratesticular PNET was neuroblastoma than for those with other types of PNETs (13 months). Chemotherapy directed against GCTs was not effective in patients who developed metastatic PNETs of GCT origin. We conclude that extratesticular PNETs in patients with testicular GCTs are usually fatal, but patients with neuroblastomatous metastases may have a more prolonged course.

Adolescent↗
PubMed1997

Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma.

PURPOSE: Salvage therapy for disseminated germ cell tumors of all histologic subtypes with vinblastine, ifosfamide, and cisplatin (VeIP) will cure approximately 25% of patients. The purpose of this study was to evaluate the activity of VeIP in patients with recurrent seminoma. PATIENTS AND METHODS: We conducted a retrospective review of 24 patients with recurrent seminoma who were treated at Indiana University with VeIP as second-line chemotherapy. All patients had received cisplatin-containing regimens as primary chemotherapy and seven had also received prior pelvic radiotherapy. All patients received four courses of VeIP. RESULTS: The minimum follow-up duration was 2 years (range, 2 to 9.1), with a median follow-up time of 7 years. Twenty of 24 patients (83%) achieved a complete remission (CR) following VeIP alone. One additional patient was rendered disease-free (NED) with the resection of residual carcinoma. Eight patients have relapsed. Four of six patients with extragonadal primary tumors and two of four who failed to achieve CR with initial chemotherapy are continuously NED with VeIP. Overall, 13 of 24 (54%) are long-term survivors with VeIP salvage chemotherapy. CONCLUSION: VeIP has significant curative potential in patients with recurrent seminoma and appears to produce a higher CR rate and more long-term survivors than is achieved in patients with nonseminomatous disease.

Adult↗
PubMed1996

A phase II study of weekly oral methotrexate and zidovudine (AZT) in advanced adenocarcinoma of the pancreas and hepatocellular carcinoma.

From January 1992 through May 1993, 31 patients with adenocarcinoma of the pancreas or hepatocellular carcinoma were treated with weekly oral methotrexate (7.5 mg/M2 every 6 hours for 6 doses) and continuous oral AZT (200 mg four times daily). Patients were treated for a total of 6 months or until disease progression. The median age was 66 (range 44-79) and the median KPS was 80. No patient had received prior chemotherapy. Hematologic toxicity was severe with 50% of patients developing hemoglobins less than 8 gm/dl and 70% with granulocyte counts less than 1000 per mm3. One patient achieved a radiographic complete remission and 2 had stable disease. Two-thirds of patients progressed within 2 months of beginning therapy. The combination of methotrexate and AZT is an inactive regimen in pancreatic and hepatocellular carcinoma and is associated with considerable toxicity.

Adenocarcinoma↗
PubMed1996

Asymptomatic solitary pulmonary nodules due to Cryptococcus neoformans in patients infected with human immunodeficiency virus.

We report the cases of three HIV-positive patients with solitary pulmonary nodules caused by Cryptococcus neoformans. Although human infection with C. neoformans occurs via the respiratory tract, isolated pulmonary infection in HIV-positive patients, in contrast with HIV-negative patients, has been thought to be relatively rare. When isolated pulmonary disease in HIV-infected patients, has been described, most of the patients have been symptomatic (symptoms have included fever, cough, and dyspnea). In addition, these patients have had diffuse interstitial infiltrates, alveolar infiltrates, or nodular infiltrates that have often been associated with hilar adenopathy and occasionally with pleural effusions. None of the patients in the previously reported series have had lesions described as small, asymptomatic, isolated pulmonary nodules.

Adult↗
PubMed1996

Comparison of transverse and longitudinal real-time ultrasound scans for prediction of lean cut yields and fat-free lean content in live pigs.

Live animal real-time ultrasound scans and carcass measures were taken on 80 pigs comprising two sexes (42 barrows; 38 gilts) and two halothane genotypes (40 carriers and 40 negatives) that were slaughtered between 108 and 148 kg live weight. Transverse scans (TRUS), at right angles to the midline, were taken on right (RS) and left (LS) sides at the last rib. Longitudinal scans (LON) were taken 6.5 cm off the midline immediately anterior (ANT) and posterior (PST) to the last rib on both the RS and LS. Longissimus muscle depth and area and backfat thickness over the longissimus muscle were measured on TRUS. Backfat thickness and longissimus muscle depth were measured at each end of the LON. Backfat thickness and longissimus muscle measurements were taken at the 10th and last rib on the RS of the carcass. Carcasses were fabricated using standard techniques to establish lean cut yields and carcass soft tissue was chemically analyzed to determine fat-free lean contents. Stepwise regression analysis was performed to develop equations to predict the weights and percentages of lean cuts and fat-free lean. Fat and muscle measures taken from ultrasound scans were generally less accurate than last rib carcass measures at predicting composition. There was little difference in R2 for equations based on either TRUS or ANT/LON; however, PST/LON, generally, were less accurate than ANT/LON. Combining measurements from more than one scan gave little improvement in R2 compared with the best single scan. Estimates of sex bias for carcass composition prediction were small. Halothane genotype and carcass lean content biases were detected; equations derived from the pooled data tended to overestimate the lean content of negative pigs and fatter carcasses and underestimate the lean content of carrier animals and leaner carcasses.

Animals↗