Direct observation of rough-smooth twin structure in silver halides by high-resolution electron microscopy.
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Journal Article↗
Biomedical subjects
S Chen
Publications and source records attributed to S Chen.
The melanoma epidemic. Is increased surveillance the solution or the problem?
Melanoma has a very bad reputation, and rightfully so. Until relatively recently, the prognosis for melanoma was dismal and, very reasonably, early detection has been proposed as a viable approach to preventing melanoma deaths. On the surface, this simple approach appears to have been a stellar success, with melanoma survival rates improving markedly. There is no question that there has been a dramatic increase in the number of people with a diagnosis of melanoma. On careful scrutiny, the numbers reflected in the increased incidence may not add up. Mortality rates and the diagnosis rate for thick tumors ( > 1.5 mm thick) have not gone up commensurate with the growing rate of diagnosis. The obvious explanation for this discrepancy is that we are doing a great job! However, this explanation must assume that an overwhelming percentage of those at risk for melanoma are in a position to benefit from our service. It is very unlikely that this is the case. It is not clear whether the increase in the number of melanoma cases diagnosed reflects an actual increase in real disease. Could this increase be in part a product of aggressive surveillance resulting in the identification of "atypical" pigmented skin tumors of limited or nonexistent potential for malignant behavior? Could the dramatic improvement in the prognosis of melanoma simply be a consequence of removing biologically benign pigmented tumors that are inadvertently classified as malignant?
Humans↗
Application to rat lung of the extended Rorschach-Hazlewood model of spin-lattice relaxation.
The spin-lattice relaxation time T1 was measured in excised degassed (airless) rat lungs over the frequency range 6.7 to 80.5 MHz. The observed frequency dependence was fitted successfully to the water-biopolymer cross-relaxation theory proposed by H. E. Rorschach and C. F. Hazlewood (RH) [J. Magn. Reson. 70, 79 (1986)]. The rotating frame spin-lattice relaxation time T1(rho) was also measured in rat lung fragments over the frequency range 0.56 to 5.6 kHz, and the observed frequency dependence was explained with an extension of the RH model. The agreement between the theory and the experimental data in both cases is good.
Animals↗
Phase I and pharmacologic study of 7- and 21-day continuous etoposide infusion in patients with advanced cancer.
PURPOSE: This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate its pharmacokinetic/pharmacodynamic profile in patients with advanced cancer. METHODS: A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses from 30 to 75 mg/m2 per day, and a second group of 37 patients a 21-day infusion (schedule B) every 28 days at doses from 18 to 40 mg/m2 per day. Patients had a median Karnofsky performance status (PS) of 80%, and 34 patients had no prior chemotherapy. Etoposide concentrations at steady state (Css) and other pharmacokinetic parameters (plasma clearance, CLp; area under the curve, AUC) were determined during the first treatment cycle. Correlation coefficients were calculated to measure the relationship between variables. RESULTS: Myelosuppression was the major toxicity, and was associated with three deaths. The maximum tolerated dose due to neutropenia was 75 mg/m2 per day for schedule A and 40 mg/m2 per day for schedule B. There was significant interpatient pharmacokinetic variability in both infusional schedules. Even though etoposide dose levels did not significantly correlate with plasma levels, the Css was > or = 1 microgram/ml in the majority of the patients. A significant correlation between AUC and neutrophil absolute decrease was noted only in schedule B (r = 0.56, P = 0.003). There were several marginal relationships in schedule B: PS versus Css (r = 0.31, P = 0.058), PS versus AUC (r = -0.38; P = 0.058) and age versus CLp (r = -0.31, P = 0.057). CONCLUSION: Overall, significant correlations were found for several hematologic variables and etoposide dose levels, but not with the Css values. One major problem with the application of pharmacodynamic models to predict hematologic toxicity in clinical practice is the presence of significant interpatient variability.
Adult↗
Nonmetastatic trophoblastic neoplasia of the cervix following termination of a cervical pregnancy.
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Adult↗
Angle judgement: is the whole the sum of its parts?
This study concerns whether the discrimination of a geometric angle depends on the orientations of its bounding lines or on angle size. In Experiment 1, thresholds for angle discrimination were measured in three observers for angles ranging from 15 to 180 deg, oriented either vertically or obliquely. Angle discrimination thresholds were found to depend primarily on angle size for most of the range of angles (angle-dependent, or Weber's law regime). However, in a small region near 90 deg (orientation-dependent regime) angle discrimination depends on the orientations of the bounding lines. When our data in the angle-dependent regime were fitted with a power function, the exponents were close to or < 0.5, suggesting that a step-increment approach was used to calculate angle. In Experiment 2, orientation discrimination thresholds for lines corresponding to the bounding lines of the vertically and obliquely oriented 15, 90 and 165 deg angles were measured. Confirming previous studies, a strong meridional anisotropy in line orientation discrimination was found for all three observers. The orientation discrimination thresholds were then used to predict the discrimination thresholds for the corresponding angles based on a simple statistical model. The predicted angle discrimination thresholds were worse than those measured empirically except for the titled 90 deg angles. This result indicates that angle discrimination thresholds are not limited by the same noise as orientation discrimination for most angles except for the tilted 90 deg angle, where the limiting factor may be the precision in determining the orientations of the bounding lines. In Experiment 3, we show that angle discrimination is quite robust to small amounts of orientation jitter, suggesting that angle judgments are made at a level beyond the early filter representation.
Differential Threshold↗
Immunohistochemical localization of Lyn (p56) protein in the adult rat brain.
Expression of a sarcoma proto-oncogene, c-lyn, was mapped in the adult rat brain using immunohistochemistry. Lyn protein was prevalent in restricted cell populations of the olfactory bulb and the basal forebrain which included nuclei of accumbens, fundal striatum, bed stria, ventral pallidum and central amygdala as well as deep entorhinal and pyriform cortices. Tightly packed Lyn-positive cells formed discrete multiple stripes crossing perpendicular to the rostral limb of the anterior commissure, and intense masses surrounding the caudal limb. In the thalamus, the habenula, anterodorsal nucleus and medial geniculate body, together with the paraventricular hypothalamic nuclei, had prominent reactive neuronal somata and dendrites in the neuropil. The lateral septal nucleus also had intense Lyn-positive neurons with overlapping dendritic fields. In addition, scattered neurons were evenly distributed throughout the striatum. The red, interpeduncular, auditory and trigeminal tract nuclei were intensely reactive. The cerebellar molecular layer was uniformly labeled except for a few isolated fiber bundles in the lowest part of this layer. The granule cells adjacent to the Purkinje cell layer appeared in reactive patches. In the spinal cord, the posteromarginal nucleus had intense labeling. The significance of this highly localized distribution pattern of Lyn protein may be related to connections forming functional compartments serving signal transduction within specific central nervous system circuitry.
Animals↗
Extensive projections from the midbrain periaqueductal gray to the caudal ventrolateral medulla: a retrograde and anterograde tracing study in the rat.
We investigated the innervation of the caudal ventrolateral medulla by the midbrain periaqueductal gray in the rat using retrograde and anterograde tract-tracing. Iontophoretic injection of Fluoro-Gold or cholera toxin B subunit into the caudal ventrolateral medulla resulted in retrogradely labeled neurons in discrete regions of the periaqueductal gray. These labeled cells were observed throughout the rostrocaudal extent of the periaqueductal gray and were distributed (as percentage of total labeled cells) in its lateral (53-67%), ventrolateral (14-28%), ventromedial (7-16%) and dorsomedial aspects (7-10%). About 70-72% of labeled cells were found in the caudal half of the periaqueductal gray and 28-30% in the rostral half. In the ventromedial periaqueductal gray, more labeled cells were seen in the contralateral side (5-13%) than the ipsilateral side (2-3%), whereas for other periaqueductal gray areas labeling was preferentially ipsilateral. Phaseolus vulgaris leucoagglutinin anterograde tracing was used to confirm the retrograde labeling results. Following iontophoretic injection into the periaqueductal gray, labeled fibers and terminals were observed throughout the rostrocaudal extent of the caudal ventrolateral medulla. Injections in the lateral and/or ventrolateral aspect of the periaqueductal gray yielded more anterograde labeling in the ipsilateral than the contralateral caudal ventrolateral medulla, while injections in the ventromedial aspect of the periaqueductal gray produced labeling preferentially in the contralateral caudal ventrolateral medulla. The present study indicates that specific regions of the periaqueductal gray project to the caudal ventrolateral medulla and may regulate cardiovascular and respiratory functions through these connections.
Animals↗
Ultrastructural localization of the plasmalemmal calcium pump in cerebellar neurons.
In a previous study, fluorescence labeling of a plasmalemmal ATPase protein with the 5F10 monoclonal antibody revealed prominent antigen in the cerebellar molecular layer surrounding the somata and dendrites of Purkinje cells. In the present study, this antibody labeled with silver enhanced nano-sized gold particles on semithin plastic sections revealed a clearly demarcated plasma membrane outlining the somata and entire dendritic arbors of Purkinje cells including their spines. Ultrastructural analysis of horseradish peroxidase preparations showed reaction product along the plasmalemma and extending on to the sub-plasmalemmal endoplasmic reticulum. In the granular layer, somata of granule cells were reactive, as were their dendritic extensions into glomeruli where reactive claws surrounded voids formed by mossy fiber rosettes. Somata and dendrites of cerebellar nuclear cells also had reactive zones that were limited to the plasma membrane and a narrow zone of the sub-plasmalemmal endoplasmic reticulum. Comparative labeling of this protein and P channel protein revealed similar plasmalemmal locations. This study shows that a specific calcium ATPase pump protein is located on the plasmalemma of certain types of cerebellar neurons. The ultrastructural distribution of calcium pump and P channel antibodies occurred in punctate sites along the plasma membrane of dendrites and spines of Purkinje cells. The close association between P-type calcium channels and the plasma membrane calcium pump is consistent with rapid extrusion of intracellular calcium from neurons endowed with large numbers of voltage-gated calcium channels.
Animals↗
The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence on clinical outcomes in psychiatry.
OBJECTIVES: This study examined factors that affect cost, reliability, and the value of determining the cytochrome P450 2D6 (CYP2D6) polymorphism in clinical practice. STUDY DESIGN: The method of deoxyribonucleic acid isolation, sample preparation, oligonucleotide primers, and polymerase chain reaction procedures were scrutinized for their effect on CYP2D6 genotyping efforts. The determination of the CYP2D6 A, B, D, E, and T alleles was used to identify the deficiency in CYP2D6 expression in 161 individuals phenotyped for CYP2D6 activity with dextromethorphan. The CYP2D6 genotype was assessed in 74 outpatients who had received diagnoses of depression. Eighteen of these patients were screened because of an adverse response to a tricyclic or antidepressant known or suspected to be a CYP2D6 substrate. RESULTS: The CYP2D6 A, B, C, D, E, and T alleles could be detected in 13 hours at a cost of $84 per sample by judicious selection of conditions and procedures. The genotype provided an accurate predictor of CYP2D6 expression in all 134 subjects who expressed the enzyme and in all 27 unrelated individuals phenotyped as deficient in CYP2D6 activity. In the patient group that experienced adverse effects, 44% of all CYP2D6 gene copies contained the A, B, D, E, or T allele(s) associated with inactive CYP2D6 expression. This was more than twice the rate for the occurrence of mutant alleles in the other 56 psychiatric patients (21%) and in 80 random subjects from the general population (20%; p < 0.05). CONCLUSIONS: Screening psychiatric patients for CYP2D6 expression may distinguish metabolic-based therapeutic problems from drug sensitivity caused by other mechanisms.
Antidepressive Agents, Tricyclic↗
Aromatase gene expression and its exon I usage in human breast tumors. Detection of aromatase messenger RNA by reverse transcription-polymerase chain reaction.
The expression of aromatase in human breast tumors has been studied by the reverse-transcription polymerase chain reaction (RT-PCR) method on 70 breast tissue specimens. An RT-PCR analysis using two oligonucleotide primers derived from the exon II of the human aromatase gene revealed that aromatase mRNA was detected in all but three tissue specimens. Furthermore, primer-directed RT-PCR was performed to determine the exon I usage in aromatase mRNA in these breast tumor specimens. The analysis has revealed that exons I.3 and PII are the two major exon Is present in aromatase mRNA isolated from breast tumors, suggesting that promoters I.3 and II are the major promoters driving aromatase expression in breast cancer and surrounding adipose stromal cells. The RT-PCR analysis also detected two products, I.3A (334 bp in length) and I.3B (222 bp in length), when it was carried out using a primer derived from exon I.3 and a reverse primer derived from exon II. The nucleotide sequences of these products have been determined and indicate that I.3A contains a region which was previously thought to be an intron. In addition, RT-PCR analyses of RNA isolated from eight pairs of breast tumor and neighboring normal tissue specimens were performed to evaluate the exon I usage and the distribution of I.3A- and I.3B-containing aromatase RNA messages in breast tumor and neighboring normal tissues. The results suggest that I.3B- and I.3A-containing messages are mainly present in breast tumor and neighboring normal tissues, respectively. Finally, the exon I/promoter usage for aromatase expression in eight cell lines (skin fibroblast, MCF-7, MDA-MB-231, T-47D, SK-BR-3, JAR, OVCAR-3, and human adipose stromal cells) was examined by primer-directed RT-PCR analyses. These studies provide a basis for further evaluation of the control mechanism of aromatase expression and estrogen biosynthesis in breast tumors.
Adipose Tissue↗
Stress controllability influences the ataxic properties of both ethanol and midazolam in the rat.
Rats were administered either 80 escapable shocks or yoked inescapable shocks, were then injected with saline or several ataxic doses of either ethanol or midazolam, and then had their motoric impairment assessed by Rotarod performance. No motoric impairment was observed following saline injection. However, inescapable shock impaired Rotarod performance in response to both ethanol and midazolam at 2 hr, but not immediately poststress. Conversely, escapable shock reduced the ataxic potency of ethanol, although it had no influence on midazolam-induced ataxia. These results indicate functional alterations in behavioral reactivity to low doses of several classes of central nervous system depressants by psychological dynamics of stress exposure. Our findings demonstrate the impact of stress controllability on behavioral reactivity to two classes of drugs of abuse.
Animals↗
Various isoforms of myomodulin identified from the male copulatory organ of Lymnaea show overlapping yet distinct modulatory effects on the penis muscle.
Male copulatory behavior in the snail Lymnaea stagnalis is controlled by several types of peptidergic neurons, including a cluster of neurons in the ventral lobe of the right cerebral ganglion that show immunoreactivity to myomodulin-A of Aplysia and innervate the penis complex. We identified structurally myomodulin-A and three related peptides from Lymnaea and showed that they are present in a characteristic ratio in both the penis nerve and penis complex, suggesting that they are processed from a single precursor and transported from the ventral lobe to the penis complex. All four peptides decreased the relaxation time of electrically evoked contractions of the penis retractor muscle. However, their effects on the amplitude of contraction were different, ranging from no effect to an increase or a decrease in the amplitude. A mixture of the peptides in a ratio as determined by direct mass spectrometry of the penis nerve decreased the contraction time, the relaxation time, and the amplitude. These effects resemble those of one particular peptide in the mixture. The direct mass spectrometry determinations of the peptide profile in the penis nerve suggest that many more, as yet unidentified, neuropeptides are involved in modulation of muscle activities of the penis complex.
Amino Acid Sequence↗
Meridional anisotropy in the discrimination of parallel and perpendicular lines--effect of body tilt.
It is well documented that orientation discrimination is poorer for stimuli oriented obliquely than for those that are vertical or horizontal. Buchanan-Smith and Heeley recently reported that in the absence of a spatial reference this anisotropy follows gravitational rather than retinal coordinates, suggesting a high-level basis for the anisotropy in unreferenced orientation discrimination tasks. In the present study, unlike the previous one, the effects of body tilt on orientation discrimination have been examined in the presence of explicit simultaneous spatial references. The thresholds for discrimination of two parallel or two perpendicular lines were estimated for the retinally principal and oblique orientations, with the body either erect or tilted 45 degrees with respect to gravity. In agreement with previous studies, meridional anisotropy for both parallelism and perpendicularity discrimination was found when observers were seated upright. When the observer's body was tilted, the anisotropy for the parallelism task was mapped to retinal and not to gravitational coordinates after compensating for countertorsion. Initially, the anisotropy for the perpendicularity task was not mapped to retinal coordinates, but after extensive practice for both the erect and the tilted body conditions it eventually followed retinal coordinates. The results reported here suggest that contrary to orientation discrimination without a spatial reference, the ultimate limits for both parallelism and perpendicularity discriminations are located at orientation-sensitive cortical neurons. However, the effect of perceptual learning in the perpendicularity task suggests that the internal frame of reference (gravity cues and body axis) also plays an important role.
Analysis of Variance↗
Prolonged infusion of etoposide in patients with advanced non-small cell lung cancer.
We assessed the efficacy and toxicity of two etoposide infusional schedules in patients with advanced non-small cell lung cancer (NSCLC). Twenty-six patients were treated with a 21-day infusion every 28 days at a dose of 25-40 mg/m2/d, and six patients with a 7-day infusion every 21 days at a dose of 45-75 mg/m2/d. Sixty-three percent of patients had a Karnofsky status of 80% or better, and only five (15%) patients had prior chemotherapy. Plasma etoposide concentrations were determined in 26 patients. Sixty-nine treatment cycles were administered. Two patients (6.3%; 90% confidence interval, 1.1-18.4%) had partial responses; with response durations of 2 and 7 months, respectively. The median survival was 4 months. Grade 3 or 4 neutropenia occurred in 13 of 69 cycles (19%) and was associated with three toxic deaths. Ten patients required RBC transfusions. Nausea was common, but was associated with vomiting in only 7% of all cycles. The interpatient variability of etoposide concentrations at steady state was significant. We conclude that the antitumor activity of prolonged infusion of etoposide is not superior to standard dose and schedule in advanced NSCLC.
Adult↗
A comparison of the hypotensive and hypoglycaemic actions of an angiotensin converting enzyme inhibitor, an AT1a antagonist and troglitazone.
OBJECTIVE: To define the relationship between changes in insulin sensitivity and attenuation of hypertension. METHODS: We investigated whether troglitazone (CS-045, an insulin sensitizer) has an antihypertensive effect in fructose (FRU)-fed Wistar rats with insulin resistance and simultaneously compared its hypotensive efficacy with those of alacepril (ALA, an angiotensin converting enzyme inhibitor) and TCV-116 (an AT1a receptor antagonist). Male rats aged 8 weeks were divided into five groups: controls fed normal chow, a FRU group fed FRU-rich (55%) chow, a FRU plus ALA group fed 30 mg/kg ALA per day, a FRU plus TCV-116 group fed 1 mg/kg TCV-116 per day and a FRU plus CS-045 group fed 70 mg/kg CS-045 per day). After 8 weeks, the body weight and systolic blood pressure were recorded and glucose tolerance was determined by glucose loading (2 g/kg, intraperitoneally) and a steady-state plasma glucose (SSPG) method. The plasma membrane glucose transporter 4 content in gastrocneumius muscle was determined by Western blot analysis. RESULTS: FRU increased blood pressure from 125 mmHg in controls to 141 mmHg (P < 0.01). ALA and TCV-116 administration decreased blood pressure to 111 and 107 mmHg, respectively (P < 0.01). CS-045 administration lowered blood pressure significantly to 121 mmHg. Area under the curve levels for plasma insulin during glucose loading increased from 1.7 in controls to 3.6 ng/ml x h in FRU-fed rats, but were lowered by the three drugs. SSPG levels increased from 12.5 in controls to 18.3 mmol/l in FRU-fed rats (P < 0.01), but were decreased by ALA and TCV-116 administration (P < 0.01). CS-045 administration also lowered SSPG levels to 15.3 mmol/l (P < 0.05). FRU-feeding induced a 1.24-fold increase in plasma membrane glucose transporter 4, which was not affected by ALA and TCV-116 administration, but was augmented 1.82-fold by CS-045 administration. Furthermore, the increased triglyceride level after FRU was diminished both by ALA and by CS-045 administration. CONCLUSION: These results suggest that, in the insulin-resistant state, troglitazone, an angiotensin converting enzyme inhibitor and an AT1a receptor antagonist show comparable hypotensive and hypoglycaemic effects.
Angiotensin Receptor Antagonists↗
Spinodal decomposition in fluids: Diffusive, viscous, and inertial regimes.
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Journal Article↗
Supercooled water and the kinetic glass transition.
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Journal Article↗