Cases from the Osler medical service at Johns Hopkins University.
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Baltimore↗
Biomedical subjects
James Lee
Publications and source records attributed to James Lee.
Design and validation of a computer-based sleep-scoring algorithm.
A computer-based sleep scoring algorithm was devised for the real time scoring of sleep-wake state in Wistar rats. Electroencephalogram (EEG) amplitude (microV(rms)) was measured in the following frequency bands: delta (delta; 1.5-6 Hz), theta (Theta; 6-10 Hz), alpha (alpha; 10.5-15 Hz), beta (beta; 22-30 Hz), and gamma (gamma; 35-45 Hz). Electromyographic (EMG) signals (microV(rms)) were recorded from the levator auris longus (neck) muscle, as this yielded a significantly higher algorithm accuracy than the spinodeltoid (shoulder) or temporalis (head) muscle EMGs (ANOVA; P=0.009). Data were obtained using either tethers (n=10) or telemetry (n=4). We developed a simple three-step algorithm that categorizes behavioural state as wake, non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep, based on thresholds set during a manually-scored 90-min preliminary recording. Behavioural state was assigned in 5-s epochs. EMG amplitude and ratios of EEG frequency band amplitudes were measured, and compared with empirical thresholds in each animal.STEP 1: EMG amplitude greater than threshold? Yes: "active" wake, no: sleep or "quiet" wake. STEP 2: EEG amplitude ratio (delta x alpha)/(beta x gamma) greater than threshold? Yes: NREM, no: REM or "quiet" wake. STEP 3: EEG amplitude ratio Theta(2)/(delta x alpha) greater than threshold? Yes: REM, no: "quiet" wake. The algorithm was validated with one, two and three steps. The overall accuracy in discriminating wake and sleep (NREM and REM combined) using step one alone was found to be 90.1%. Overall accuracy using the first two steps was found to be 87.5% in scoring wake, NREM and REM sleep. When all three steps were used, overall accuracy in scoring wake, NREM and REM sleep was determined to be 87.9%. All accuracies were derived from comparisons with unequivocally-scored epochs from four 90-min recordings as defined by an experienced human rater. The algorithms were as reliable as the agreement between three human scorers (88%).
Algorithms↗
Liquid chromatographic separation of the enantiomers of trans-chlordane, cis-chlordane, heptachlor, heptachlor epoxide and alpha-hexachlorocyclohexane with application to small-scale preparative separation.
Analytical high-performance liquid chromatographic separations of the individual enantiomers of five polychlorinated compounds were obtained on polysaccharide stereoselective HPLC columns. The enantiomers of the pesticides trans-chlordane, cis-chlordane and heptachlor were separated on CHIRALCEL OD using a hexane mobile phase. The enantiomers of the heptachlor metabolite, heptachlor epoxide, were separated on CHIRALPAK AD using a methanol mobile phase. The enantiomers of alpha-hexachlorocyclohexane (alpha-HCH), were separated on CHIRALCEL OJ using a hexane/2-propanol mobile phase. Similar chromatographic conditions using preparative columns were used to isolate approximately 250 mg of each of the individual enantiomers. The purified individual enantiomers have been submitted for testing of their endocrine disruptor (ED) activity.
Chlordan↗
In vitro dissolution and in vivo oral absorption of methylphenidate from a bimodal release formulation in healthy volunteers.
PURPOSE: The objective of this study was to evaluate the in vitro dissolution and in vivo absorption of D,L-threo-methylphenidate (MPH) from a novel bimodal release formulation (Ritalin LA capsule) compared with an immediate-release formulation (Ritalin IR tablet) in healthy volunteers. METHODS: The bimodal release formulation contains 50% of the dose in the immediate-release (IR) beads and 50% in polymethacrylate-coated, delayed-release (DR) beads. To better understand the impact of dissolution from the DR beads on oral absorption of MPH, three Ritalin LA formulations with different dissolution profiles for the DR beads (referred to as slow-, medium and fast-release formulations) were prepared, and tested together with the immediate-release formulation in 18 healthy male and female volunteers after a single oral dose under fasted conditions. The rate and extent of oral absorption of MPH were evaluated based on the overall Cmax, tmax and AUC values, as well as the Cmax, tmax and AUC values for each individual peak of the bimodal plasma concentration-time profile. The in vivo absorption-time profile was also examined by deconvolution. RESULTS: All three Ritalin LA formulations demonstrated similar bimodal plasma concentration-time profiles with two peak concentrations observed at approximately 2 and approximately 6 h post dose, mimicking that of Ritalin IR tablets given 4 h apart. Deconvolution results showed that the absorption of MPH was biphasic, with a rapid absorption phase between 0 to approximately 2 h, and a somewhat slower second absorption between approximately 3-6 h, consistent with the in vitro bimodal release characteristics of Ritalin LA formulation. The three Ritalin LA formulations were bioequivalent to one another based on the overall Cmax and AUC values and the corresponding values describing the first and second peaks, although their in vitro dissolution profiles for the DR beads were different. Compared with Ritalin IR, the Ritalin LA formulation demonstrated a similar rate of absorption for the first peak, a lower second Cmax and a higher trough concentration between peaks, as well as similar overall plasma AUC. CONCLUSIONS: Following a single oral drug administration, Ritalin LA demonstrated a two-peak plasma concentration-time profile, similar to that of the IR formulation given 4 h apart, but with less fluctuation in the plasma concentration-time profile. The in vivo biphasic absorption of MPH appeared to be well correlated with the bimodal dissolution characteristics of this new Ritalin LA formulation, and some changes in the dissolution profiles for the DR beads appeared not to affect the overall bioavailability of MPH in humans.
Administration, Oral↗
Use of topical sRAGE in diabetic wounds increases neovascularization and granulation tissue formation.
Advanced glycation end products (AGEs) accumulate in diabetic wounds as a result of the glycosylation of various proteins. Interaction of AGEs with the receptor for AGEs (RAGE) results in an exaggerated inflammatory response and compromised collagen production. These changes lead to impaired wound healing. A soluble form of RAGE (sRAGE) has been shown to bind AGEs and thereby blunt their pathogenetic effects. Using genetically diabetic C57BLks-db/db mice, the authors applied sRAGE topically to standardized full-thickness wounds to improve diabetic wound healing. They measured various parameters of wound healing such as neovascularization, reepithelialization, collagen formation, and granulation tissue area. Their results showed a statistically significant increase in granulation tissue area and microvascular density in the sRAGE group compared with untreated wounds. There was a trend toward a smaller epithelial gap in the sRAGE-treated group that did not reach statistical significance. The authors conclude that sRAGE may be a powerful treatment of accelerating diabetic wound healing.
Administration, Topical↗
Religiosity in a hemodialysis population and its relationship to satisfaction with medical care, satisfaction with life, and adherence.
BACKGROUND: The religious beliefs and spirituality of patients on hemodialysis (HD) therapy have not been studied extensively. Studies of the dialysis population seem to indicate that religion may be associated with increased patient satisfaction with life and increased levels of social support. METHODS: Using multiple religiosity scales and scales to assess patient satisfaction with life and social support, we studied the relationship between religiosity and medical and/or social factors and adherence to treatment in 74 HD patients. RESULTS: High scores on the Intrinsic Religiosity Scale were associated strongly with high scores on the Satisfaction With Life Scale, whereas age and high Organizational Religious Activity Scale scores were associated strongly with high scores on the Satisfaction With Medical Care Scale. Older age was associated strongly with increased adherence. No relationship existed between religiosity and adherence in our population. CONCLUSION: Religious beliefs are related strongly to measures of satisfaction with life, whereas religious behaviors are related to satisfaction with medical care. Age is the single most important demographic factor associated with adherence. Because of the complex nature of religiosity, additional investigation is in order.
Adult↗
Cohort study of tofu intake and prostate cancer: no apparent association.
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Adult↗
Gene expression alterations during HGF-induced dedifferentiation of a renal tubular epithelial cell line (MDCK) using a novel canine DNA microarray.
Hepatocyte growth factor (HGF) elicits a broad spectrum of biological activities, including epithelial cell dedifferentiation. One of the most widely used and best-studied polarized epithelial cell lines is the Madin-Darby canine kidney (MDCK) cell line. Here, we describe and validate the early response of polarized monolayers of MDCK cells stimulated with recombinant HGF using a novel canine DNA microarray designed to query 12,473 gene sequences. In our survey, eight genes previously implicated in the HGF signaling pathway were differentially regulated, demonstrating that the system was responsive to HGF. Also identified were 117 genes not previously known to be involved in the HGF pathway. The results were confirmed by real-time PCR or Western blot analysis for 38 genes. Of particular interest were the large number of differentially regulated genes encoding small GTPases, proteins involved in endoplasmic reticulum translation, proteins involved in the cytoskeleton, the extracellular matrix, and the hematopoietic and prostaglandin systems.
Animals↗
The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.
A large-scale effort, termed the Secreted Protein Discovery Initiative (SPDI), was undertaken to identify novel secreted and transmembrane proteins. In the first of several approaches, a biological signal sequence trap in yeast cells was utilized to identify cDNA clones encoding putative secreted proteins. A second strategy utilized various algorithms that recognize features such as the hydrophobic properties of signal sequences to identify putative proteins encoded by expressed sequence tags (ESTs) from human cDNA libraries. A third approach surveyed ESTs for protein sequence similarity to a set of known receptors and their ligands with the BLAST algorithm. Finally, both signal-sequence prediction algorithms and BLAST were used to identify single exons of potential genes from within human genomic sequence. The isolation of full-length cDNA clones for each of these candidate genes resulted in the identification of >1000 novel proteins. A total of 256 of these cDNAs are still novel, including variants and novel genes, per the most recent GenBank release version. The success of this large-scale effort was assessed by a bioinformatics analysis of the proteins through predictions of protein domains, subcellular localizations, and possible functional roles. The SPDI collection should facilitate efforts to better understand intercellular communication, may lead to new understandings of human diseases, and provides potential opportunities for the development of therapeutics.
Cell Adhesion Molecules, Neuronal↗
Serum insulin-like growth factor I and subsequent risk of colorectal cancer among Japanese-American men.
Recent reports suggest that colorectal cancer is positively related to insulin-like growth factor I (IGF-I) and inversely related to insulin-like growth factor binding protein 3 (IGFBP-3). To evaluate these associations further and separately for colon and rectal cancer, the authors conducted a nested case-control study in a cohort of 9,345 Japanese-American men examined in Hawaii in 1971-1977. A total of 177 incident colon cancer cases and 105 incident rectal cancer cases were identified from 1972 to 1996. These patients' stored sera and those of 282 age-matched controls were measured for IGF-I and IGFBP-3. The adjusted mean level of IGF-I was higher in colon cancer cases than in controls (154.7 ng/ml vs. 144.4 ng/ml; p = 0.01). However, the multivariate odds ratio for the highest quartile compared with the lowest was just 1.8 (95% confidence interval: 0.8, 4.3). Adjusted mean IGF-I levels were similar between rectal cancer cases and their controls. For IGFBP-3, adjusted mean levels were lower for both colon and rectal cancer cases than for their matched controls, but the differences were not significant. The IGF-I results weakly support findings from other studies and suggest that there are differences in IGF-I findings between colon and rectal cancer cases. It is possible that IGF-related risk is confounded by other factors that may vary among different cohorts. Further research is needed to clarify these relations.
Age of Onset↗
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.
Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Serum vitamins and the subsequent risk of bladder cancer.
PURPOSE: We determined whether serum vitamins are inversely related to bladder cancer risk. MATERIALS AND METHODS: A cohort of 9,345 Japanese-American men was examined from 1971 to 1977. At examination a blood specimen was obtained and the serum was frozen. After a surveillance period of more than 20 years 111 tissue confirmed incident cases of bladder cancer were identified. Stored serum and that of 111 age matched controls were tested by high pressure liquid chromatography for certain micronutrients, including lutein, zeaxanthin, anhydrolutein, alpha-cryptoxanthin, beta-cryptoxanthin, lycopene, dihydrolycopene, alpha-carotene, beta-carotene, total carotenoids, retinol, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol and total tocopherols. RESULTS: Based on quartiles of serum micronutrient levels the ORs for bladder cancer were determined using the general estimating equations approach. There were statistically significant inverse linear trends in risk for alpha-carotene (p <0.01), beta-carotene (p = 0.03), lutein plus zeaxanthin (p = 0.03), beta-cryptoxanthin (p = 0.04) and total carotenoids (p = 0.02). However, after adjustment for pack-years of cigarette smoking none of the inverse trends remained significant. CONCLUSIONS: These results suggest that cigarette smoking, which is a strong risk factor for bladder cancer, may explain the apparent protective effect of individual and total carotenoids against this common cancer.
Aged↗
Kinetics of cellular responses to intraperitoneal Brugia pahangi infections in normal and immunodeficient mice.
Filarial infections evoke exuberant inflammatory responses in the peritoneal cavities of immunocompetent mice. Clearance of infection appears to be dependent on complex interactions between B1 and B2 B lymphocytes, T cells, eosinophils, macrophages, and the products of these cells. In an earlier communication, we described the course of infection in normal immunocompetent mice. In this study, we utilize mice with well-characterized mutations that disable one or more effector components of adaptive immunity in order to determine their roles in host protection. We characterize peritoneal exudate cells by flow cytometry and determine the kinetics of accumulation of each of the different cell types following infection with Brugia pahangi. We find that (i) four-color flow-cytometric analysis of peritoneal exudate cells using anti-CD3, -CD11b, -CD19, and -Gr1 can distinguish up to six different populations of cells; (ii) an initial influx of neutrophils occurs within 24 h of infection, independent of the adaptive immune status of mice, and these cells disappear by day 3; (iii) an early influx of eosinophils is seen at the site of infection in all strains studied, but a larger, second wave occurs only in mice with T cells; (iv) the presence of T cells and eosinophils is important in causing an increase in macrophage size during the course of infection; and (v) most unexpectedly, T-cell recruitment appears to be optimal only if B cells are present, since JHD mice recruit significantly fewer T cells to the site of infection.
Animals↗
Induction of primary virus-cross-reactive human immunodeficiency virus type 1-neutralizing antibodies in small animals by using an alphavirus-derived in vivo expression system.
We have studied the induction of neutralizing antibodies by in vivo expression of the human immunodeficiency virus type 1 (HIV-1) envelope by using a Venezuelan equine encephalitis virus (VEE) replicon system with mice and rabbits. The HIV-1 envelope, clone R2, has broad sensitivity to cross-reactive neutralization and was obtained from a donor with broadly cross-reactive, primary virus-neutralizing antibodies (donor of reference serum, HIV-1-neutralizing serum 2 [HNS2]). It was expressed as gp160, as secreted gp140, and as gp160deltaCT with the cytoplasmic tail deleted. gp140 was expressed in vitro at a high level and was predominantly uncleaved oligomer. gp160deltaCT was released by cells in the form of membrane-bound vesicles. gp160deltaCT induced stronger neutralizing responses than the other forms. Use of a helper plasmid for replicon particle packaging, in which the VEE envelope gene comprised a wild-type rather than a host range-adapted sequence, also enhanced immunogenicity. Neutralizing activity fractionated with immunoglobulin G. This activity was cross-reactive among a panel of five nonhomologous primary clade B strains and a Chinese clade C strain and minimally reactive against a Chinese clade E (circulating recombinant form 1) strain. The comparative neutralization of these strains by immune mouse sera was similar to the relative neutralizing effects of HNS2, and responses induced in rabbits were similar to those induced in mice. Together, these results demonstrate that neutralizing antibody responses can be induced in mice within 2 to 3 months that are similar in potency and cross-reactivity to those found in the chronically infected, long-term nonprogressive donor of HNS2. These findings support the expectation that induction of highly cross-reactive HIV-1 primary virus-neutralizing activity by vaccination may be realized.
AIDS Vaccines↗
An alternative anesthetic technique for the morbidly obese patient undergoing endovascular repair of an abdominal aortic aneurysm.
UNLABELLED: Abdominal aortic aneurysms have been treated by open operative repair for many years. A frequent rate of morbidity is associated with the natural history of abdominal aortic aneurysms in combination with open surgical repair. Recently a new technique that is less surgically invasive has been developed as an alternative to open repair. The present case report outlines a less invasive anesthetic technique for the morbidly obese patient. IMPLICATIONS: This case report discusses a minimally invasive anesthetic approach towards the morbidly obese patient undergoing endovascular abdominal aortic aneurysm repair. It demonstrates a safe and cost-effective means of managing a patient with numerous comorbidities. We also discuss an anesthetic/surgical approach on how to provide maximum analgesia with minimal anesthesia.
Adult↗
The effect of nonsense codons on splicing: a genomic analysis.
The phenomenon of nonsense-associated altered splicing raises the possibility that the recognition of in-frame nonsense codons is used generally for exon identification during pre-mRNA splicing. However, nonsense codon frequencies in pseudo exons and in regions flanking 5' splice sites are no greater than that expected by chance, arguing against the widespread use of this strategy as a means of rejecting potential splice sites.
Codon, Nonsense↗
Pharmacokinetics of methylphenidate after oral administration of two modified-release formulations in healthy adults.
OBJECTIVE: To compare the rate and extent of absorption of DL-threo-methylphenidate (MPH) from two modified-release MPH formulations at their respective recommended starting doses in healthy adult volunteers. DESIGN: Open-label, randomised, crossover, bioavailability study. PARTICIPANTS: Twenty healthy adult male and female volunteers. METHODS: Subjects received single doses of two modified-release formulations of MPH, a 20mg capsule (Ritalin) LA) and an 18 mg tablet (Concerta). A total of 19 plasma samples was collected over 24 hours, and MPH plasma concentrations were determined by liquid chromatography-mass spectrometry (LC-MS/MS). These values were used to calculate standard noncompartmental pharmacokinetic parameters describing the rate (peak concentration and time to peak concentration) and extent (area under the concentration-time curve, AUC) of absorption of the two formulations. The relative bioavailability of the two drugs was assessed using a 90% confidence interval, based on the lower and upper endpoints of the confidence interval for the ratios of the geometric means (log transformed) being within the 0.80-1.25 equivalence criterion. RESULTS: Nineteen subjects, ten male and nine female, aged 21-34 years completed both treatment phases of the study. The Ritalin LA formulation displayed a distinctly biphasic pharmacokinetic profile, with mean initial peak plasma concentration of 7 microg/L at an average of 2.1 hours after administration and a second peak of 9.3 microg/L occurring at 5.6 hours. In contrast, the profile of the Concerta formulation rapidly reached an initial plateau concentration of 3.4 microg/L at 3.3 hours after administration and a second mean plateau concentration of 5.9 microg/L approximately 6 hours after administration. Substantially more MPH was absorbed from Ritalin LA than from Concert over the first 4 hours; the respective AUC(4) values were 18.5 and 9.3 microg x h/L (p < 0.001). The overall extent of absorption of MPH was similar between the two formulations. Oral clearance was identical between the two dosage forms. CONCLUSIONS: The Ritalin LA formulation exhibited more rapid initial absorption and reached significantly higher peak plasma concentrations compared with the Concerta formulation, although the oral bioavailability of MPH was similar between the two formulations. The Ritalin LA capsule demonstrated a distinctly bimodal plasma concentration-time profile. MPH plasma concentrations resulting from Concerta reached a peak at 6 hours. These results indicate that the recommended starting dose of the Ritalin LA 20 mg capsule formulation provides more rapid absorption and higher peak plasma concentrations than the recommended 18 mg starting dose of the Concerta formulation.
Administration, Oral↗
Regulation of directionality in bacteriophage lambda site-specific recombination: structure of the Xis protein.
Upon induction of a bacteriophage lambda lysogen, a site-specific recombination reaction excises the phage genome from the chromosome of its bacterial host. A critical regulator of this process is the phage-encoded excisionase (Xis) protein, which functions both as a DNA architectural factor and by cooperatively recruiting integrase to an adjacent binding site specifically required for excision. Here we present the three-dimensional structure of Xis and the results of a structure-based mutagenesis study to define the molecular basis of its function. Xis adopts an unusual "winged"-helix motif that is modeled to interact with the major- and minor-grooves of its binding site through a single alpha-helix and loop structure ("wing"), respectively. The C-terminal tail of Xis, which is required for cooperative binding with integrase, is unstructured in the absence of DNA. We propose that asymmetric bending of DNA by Xis positions its unstructured C-terminal tail for direct contacts with the N-terminal DNA-binding domain of integrase and that an ensuing disordered to ordered transition of the tail may act to stabilize the formation of the tripartite integrase-Xis-DNA complex required for phage excision.
Amino Acid Motifs↗