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Biomedical subjects

J L Miller

Publications and source records attributed to J L Miller.

At least 19 recordsLinked to original sources
PubMed2006

Sex differences in prenatal oral-motor function and development.

The aim of this study was to investigate sex-related differences in the prenatal development of early oral, lingual, pharyngeal, and laryngeal motor activities. Sonographic images of oral-upper airway regions were observed in 85 healthy fetuses (43 males, 42 females; mean gestational age 24wks 3d [SD 0.69]; range 15-38wks). Biometric data on morphologic development and associated motor patterns were compared across second and third trimesters. Results showed that while males and females demonstrated statistically similar patterns of general physical growth (p>0.05), significant differences in development of specific lingual and pharyngeal structures were present (p<0.05). Significant differences were found for laryngeal and pharyngeal motor activity, and oral-lingual movements (p<0.05). Complex oral-motor and upper airway skills emerged earlier in females, suggesting a sex-specific trajectory of motor development. It was concluded that differential patterns of prenatal motor development may be important in defining sex-specific indices of oral skill maturation.

Female↗
PubMed2005

Identification and characterization of an SKN7 homologue in Cryptococcus neoformans.

Cryptococcus neoformans is an encapsulated fungal pathogen that primarily infects the central nervous system of immunocompromised individuals, causing life-threatening meningoencephalitis. The capacity of C. neoformans to subvert host defenses and disseminate by intracellular parasitism of alveolar macrophages in the immune-compromised host has led to studies to evaluate genes associated with C. neoformans resistance to oxidative stress. In the present study, we identify and characterize a C. neoformans homologue to SKN7, a transcription factor in Saccharomyces cerevisiae that regulates the oxidative stress response, cell cycle, and cell wall biosynthesis. To examine the contribution of SKN7 in the pathogenesis of fungal infections, we created skn7 mutants via targeted disruption. The skn7 mutants were observed to be more susceptible to reactive oxygen species in vitro and were significantly less virulent than the wild-type strain and a reconstituted strain as measured by cumulative survival in the mouse inhalational model. The Skn7 protein was observed to be important for expression of thioredoxin reductase in response to oxidative challenge. Interestingly, skn7 mutants were also observed to flocculate following in vitro culture, a novel phenotype not observed in skn7 mutants derived from other fungi. These findings demonstrate that SKN7 contributes to the virulence composite but is not required for pathogenicity in C. neoformans. In addition, flocculation of C. neoformans skn7 mutants suggests a potentially unique function of SKN7 not previously observed in other cryptococcal strains or skn7 mutants.

Animals↗
PubMed2005

Individual and combined effects of peroxisome proliferator-activated receptor and {gamma} agonists, fenofibrate and rosiglitazone, on biomarkers of lipid and glucose metabolism in healthy nondiabetic volunteers.

This open-label, randomized, placebo-controlled, incomplete-block, 3-period crossover pilot study investigated the effects of peroxisome proliferator-activated receptor alpha- and gamma-agonists on biomarkers of lipid and glucose metabolism in 12 nondiabetic subjects. Plasma samples were collected before and after each 14-day treatment with placebo, fenofibrate (201 mg/d), rosiglitazone (4 mg twice daily), and combined fenofibrate (201 mg/d) plus rosiglitazone (4 mg twice daily). Except for triglycerides (P < .042) and free fatty acids (P < .074), no significant interaction was demonstrated between fenofibrate and rosiglitazone; thus, the effect due to each drug alone was evaluated (presence/absence of drug). Fenofibrate significantly (P < .050) increased lipoprotein lipase activity (35%) and decreased apolipoproteins B (13%) and C-III (20%). Rosiglitazone significantly (P < .050) decreased fasting glucose (7.3%) and increased apolipoprotein C-III (19%) and adiponectin (137%). Fenofibrate and rosiglitazone also produced effects on triglycerides and free fatty acids, but it was not possible to determine if these effects were synergistic in nature.

Adolescent↗
PubMed2004

193-nm photodissociation of acryloyl chloride to probe the unimolecular dissociation of CH2CHCO radicals and CH2CCO.

The work presented here uses photofragment translational spectroscopy to investigate the primary and secondary dissociation channels of acryloyl chloride (CH2==CHCOCl) excited at 193 nm. Three primary channels were observed. Two C-Cl fission channels occur, one producing fragments with high kinetic recoil energies and the other producing fragments with low translational energies. These channels produced nascent CH2CHCO radicals with internal energies ranging from 23 to 66 kcal/mol for the high-translational-energy channel and from 50 to 68 kcal/mol for the low-translational-energy channel. We found that all nascent CH2CHCO radicals were unstable to CH2CH + CO formation, in agreement with the G3//B3LYP barrier height of 22.4 kcal/mol to within experimental and computational uncertainties. The third primary channel is HCl elimination. All of the nascent CH2CCO coproducts were found to have enough internal energy to dissociate, producing CH2C: + CO, in qualitative agreement with the G3//B3LYP barrier of 39.5 kcal/mol. We derive from the experimental results an upper limit of 23 +/- 3 kcal/mol for the zero-point-corrected barrier to the unimolecular dissociation of the CH2CHCO radical to form CH2CH + CO.

Journal Article↗
PubMed2004

Irrigation runoff insecticide pollution of rivers in the Imperial Valley, California (USA).

The Alamo and New Rivers located in the Imperial Valley, California receive large volumes of irrigation runoff and discharge into the ecologically sensitive Salton Sea. Between 1993 and 2002 we conducted a series of studies to assess water quality using three aquatic species: a cladoceran (Ceriodaphnia dubia), a mysid (Neomysis mercedis), and a larval fish (Pimephales promelas). Although no mortality was observed with the P. promelas, high-level toxicity to the invertebrate species was documented in samples from both rivers during many months of each year. Toxicity identifications and chemical analyses identified the organophosphorus insecticides (OP), chlorpyrifos and diazinon, as the cause of C. dubia toxicity. The extent of the C. dubia mortality was highly correlated with quantities of these OPs applied in the river watersheds. C. dubia mortality occurred during more months of our 2001/2002 study than in the 1990s investigations. During 2001/2002, the extensive C. dubia mortality observed in New River samples was caused by OP insecticide pollution that originated from Mexico. Mortality to N. mercedis in New River samples was likely caused by contaminants other than OP insecticides. Our studies document OP insecticide-caused pollution of the Alamo River over a 10-year period and provide the necessary information for remediation efforts.

Agriculture↗
PubMed2004

In vitro and in vivo efficacies of the new triazole albaconazole against Cryptococcus neoformans.

The activity of albaconazole (UR-9825; J. Uriach & Cía. S.A., Barcelona, Spain) was compared to that of fluconazole against 12 isolates of Cryptococcus neoformans in vitro and against 1 isolate in vivo in a rabbit model of cryptococcal meningitis. Albaconazole was 100-fold more potent in vitro than fluconazole on a per-weight basis and was fungicidal at potentially relevant concentrations for two isolates. MICs ranged from </=0.0012 to 1.25 micro g/ml, with the MICs for most isolates being between 0.039 and 0.156 micro g/ml. Isolates were from human immunodeficiency virus (HIV)-infected and non-HIV-infected patients and were of serotypes A, B, and C; and the fluconazole MICs for some of the isolates were elevated. Infected rabbits were treated with either fluconazole or albaconazole at dosages ranging from 5 to 80 mg/kg of body weight/day. The peak concentrations of albaconazole in serum and cerebrospinal fluid (CSF) averaged 4.14 and 0.62 micro g/ml, respectively, in animals receiving 80 mg/kg/day. Comparison of the concentrations in serum and CSF suggested a level of CSF penetration of approximately 15%. Despite limited penetration into the subarachnoid space, at all three doses tested albaconazole was as effective as fluconazole for the treatment of cryptococcal meningitis in rabbits.

Animals↗
PubMed2003

Pegylation of charged polymer-photosensitiser conjugates: effects on photodynamic efficacy.

Conjugates between photosensitisers (PS) and charged polymeric carriers are under investigation for photodynamic therapy of cancer and may allow targeting to certain cell types or compartments in tumours. Covalent attachment of polyethylene glycol to macromolecules (pegylation) may alter their pharmacokinetics, cell type targeting, and photophysical properties. Macrophages may take up large amounts of aggregated PS, thus lessening the selectivity for cancer cells in tumours. We investigated the effect of pegylation on the uptake and phototoxicity of poly-L-lysine chlorin(e6) conjugates with either cationic or anionic charges in two cell lines, human ovarian cancer cells and mouse macrophages. The cationic conjugate after pegylation became less aggregated, consumed less oxygen and had reduced cellular uptake. However, the phototoxicity corrected for cellular uptake increased three- to five-fold. In contrast, the anionic succinylated conjugate on pegylation became more aggregated, consumed similar amounts of oxygen, and had higher cellular uptake. The anionic conjugate showed the highest relative phototoxicity towards both the cell lines (compared to the other three conjugates) and it decreased most towards the macrophages after pegylation. Pegylation reduced the amount of oxygen consumed per chlorin(e6) molecule when photosensitised cells were illuminated. These in vitro studies suggest that pegylation alters the phototoxicity of PS conjugates depending on the effect produced on the aggregation state.

Animals↗
PubMed2002

Long-term results of the FemSoft urethral insert for the management of female stress urinary incontinence.

A 5-year ongoing, controlled multicenter study enrolled 150 women. Outcome measures included pad weight tests (PWT), voiding diary (VD), quality of life (QOL) and satisfaction questionnaires. Outcome measures during the baseline period were compared to evaluations during follow-up. Concurrent evaluations with and without device use were also performed. Safety evaluations included urinalysis and culture, leak-point pressure (LPP) and cystoscopy. Adverse events (AE) were recorded throughout the study. One to 2 years of follow-up were collected on all study participants (mean 15 months). Statistically significant reductions in overall daily incontinence episodes (P<0.001) and PWT urine loss (P<0.001) were observed with the device at all follow-up intervals, and 93% of women had a negative PWT at 12 months. Women were satisfied with ease of use of the device, comfort and dryness, and significant improvements in QOL were observed (P<0.001). Subgroup analysis revealed that the insert was effective, despite the presence of urgency, low LPP, failed surgery and advanced age. AE included symptomatic urinary tract infection in 31.3%, mild trauma with insertion in 6.7%, hematuria in 3.3%, and migration in 1.3% of women. The results of PWT and VD demonstrated device efficacy. Women were satisfied and significant improvements in QOL were observed. AE were transient and required minimal or no treatment. The urethral insert should be considered as an option for the management of SUI.

Equipment Design↗
PubMed2001

Pegylation of a chlorin(e6) polymer conjugate increases tumor targeting of photosensitizer.

Photodynamic therapy is emerging as a viable modality for the treatment of many cancers. A limiting factor in its use against intracavity tumors such as disseminated ovarian cancer is insufficient selectivity of the photosensitizer for tumor compared with normal tissue. We report on an approach to improve tumor targeting by exploiting differences between cell types and by chemical modification of a photosensitizer conjugate. Attachment of polyethylene glycol (pegylation) to a polyacetylated conjugate between poly-l-lysine and chlorin(e6) increased the relative phototoxicity in vitro toward an ovarian cancer cell line (OVCAR-5) while reducing it toward a macrophage cell line (J774), compared with the nonpegylated conjugate. Surprisingly, the increased phototoxicity of the pegylated conjugate correlated with reduced oxygen consumption. Pegylation also reduced the tendency of the conjugate to aggregate and reduced the consumption of oxygen when the conjugates were illuminated in solution in serum containing medium, suggesting a switch in photochemical mechanism from type II (singlet oxygen) to type I (radicals or electron transfer). Pegylation led to more mitochondrial localization as shown by confocal fluorescence microscopy in OVCAR-5 cells, and, on illumination, produced a switch in cell death mechanism toward apoptosis not seen with J774 cells. Conjugates were injected i.p. into nude mice bearing i.p. OVCAR-5 tumors, and the pegylated conjugate gave higher amounts of photosensitizer in tumor and higher tumor:normal tissue ratios and increased the depth to which the chlorin(e6) penetrated into the peritoneal wall. Taken together, these results suggest that pegylation of a polymer-photosensitizer conjugate improves tumor-targeting and may increase the efficacy of photodynamic therapy for ovarian cancer.

Animals↗
PubMed2001

Transcription patterning of uncoupled proliferation and differentiation in myelodysplastic bone marrow with erythroid-focused arrays.

Because abnormal erythroid differentiation is the most common manifestation of the myelodysplastic syndromes (MDS), it was hypothesized that erythroid gene expression may be used to illustrate myelodysplastic transcription patterns. Ten normal bone marrow aspirates (NBM) were first analyzed using an erythroid-focused cDNA array to define steady-state transcription levels. Proliferation and differentiation gene subsets were identified by statistically significant differences between NBM and erythroleukemia gene expression. Next, cDNAs from 5 separate MDS aspirates were studied: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation (RAEB-T), and RAEB-T/secondary MDS. A distinct pattern of significantly increased proliferation-associated and reduced differentiation-associated gene activity was established for MDS.

Aged↗
PubMed2001

Characterization of viable autofluorescent macrophages among cultured peripheral blood mononuclear cells.

BACKGROUND: Inflammatory macrophages that demonstrate intense autofluorescence have been isolated directly from alveolar and peritoneal tissues, but their generation in vitro remains vague. We use flow cytometry to identify a population of autofluorescent macrophages as they arise among nonadherent populations of cultured blood mononuclear cells. METHODS: Cells were obtained from donated blood buffy coats and placed in culture for 14 days. Unstained populations from the cells remaining in suspension were sampled daily using flow cytometry. During the first 5 culture days, a distinct population of autofluorescent cells arose and comprised an average of < or =14% of the total cell population. This population declined to less than 6% by culture day 8. RESULTS: The cells were identified as viable macrophages expressing CD68, lysozyme, and HLA-DR. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) demonstrated a unique cytokine profile with IL-1 alpha expression levels 138-fold higher than those measured in uncultured monocytes. No significant elevation in the levels of other cytokines was identified. Upon replating, the sorted populations became readherent, were able to ingest plastic beads, and remained viable for 6 or more additional weeks in culture without evidence of proliferation or multinucleation. CONCLUSION: Viable autofluorescent macrophage populations arising among cultured peripheral blood may be easily identified and isolated for further study using flow cytometry. Cytometry 44:38-44, 2001. Published 2001 Wiley-Liss, Inc.

Cell Differentiation↗
PubMed2001

Human erythroid porphobilinogen deaminase exists in 2 splice variants.

Human porphobilinogen deaminase (PBGD) is, reportedly, encoded by 2 distinct messenger RNAs (mRNAs) transcribing from a single gene. The ubiquitous form of the PBGD gene product is often used as an endogenous reference in gene expression studies because it is pseudogene free and has minimal transcriptional variability among tissues. A distinct erythroid-specific gene product has also been described because of the alternate splicing of the gene. Here is reported the existence of an additional erythroid-specific isoform of PBGD mRNA in primary cells.

Alternative Splicing↗
PubMed2001

A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins.

BACKGROUND: Experimental evidence from rodent models indicates that blood can contain transmissible spongiform encephalopathy (TSE) infectivity, which suggests a potential risk for TSE transmission via proteins isolated from human plasma. Because methods that can reduce TSE infectivity typically are detrimental to protein function, infectivity must be removed to ensure the safety of these therapeutic proteins. Animal bioassays are conventionally used to detect infectivity, but the pathogenic form of the prion protein (PrP(Sc)) can serve as a marker for TSE infectivity. STUDY DESIGN AND METHODS: Seven plasma protein-purification steps were performed after the plasma intermediates were spiked with TSE-infected material. Resulting fractions were analyzed for PrP(Sc) by using a Western blot assay and for TSE infectivity by using an animal bioassay. Western blots were quantitated by an endpoint dilution analysis, and infectivity titers were calculated by the Spearman-Kärber method. RESULTS: PrP(Sc) partitioning paralleled TSE infectivity partitioning, regardless of the nature of the protein-purification step. The detection ranges for PrP(Sc) and infectivity were 0 to 5.3 log and 1.1 to 8.9 log median infectious dose per unit, respectively. Clearance of PrP(Sc) and infectivity ranged from 1.0 to 6.0 log. CONCLUSION: Purification steps for isolating therapeutic proteins from human plasma showed the removal of both PrP(Sc) and TSE infectivity. PrP(Sc) partitioning coincided with infectivity partitioning, which showed a close relationship between PrP(Sc) and TSE infectivity. By exploiting this association, the in vitro Western blot assay for PrP(Sc) was valuable for estimating the partitioning of TSE infectivity during plasma protein purification.

Animals↗
PubMed2001

DNA analysis for the Dombrock polymorphism.

BACKGROUND: RBC typing for Do(a) and Do(b) is notoriously difficult, and inaccurate typing can predispose patients to hemolytic transfusion reactions. The DO1/DO2 polymorphism is associated with three nucleotide changes: 378 C>T, 624 T>C and 793 A>G. While the 378 C>T- and 624 T>C-containing codons are silent mutations, the 793 A>G polymorphism in codon 265 encodes asparagine for Do(a) and aspartic acid for Do(b). STUDY DESIGN AND METHODS: Described here are two PCR-RFLP assays, one using the Mnl I site associated with 624C (DO2) and the other altering two nucleotides within the sense primer, which allows recognition of 793G by the Eam 1105 I. RESULTS: The assays have been performed on over 100 samples for which the RBC typing of one or both antigens was known. Eight samples had been historically mistyped by hemagglutination. CONCLUSION: This RFLP assay provides a practical method for typing donor blood for Dombrock alleles.

Base Sequence↗
PubMed2001

Molecular basis of the Dombrock null phenotype.

BACKGROUND: The Dombrock blood group system consists of two antithetical antigens, Do(a) and Do(b), and three high-incidence antigens, Gregory (Gy(a)), Holley (Hy), and Joseph (Jo(a)). The null phenotype of the Dombrock blood group system (Do(null)) was identified when it was found that Gy(a-) RBCs also lack Do(a), Do(b), Hy, and Jo(a). STUDY DESIGN AND METHODS: DNA from three Gy(a-) persons was analyzed. PCR products for each of the three DO exons and their flanking intronic regions were sequenced in both directions. The cDNA from two of the people was subjected to PCR using primers in exon 1 and exon 3, and the products were sequenced. RESULTS: The Do(null) phenotype is associated with a single nucleotide mutation in the acceptor splice site of DO (IVS1-2a>g), which results in outsplicing of exon 2. CONCLUSION: Outsplicing of exon 2 is predicted to cause a -1 frameshift and a premature stop codon. Any product of such a transcript would lack the glycosyl-phosphatidylinositol-anchor motif, and RBCs would be devoid of the Do glycoprotein.

Amino Acid Sequence↗
PubMed2001

Ensuring the pathogen safety of intravenous immunoglobulin and other human plasma-derived therapeutic proteins.

Countless patients and clinicians rely on therapeutic proteins, such as intravenous immunoglobulins (IVIGs), isolated from human blood plasma. Since plasma is predisposed to contamination by a variety of blood-borne pathogens, ascertaining and ensuring the pathogen safety of plasma-derived therapeutics is a priority among manufacturers. Even though the pathogen safety records for IVIG and other plasma proteins are excellent, the industry remains active in research programs aimed at improving the margin of safety. Industry initiatives designed to increase the safety of plasma-derived products range from donor screening and testing to implementing methods into the manufacturing processes that can inactivate or remove pathogens from product streams. In general, the industry's comprehensive strategy is designed to provide patients and caregivers with the safest plasma products possible.

Bacteria↗
PubMed2001

Metastatic paraganglionoma presenting as a scalp nodule.

Malignant neoplasms with neural differentiation uncommonly present as cutaneous masses. However, a rapidly growing skin lesion in patients with a past history of retroperitoneal soft tissue tumors suggests that dissemination of that lesion may be taking place.

Adult↗