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PubMed2004

Comparative penetration of moxifloxacin and gatifloxacin in rabbit aqueous humor after topical dosing.

PURPOSE: To evaluate the aqueous penetration of the fourth-generation fluoroquinolones moxifloxacin and gatifloxacin. SETTING: University of Arizona, Tucson, Arizona, USA. METHODS: Forty eyes of 20 New Zealand white rabbits were divided into 2 experimental groups. In Experiment I rabbits (20 eyes), a commercial preparation of topical gatifloxacin 0.3% was administered to 9 eyes and moxifloxacin 0.5% to 9 eyes; 2 eyes served as a control. Eyes were dosed according to a keratitis protocol; ie, every 15 minutes for 4 hours. The aqueous humor was sampled 10 minutes after the last dose. Experiment II rabbits (20 eyes) were dosed according to a cataract prophylaxis protocol; ie, 4 times a day for 10 days. The aqueous humor was sampled 1 hour after the last dose of antibiotic in 12 eyes and 24 hours after the last dose in 8 eyes. High-performance liquid chromatography was used to determine the fluoroquinolone concentration. RESULTS: In the keratitis dosing protocol, the mean concentration of moxifloxacin in the aqueous (n=9) was 11.057 microg/mL (range 7.66 to 18.87 microg/mL), which was significantly higher than the mean concentration of gatifloxacin (n=8) (7.570 microg/mL [range 4.75 to 10.86 microg/mL]) (P=.030). In the cataract prophylaxis dosing protocol, the mean aqueous concentration of moxifloxacin (n=6) was 1.745 microg/mL (range 0.92 to 3.87 mg/mL). The mean concentration of gatifloxacin (n=6) was 1.207 microg/mL (range 0.44 to 2.44 microg/mL). The difference was not statistically significant (P=.359). CONCLUSIONS: Higher mean levels (x1.46) of aqueous penetration were achieved with moxifloxacin than with gatifloxacin in the keratitis-dosing model. There was no statistically significant difference between the 2 drugs in the cataract prophylaxis dosing model. Both antibiotics had aqueous levels in excess of the minimum inhibitory concentration for most pathogenic organisms in both models.

Administration, Topical↗

PubMed2005

Do others really know us better? Predicting migraine activity from self- and other-ratings of negative emotion.

OBJECTIVE: The validity of self-reported negative emotion to predict health status is limited by response biases, introspection limitations, and methodological confounds. The reports of significant others about the patients' negative emotion may circumvent these limitations. This study sought to compare the validity of self- versus other-reported negative emotion as a correlate of migraine headache activity. METHODS: On 89 patients with migraine headache (74 women and 15 men), we correlated self-ratings and significant-other-ratings of patients' negative emotion with patients' report of migraine frequency and severity, which were assessed both cross-sectionally and prospectively, 3 months later. RESULTS: Other-reported negative emotion correlated with migraine activity better than did self-reported negative emotion, both cross-sectionally and prospectively. Patterns were different for women and men, however. Among women, other-reported negative emotion was positively associated with migraine activity. Among men, other-reported negative emotion was inversely associated with migraine frequency and severity. CONCLUSION: The results suggest that it may be valuable to obtain significant-other-ratings when assessing negative emotion in patients and that the genders may differ in how others' ratings are related to the patients' health.

Adolescent↗

PubMed2004

Protection against hypoxic-ischemic injury in transgenic mice overexpressing Kir6.2 channel pore in forebrain.

The role of the K-ATP channel pore-forming subunit Kir6.2 on protection from cerebral hypoxic-ischemic injury was assessed in transgenic mice overexpressing normal Kir6.2 or a dominant negative form (AFA) of this subunit in the forebrain. The resulting mice overexpress either the Kir6.2 or the AFA transgene mainly in the cerebral cortex and hippocampus. The Kir6.2 transgenic mice are resistant to hypoxic-ischemic injury showing a decreased region of cortical damage as compared to the dominant negative AFA and the wild-type mice. Moreover, the overexpression of Kir6.2 allowed an important silencing of the neurons present in forebrain regions thus protecting them from ischemic injury. Interestingly, the phenotype observed in Kir6.2 transgenic mice was observed without increased sulfonylurea binding. Taken together, these results indicate that the transgenic overexpression of Kir6.2 in forebrain significantly protects mice from hypoxic-ischemic injury and neuronal damage seen in stroke.

Action Potentials↗

PubMed2002

Brugian infections in the peritoneal cavities of laboratory mice: kinetics of infection and cellular responses.

Standard, immunocompetent, inbred strains of mice are non-permissive for infection with the human filarial nematode, Brugia malayi or the closely related Brugia pahangi. This non-permissiveness allows one to address the mechanism(s) that might be used by mammalian hosts to eliminate large, multicellular, metazoan, extracellular invertebrate pathogens. We describe here the time course of intraperitoneal Brugian infections in naïve and primed +/+ mice from two commonly used, inbred laboratory strains (C57BL/6J and BALB/cByJ). We believe that this documentation of the course of infection in normal mice will serve as a reference for future studies using mice with gene-targeted immunological deficits or which have been pharmacologically or immunologically manipulated to manifest such deficits. Our data show that even though both strains of mice eliminate the parasite before the onset of patency, there are significant differences in the time course of infection and in the fractions of input larvae that can be recovered at any time after infection. In a secondary infection, the time course of elimination is accelerated. We examined the cells in the peritoneal cavity, the site of infection, by flow microfluorimetry using forward and side scatter properties and cell surface antigen expression using fluorescent antibodies. These studies reveal a complex cellular pattern, predominated by B lymphocytes, macrophages, and eosinophils. The most notable gross morphological findings at necropsy during the phase of elimination of the parasite are nodules of tissue containing larvae, which appear viable in some cases and undergoing various stages of disintegration in others. These nodules, which are histologically granulomas, are primarily composed of macrophages and eosinophils, with few if any lymphocytes. Transmission electron micrographs reveal that eosinophils can penetrate under the cuticles of the larvae and be seen in close approximation with internal structures. These granulomas may represent an important mechanism by which worms are eliminated.

Animals↗

PubMed2006

Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment.

BACKGROUND: Effective countermeasures are urgently needed to prevent and treat infections caused by highly pathogenic and biological threat agents such as Marburg virus (MARV). We aimed to test the efficacy of a replication-competent vaccine based on attenuated recombinant vesicular stomatitis virus (rVSV), as a postexposure treatment for MARV haemorrhagic fever. METHODS: We used a rhesus macaque model of MARV haemorrhagic fever that produced 100% lethality. We administered rVSV vectors expressing the MARV Musoke strain glycoprotein to five macaques 20-30 min after a high-dose lethal injection of homologous MARV. Three animals were MARV-positive controls and received non-specific rVSV vectors. We tested for viraemia, undertook analyses for haematology and serum biochemistry, and measured humoral and cellular immune responses. FINDINGS: All five rhesus monkeys that were treated with the rVSV MARV vectors as a postexposure treatment survived a high-dose lethal challenge of MARV for at least 80 days. None of these five animals developed clinical symptoms consistent with MARV haemorrhagic fever. All the control animals developed fulminant disease and succumbed to the MARV challenge by day 12. MARV disease in the controls was indicated by: high titres of MARV (10(3)-10(5) plaque-forming units per mL); development of leucocytosis with concurrent neutrophilia at end-stage disease; and possible damage to the liver, kidney, and pancreas. INTERPRETATION: Postexposure protection against MARV in non-human primates provides a paradigm for the treatment of MARV haemorrhagic fever. Indeed, these data suggest that rVSV-based filoviral vaccines might not only have potential as preventive vaccines, but also could be equally useful for postexposure treatment of filoviral infections.

Animals↗

PubMed2003

Ventricular adrenomedullin is associated with myocyte hypertrophy in human transplanted heart.

Adrenomedullin (ADM) is a vasoactive and natriuretic peptide. While it is known that ADM is increased in failing human ventricles, the expression of ADM in human ventricular allografts remains unknown. The present study was designed to investigate tissue localization and intensity of ADM expression in ventricular biopsy specimens and to characterize ventricular ADM in human cardiac allografts. Thirty-three post-transplant endomyocardial biopsy specimens were examined immunohistochemically. The average score (range: 0-4) of ADM immunoreactivity (IR) was 2.4+/-0.9 (mean+/-standard deviation). Right ventricular (RV) systolic pressure was significantly increased with high ADM-IR (p=0.048) and the ADM-IR positively associated with myocyte size (r(2)=0.23, p=0.010). In contrast, ADM-IR was not associated with systemic blood pressure, serum creatinine, cyclosporine concentration, cardiac fibrosis, or allograft rejection. The present study shows that ADM-IR is present in human ventricular endomyocardium after transplantation, and ADM-IR is associated with the magnitude of RV pressure and myocyte size, suggesting an important role for ventricular ADM in the counteraction against overload as well as in the progress of myocyte hypertrophy after heart transplantation.

Adolescent↗

PubMed2003

Changes in auditory cortex and the development of mismatch negativity between 2 and 6 months of age.

Evoked responses to stimulus deviance were compared in infants between 2 and 6 months of age. A deviant stimulus containing a short silent gap occasionally replaced a repeating standard stimulus matched in duration, intensity and approximate spectral content. At two months, the standard stimuli evoked only a positive slow wave, and its amplitude was increased in response to the deviant stimuli. By 6 months, the deviant stimuli evoked an increased negativity at approximately 200 ms, similar to the mismatch negativity (MMN) response in adults. The results are considered with respect to layer-specific cortical maturation during this period.

Acoustic Stimulation↗

PubMed2003

Evidence-based treatment for schizophrenia.

Taken together, the research on what treatments help people with schizophrenia point to the value of treatment programs that combine medications with a range of psychosocial services. Provision of such packages of services likely reduces the need for crisis-oriented care hospitalizations and emergency room visits and enables greater recovery. For most people with schizophrenia, the combination of psychopharmacological and psychosocial interventions improves outcomes. Several psychosocial treatments have demonstrated efficacy. These include family intervention, supported employment, assertive community treatment, skills training, and CBT. In the same way that psychopharmacologic management must be tailored individually to the needs and preferences of the patient, so too should the selection of psychosocial treatments. At the very least, all people with schizophrenia should be provided with education about their illness. Beyond illness education, all of the recommended psychosocial interventions would be used rarely during any one phase of illness for an individual. Some psychosocial treatments share treatment components, and patients have different clinical and social needs at different points in their illness course. Knowledge regarding how best to combine treatments to optimize outcomes is scarce.

Antipsychotic Agents↗

PubMedDate not supplied

Lumbar spine listhesis in older African American women.

BACKGROUND CONTEXT: Degenerative changes in the lumbar spine may result in a loss of spinal stability and subluxation of one vertebra relative to another. Cadaveric studies and clinical case series have suggested that listhesis may be much more common in African Americans than in whites. PURPOSE: To determine the prevalence of lumbar spine listhesis (anterolisthesis and retrolisthesis) among African American women aged 65 years and older and the relationship of listhesis to low back pain, physical function and quality of life. STUDY DESIGN/SETTING: Cross-sectional study. PATIENT SAMPLE: A total of 481 African American women aged 65 years and older who were enrolled in the Study of Osteoporotic Fractures. These women were recruited from population-based listings in Baltimore, MD, Minneapolis, MN, Pittsburgh, PA, and Portland, OR. OUTCOME MEASURES: Not applicable. METHODS: Lateral radiographs of the lumbar spine were digitized, and listhesis (anterolisthesis and retrolisthesis) was assessed at spinal levels L3-L4, L4-L5 and L5-S1. Usable data were obtained for 470 women. Listhesis was defined as present when the subluxation (antero or retro) was 3 mm or more. RESULTS: The overall prevalence of anterolisthesis was 58.3% and varied by spinal level (13.2% at L3-L4, 36.5% at L4-L5 and 29.6% at L5-S1). The prevalence increased with age but was lower among oophorectomized women and those currently on estrogen replacement therapy. Anterolisthesis was not associated (p>.05) with disc height nor was it related to back function. Retrolisthesis occurred in 4% of women and was associated with decreased disc height and an increased prevalence of spinal problems and walking problems. CONCLUSIONS: The prevalence of anterolisthesis among older African American women living in the community was two to three times greater than that found in white women of a similar age. This condition was not related to an increased frequency of back problems nor did it adversely affect general physical function. Retrolisthesis was relatively rare but was associated with decreased back function.

Black or African American↗

PubMed2006

Social networks and inflammatory markers in the Framingham Heart Study.

Lack of social integration predicts coronary heart disease mortality in prospective studies; however, the biological pathways that may be responsible are poorly understood. The specific aims of this study were to examine whether social networks are associated with serum concentrations of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1). Participants in the Framingham Study attending examinations from 1998 to 2001 (n=3267) were eligible for inclusion in the study. Social networks were assessed using the Berkman-Syme Social Network Index (SNI). Concentrations of IL-6, CRP, sICAM-1 and MCP-1 were measured in fasting serum samples. Multivariable linear regression analyses were used to assess the association of social networks with inflammatory markers adjusting for potential confounders including age, smoking, blood pressure, total:HDL cholesterol ratio, body mass index, lipid-lowering and antihypertensive medication, diabetes, cardiovascular disease, depression and socioeconomic status. Results found that the SNI was significantly inversely associated with IL-6 in men (p=0.03) after adjusting for potential confounders. In age-adjusted analyses, social networks also were significantly inversely associated with IL-6 for women (p=0.03) and were marginally to modestly associated with CRP and sICAM-1 for men (p=0.08 and 0.02, respectively), but these associations were not significant in the multivariate analyses. In conclusion, social networks were found to be inversely associated with interleukin-6 levels in men. The possibility that inflammatory markers may be potential mediators between social integration and coronary heart disease merits further investigation.

Biomarkers↗

PubMed2002

Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662.

In the course of a high throughput screen to search for ligands of peroxisome proliferator activated receptor-gamma (PPARgamma), we identified GW9662 using a competition binding assay against the human ligand binding domain. GW9662 had nanomolar IC(50) versus PPARgamma and was 10- and 600-fold less potent in binding experiments using PPARalpha and PPARdelta, respectively. Pretreatment of all three PPARs with GW9662 resulted in the irreversible loss of ligand binding as assessed by scintillation proximity assay. Incubation of PPAR with GW9662 resulted in a change in the absorbance spectra of the receptors consistent with covalent modification. Mass spectrometric analysis of the PPARgamma ligand binding domain treated with GW9662 established Cys(285) as the site of covalent modification. This cysteine is conserved among all three PPARs. In cell-based reporter assays, GW9662 was a potent and selective antagonist of full-length PPARgamma. The functional activity of GW9662 as an antagonist of PPARgamma was confirmed in an assay of adipocyte differentiation. GW9662 showed essentially no effect on transcription when tested using both full-length PPARdelta and PPARalpha. Time-resolved fluorescence assays of ligand-modulated receptor heterodimerization, coactivator binding, and corepressor binding were consistent with the effects observed in the reporter gene assays. Control activators increased PPAR:RXR heterodimer formation and coactivator binding to both PPARgamma and PPARdelta. Corepressor binding was decreased. In the case of PPARalpha, GW9662 treatment did not significantly increase heterodimerization and coactivator binding or decrease corepressor binding. The experimental data indicate that GW9662 modification of each of the three PPARs results in different functional consequences. The selective and irreversible nature of GW9662 treatment, and the observation that activity is maintained in cell culture experiments, suggests that this compound may be a useful tool for elucidation of the role of PPARgamma in biological processes.

Adipocytes↗

PubMed2002

Mononuclear nitrogen/sulfur-ligated zinc methoxide and hydroxide complexes: investigating ligand effects on the hydrolytic stability of zinc alkoxide species.

The synthesis and properties of mononuclear zinc methoxide ([(ebnpa)Zn-OCH3]ClO4) (1) and hydroxide ([(ebnpa)Zn-OH]ClO4) (2) complexes of a new mixed nitrogen/sulfur ligand (ebnpa = N-2-(ethylthio)ethyl-N,N-bis(6-neopentylamino-2-pyridylmethyl)amine) are reported. The structures of 1 and 2 were determined by X-ray diffraction. Each possesses a single zinc-coordinated anion (methoxide or hydroxide) and exhibits an overall trigonal bipyramidal geometry. Structural and spectroscopic studies indicate the presence of two hydrogen-bonding interactions involving the oxygen atom of the zinc-bound anion in each complex. Treatment of [(ebnpa)Zn-OH]ClO4 with CH3OH results in the formation of an equilibrium mixture of 1 and 2. 1H NMR spectroscopic methods were used to examine the equilibrium as a function of temperature, yielding KMe (304 K) = 0.30(8), DeltaHMe = -0.9(1) kcal/mol, and DeltaSMe = -5(1) eu. The negative enthalpy indicates that spontaneous zinc alkoxide formation from a hydroxide precursor occurs in this system at low temperature. Using the experimentally determined DeltaHMe value, we found the homolytic Zn-O bond dissociation energy (BDE) in the Zn-OCH3 unit to be approximately -14 kcal/mol relative to the Zn-O BDE in the Zn-OH unit.

Alcohol Dehydrogenase↗

PubMed2002

Parallel synthesis of potent, pyrazole-based inhibitors of Helicobacter pylori dihydroorotate dehydrogenase.

The identification of several potent pyrazole-based inhibitors of bacterial dihydroorotate dehydrogenase (DHODase) via a directed parallel synthetic approach is described below. The initial pyrazole-containing lead compounds were optimized for potency against Helicobacter pylori DHODase. Using three successive focused libraries, inhibitors were rapidly identified with the following characteristics: K(i) < 10 nM against H. pylori DHODase, sub-microg/mL H. pylori minimum inhibitory concentration activity, low molecular weight, and >10 000-fold selectivity over human DHODase.

Combinatorial Chemistry Techniques↗

PubMed2003

Impact of a primary care quality improvement intervention on use of psychotherapy for depression.

We examine the impact of the two Partners in Care (PIC) primary care quality improvement (QI) interventions on counseling services. The QI interventions aimed to increase service use, and thereby improve outcomes, and have been shown to indeed improve patient outcomes (e.g., K. B. Wells et al., 2000). But whether or not use of counseling services actually increased has not yet been examined. The QI interventions contained many overlapping elements; however, QI-Therapy emphasized cognitive-behavioral therapy, and QI-Meds emphasized medications and case management. QI-Therapy patients used more counseling than UC patients at 6 months, though increases were modest. Some treatment effects persisted until 12 months, but not beyond. QI-Therapy and QI-Meds patients reported more treatment overall (therapy or medication) than UC patients at 6 months, and this effect persisted in the QI-Meds clinics until 12 months. Treatment effects were more pronounced among those most in need. Despite high rates of referral to psychotherapy within the QI-Therapy clinics (81%), only a minority of patients actually attended a psychotherapy session within the study (30%). We discuss the uptake of therapy in this study as a way to inform future efforts at QI.

Adult↗

PubMed2003

Toward targeted oral vaccine delivery systems: selection of lectin mimetics from combinatorial libraries.

PURPOSE: Various lectins bind specifically to oligosaccharides on intestinal cells. Exploiting this specificity, Ulex europaeus agglutinin I (UEA1) has been used as a ligand for targeted oral vaccine delivery to M cells (antigen-presenting cells) in follicle-associated epithelium. In this study we characterized compounds identified from mixture-based positional scanning synthetic combinatorial libraries, which mimic UEA1 and, thus, may have properties applicable to targeted drug delivery. METHODS: Two UEA1 mimetics were synthesized and their activity was verified on live cells. The ability of the lead compound, a tetragalloyl D-Lysine amide construct (4-copy gallic acid construct), to deliver dye-loaded polystyrene particles to M cells was assessed in an in situ mouse gut loop model. RESULTS: The 4-copy gallic acid construct inhibited UEA1 binding to Caco-2 cell membranes with an IC50 of 3 microM, a 650- to 5000-fold increase over the natural UEA1 substrate alpha-L-fucose. The biotin-labeled derivative of this construct demonstrated comparable binding activity as verified on live cells by fluorescence-activated cell sorting. Preclinical studies confirmed its ability to mediate M cell-specific delivery of streptavidin-coated particles in vivo. CONCLUSIONS: Polyphenolic compounds, D-Lysine scaffolds with multiple galloyl groups, can mimic functional activities of UEA1. Properties of such molecules, including low molecular weight, stability, ease of synthesis and low cost, highlight their potential for application in targeted vaccine delivery.

Administration, Oral↗

PubMed2002

Understanding team-based quality improvement for depression in primary care.

OBJECTIVE: To assess the impacts of the characteristics of quality improvement (QI) teams and their environments on team success in designing and implementing high quality, enduring depression care improvement programs in primary care (PC) practices. STUDY SETTING/DATA SOURCES: Two nonprofit managed care organizations sponsored five QI teams tasked with improving care for depression in large PC practices. Data on characteristics of the teams and their environments is from observer process notes, national expert ratings, administrative data, and interviews. STUDY DESIGN: Comparative formative evaluation of the quality and duration of implementation of the depression improvement programs developed by Central Teams (CTs) emphasizing expert design and Local Teams (LTs) emphasizing participatory local clinician design, and of the effects of additional team and environmental factors on each type of team. Both types of teams depended upon local clinicians for implementation. PRINCIPAL FINDINGS: The CT intervention program designs were more evidence-based than those of LTs. Expert team leadership, support from local practice management, and support from local mental health specialists strongly influenced the development of successful team programs. The CTs and LTs were equally successful when these conditions could be met, but CTs were more successful than LTs in less supportive environments. CONCLUSIONS: The LT approach to QI for depression requires high local support and expertise from primary care and mental health clinicians. The CT approach is more likely to succeed than the LT approach when local practice conditions are not optimal.

Aged↗

PubMed2004

Ethnic differences in battered women's formal help-seeking strategies: a focus on health, mental health, and spirituality.

The primary goal of this study was to identify ethnic differences in battered women's use of health, mental health, and spiritual coping strategies, as well as differences in the perceived helpfulness of each strategy. The authors recruited a sample of 376 African American and Caucasian victims of interpersonal violence from various sites. In comparison with Caucasian women in the sample, African American women were significantly more likely to report using prayer as a coping strategy and significantly less likely to seek help from mental health counselors. The 2 groups did not significantly differ in terms of the extent to which they sought help from clergy or medical professionals. African American women found prayer to be more helpful than did Caucasian women.

Adaptation, Psychological↗

PubMed2004

A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms.

We describe a genetic variation map for the chicken genome containing 2.8 million single-nucleotide polymorphisms (SNPs). This map is based on a comparison of the sequences of three domestic chicken breeds (a broiler, a layer and a Chinese silkie) with that of their wild ancestor, red jungle fowl. Subsequent experiments indicate that at least 90% of the variant sites are true SNPs, and at least 70% are common SNPs that segregate in many domestic breeds. Mean nucleotide diversity is about five SNPs per kilobase for almost every possible comparison between red jungle fowl and domestic lines, between two different domestic lines, and within domestic lines--in contrast to the notion that domestic animals are highly inbred relative to their wild ancestors. In fact, most of the SNPs originated before domestication, and there is little evidence of selective sweeps for adaptive alleles on length scales greater than 100 kilobases.

Alleles↗