Biomedical subjects
Publications and source records attributed to S R Miller.
A scandium terephthalate with isolated ScO6 octahedra and fully-linked carboxylate groups is prepared hydrothermally and possesses a novel hybrid framework structure with high thermal stability and a pore volume for N2 adsorption of 0.26 cm(3) g(-1) at 77 K.
The creation of a mathematical simulation model of photosynthetic microbial mats is important to our understanding of key biogeochemical cycles that may have altered the atmospheres and lithospheres of early Earth. A model is presented here as a tool to integrate empirical results from research on hypersaline mats from Baja California Sur (BCS), Mexico into a computational system that can be used to simulate biospheric inputs of trace gases to the atmosphere. The first version of our model, presented here, calculates fluxes and cycling of O(2), sulfide, and dissolved inorganic carbon (DIC) via abiotic components and via four major microbial guilds: cyanobacteria (CYA), sulfate reducing bacteria (SRB), purple sulfur bacteria (PSB) and colorless sulfur bacteria (CSB). We used generalized Monod-type equations that incorporate substrate and energy limits upon maximum rates of metabolic processes such as photosynthesis and sulfate reduction. We ran a simulation using temperature and irradiance inputs from data collected from a microbial mat in Guerrero Negro in BCS (Mexico). Model O(2), sulfide, and DIC concentration profiles and fluxes compared well with data collected in the field mats. There were some model-predicted features of biogeochemical cycling not observed in our actual measurements. For instance, large influxes and effluxes of DIC across the MBGC mat boundary may reveal previously unrecognized, but real, in situ limits on rates of biogeochemical processes. Some of the short-term variation in field-collected mat O(2) was not predicted by MBGC. This suggests a need both for more model sensitivity to small environmental fluctuations for the incorporation of a photorespiration function into the model.
BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.
Determining the molecular basis of enzyme adaptation is central to understanding the evolution of environmental tolerance but is complicated by the fact that not all amino acid differences between ecologically divergent taxa are adaptive. Analysing patterns of nucleotide sequence evolution can potentially guide the investigation of protein adaptation by identifying candidate codon sites on which diversifying selection has been operating. Here, I test whether there is evidence for molecular adaptation of the carbon fixation gene rbcL for a clade of hot spring cyanobacteria in the genus Synechococcus that has diverged in thermotolerance. Amino acid replacements during Synechococcus radiation have resulted in an increase in the number of hydrophobic residues in the RbcLs of more thermotolerant strains. A similar increase in hydrophobicity has been observed for many thermostable proteins. Maximum likelihood models which allow for heterogeneity among codon sites in the ratio of nonsynonymous to synonymous nucleotide substitutions estimated a class of amino acid sites as a target of positive selection. Depending on the model, a single amino acid site that interacts with a flexible element involved in the opening and closing of the active site was estimated with either low or moderate support to be a member of this class. Site-directed mutagenesis approaches are being explored in order to directly test its adaptive significance.
A large sample of undergraduates (N = 2,326) were screened for general health. The screen discretely included items assessing postconcussion symptomatology and neurologic history. A subsample of experiment-blind participants whose self-reported postconcussion symptom levels were >0.5 SD below the screening sample mean (low symptomatic; n = 45) or >0.5 SD above the screening sample mean (high symptomatic; n = 53) were re-evaluated for postconcussion symptomatology 3 to 90 days later. The sample included 50 participants who reported history of mild head injury (MHI) and 48 controls. MHI was defined as loss of consciousness of < or =20 minutes within the past 10 years, but no more recent than 3 months. Persons with history of >1 head injury or with other neurologic history were not included in the study. The stability of postconcussion symptoms differed by high symptomatic versus low symptomatic presentation (high symptomatic presentation was more variable) and by gender (females were more variable), but not by actual history of MHI. Sex differences in self-reported postconcussion symptomatology are consistent with gender-related differences in reporting of other physical and psychological symptoms. In addition to demonstrating differences in the stability of self-reported postconcussion symptomatology, the current study provides normative test-retest data for the Postconcussion Symptom Checklist for extreme responders by gender and MHI status.
Synechococcus sp. strain SH-94-5 is a nitrate assimilation-deficient cyanobacterium which was isolated from an ammonium-replete hot spring in central Oregon. While this clone could grow on ammonium and some forms of organic nitrogen as sole nitrogen sources, it could not grow on either nitrate or nitrite, even under conditions favoring passive diffusion. It was determined that this clone does not express functional nitrate reductase or nitrite reductase and that the lack of activity of either enzyme is not due to inactivation of the cyanobacterial nitrogen control protein NtcA. A few other naturally occurring cyanobacterial strains are also nitrate assimilation deficient, and phylogenetic analyses indicated that the ability to utilize nitrate has been independently lost at least four times during the evolutionary history of the cyanobacteria. This phenotype is associated with the presence of environmental ammonium, a negative regulator of nitrate assimilation gene expression, which may indicate that natural selection to maintain functional copies of nitrate assimilation genes has been relaxed in these habitats. These results suggest how the evolutionary fates of conditionally expressed genes might differ between environments and thereby effect ecological divergence and biogeographical structure in the microbial world.
Solitary fractures of the cuboid are rare. Proper diagnosis and treatment of subtle cuboid fractures are essential to minimize long-term disability and must begin with the appropriate clinical suspicion. Treatment of overt cuboid fractures has changed over time and now includes aggressive repair of the fracture. The authors provide an overview of cuboid fractures and report on a patient with a minimally displaced fracture who was treated conservatively.
PURPOSE: To determine the efficacy of a nonendoscopic brow/forehead lift. METHODS: Case series of 12 patients. Small scalp and upper eyelid blepharoplasty incisions were used to elevate the brows/forehead and perform protractor myectomy. RESULTS: All patients achieved an aesthetically pleasing eyebrow and forehead lift with reduction of vertical and horizontal glabellar creases. Complications included one patient who experienced prolonged ecchymosis after corrugator muscle resection and one patient who had asymmetric lid folds after surgery. The length of follow-up ranged from 9 to 35 months. CONCLUSIONS: The small incision nonendoscopic browlift technique provides a useful alternative to the endoscopic approach.
A broad-spectrum vaginal microbicide must be effective against a variety of sexually transmitted disease pathogens and be minimally toxic to the cell types found within the vaginal epithelium, including vaginal keratinocytes. We assessed the sensitivity of primary human vaginal keratinocytes to potential topical vaginal microbicides nonoxynol-9 (N-9), C31G, and sodium dodecyl sulfate (SDS). Direct immunofluorescence and fluorescence-activated cell sorting analyses demonstrated that primary vaginal keratinocytes expressed epithelial cell-specific keratin proteins. Experiments that compared vaginal keratinocyte sensitivity to each agent during a continuous, 48-h exposure demonstrated that primary vaginal keratinocytes were almost five times more sensitive to N-9 than to either C31G or SDS. To evaluate the effect of multiple microbicide exposures on cell viability, primary vaginal keratinocytes were exposed to N-9, C31G, or SDS three times during a 78-h period. In these experiments, cells were considerably more sensitive to C31G than to N-9 or SDS at lower concentrations within the range tested. When agent concentrations were chosen to result in an endpoint of 25% viability after three daily exposures, each exposure decreased cell viability at the same constant rate. When time-dependent sensitivity during a continuous 48-h exposure was examined, exposure to C31G for 18 h resulted in losses in cell viability not caused by either N-9 or SDS until at least 24 to 48 h. Cumulatively, these results reveal important variations in time- and concentration-dependent sensitivity to N-9, C31G, or SDS within populations of primary human vaginal keratinocytes cultured in vitro. These investigations represent initial steps toward both in vitro modeling of the vaginal microenvironment and studies of factors that impact the in vivo efficacy of vaginal topical microbicides.
The extension of ecological tolerance limits may be an important mechanism by which microorganisms adapt to novel environments, but it may come at the evolutionary cost of reduced performance under ancestral conditions. We combined a comparative physiological approach with phylogenetic analyses to study the evolution of thermotolerance in hot spring cyanobacteria of the genus Synechococcus. Among the 20 laboratory clones of Synechococcus isolated from collections made along an Oregon hot spring thermal gradient, four different 16S rRNA gene sequences were identified. Phylogenies constructed by using the sequence data indicated that the clones were polyphyletic but that three of the four sequence groups formed a clade. Differences in thermotolerance were observed for clones with different 16S rRNA gene sequences, and comparison of these physiological differences within a phylogenetic framework provided evidence that more thermotolerant lineages of Synechococcus evolved from less thermotolerant ancestors. The extension of the thermal limit in these bacteria was correlated with a reduction in the breadth of the temperature range for growth, which provides evidence that enhanced thermotolerance has come at the evolutionary cost of increased thermal specialization. This study illustrates the utility of using phylogenetic comparative methods to investigate how evolutionary processes have shaped historical patterns of ecological diversification in microorganisms.
A highly desirable approach to prevention of human immunodeficiency virus type 1 (HIV-1) transmission during sexual intercourse is the development of nontoxic, topical, broad spectrum microbicides effective against transmission of cell-associated and cell-free virus. Toward this end, the HIV-1 inactivation potential of surface active agents C31G and an alkyl sulfate, sodium dodecyl sulfate (SDS) was assessed. Because of its extensive use as a microbicidal agent, nonoxynol-9 (N-9) was used as a reference against which C31G and SDS were compared. Viral inactivation was measured using HIV-1 LTR-beta-galactosidase indicator cells (expressing CD4 or CD4/CCR5) derived from HeLa cells, a cell line of human cervical adenocarcinoma origin. In experiments which examined inactivation of cell-free HIV-1, C31G was generally more effective than N-9. Viral inactivation by SDS occurred at twice the concentration necessary to achieve similar levels of inactivation using either N-9 or C31G. Using HeLa and HeLa-derived cells in cytotoxicity studies, it was demonstrated that SDS is as much as 11 and five times less cytotoxic than N-9 or C31G, respectively, during 48 h of continuous exposure. SDS (unlike C31G and N-9) can inactivate non-enveloped viruses such as human papillomavirus (HPV) [Howett, M.K., Neely, E.B., Christensen, N.D., Wigdahl, B., Krebs, F.C., Malamud, D., Patrick, S.D., Pickel, M.D., Welsh, P.A., Reed, C.A., Ward, M.G., Budgeon, L.R., Kreider, J.W., 1999. A broad-spectrum microbicide with virucidal activity against sexually transmitted viruses. Antimicrob. Agents Chemother. 43(2), 314-321]. Since addition of SDS to C31G or N-9 may make the resulting microbicidal mixtures broadly effective against both enveloped and non-enveloped viruses, several surface active agent combinations were evaluated for their abilities to inactivate HIV-1. Addition of SDS to either C31G or N-9 resulted in mixtures that were only slightly less effective than equivalent concentrations of C31G or N-9 alone. To investigate inactivation of cell-associated infectivity, HIV-1 IIIB-infected SupT1 cells were treated with N-9, C31G, or SDS. Inactivation of cell-associated infectivity required higher microbicide concentrations than were needed for inactivation of cell-free virus. However, the relative activities of N-9, C31G, or SDS were similar to those seen in assays of inactivation using cell-free virus. These studies suggest that C31G and SDS may be attractive candidates for human trials as topical microbicides effective against HIV-1 transmission since both function at concentrations that provide effective viral inactivation with low levels of cytotoxicity. SDS microbicides (used alone or with other microbicides) may provide the added advantage of protection from HPV infection.
Tinea nigra, a superficial fungal infection caused by Phaeoannellomyces werneckii, presents as a hyperpigmented, nonscaling macule of variable size and shape. Typically lacking induration, erythema, or pruritus, these "ink spot" lesions may resemble junctional nevi or malignant melanoma. Rapid, noninvasive diagnosis can be provided by potassium hydroxide examination, demonstrating numerous large, dematiaceous hyphae.
BACKGROUND AND OBJECTIVES: Delayed breast cellulitis is an infrequently reported entity after conservation therapy for breast cancer. We describe our experience with this entity at Naval Medical Center, San Diego. METHODS: Eight patients who presented with delayed cellulitis after wide local excision/axillary dissection and breast radiotherapy (RT) are presented. Their clinical characteristics and therapy are described and possible causative factors are analyzed. RESULTS: The latency of breast cellulitis is variable after breast conservation therapy, although most cases in our experience and in the literature occur within a year post-RT. These infections are frequently refractory to a single course of antibiotics (n = 4 cases in our experience). Some patients suffer multiple episodes separated by months. CONCLUSIONS: Breast cancer patients are at risk for delayed cellulitis after conservative surgery and RT. The mechanism of such events probably involves lymph stasis, however, therapy is no different from the more frequently occurring cases of cellulitis presenting perioperatively.
STUDY OBJECTIVE: To determine whether placing price labels on the vial caps of muscle relaxants increases cost consciousness among anesthesiologists. DESIGN: Retrospective study. SETTING: University hospital departments of anesthesia and pharmacy. MEASUREMENTS AND MAIN RESULTS: We placed price labels on the vial caps of all muscle relaxants for a study period of 1 year. At the beginning of the investigation, we informed the anesthesiologists of the study, discussed the prices for different muscle relaxants, and encouraged utilizing less expensive muscle relaxants whenever possible without compromising patient care. The price labels on the vial caps served as visual reminders of the various costs of muscle relaxants during daily practice. We compared the total amount spent on each muscle relaxant during the period from October 1993 to September 1994 with the period from October 1994 to September 1995. The total number of surgical cases from October 1993 to September 1994 and from October 1994 to September 1995 was unchanged and equaled 20,389 and 20,358 cases, respectively. Expenditures for pancuronium increased 104.1%. Total expenditure decreased by 12.5%, with a net savings of $47,111. CONCLUSION: Expenditures for the less costly pancuronium increased while expenditures for vecuronium and atracurium decreased. Price labeling of muscle relaxants in conjunction with education reduces total pharmacy expenditure on muscle relaxants.
The discovery of a series of novel (aryloxy)alkylamines with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. A number of compounds demonstrated subnanomolar Ki values for binding to the D4 receptor, with several 100-fold selectivities toward the D2 and D3 receptors. Several compounds with combined D3/D4 receptor binding selectivity were also identified. A limited structure-activity relationship study of this chemical series is discussed. In a mitogenesis functional assay, the effect of the test compounds on cellular uptake of [3H]thymidine in D4-transfected CHO 10,001 cells was measured and compared to the response of the full dopamine agonist quinpirole. The activity of the compounds varied from full antagonist to weak partial agonist activity (intrinsic activity of 0-19% in comparison to quinpirole).
The discovery of a series of chromeno[3,4-c]pyridin-5-ones with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. Several compounds demonstrated single digit nanomolar Ki values for binding to the D4 receptor with several hundred-fold selectivities toward the D2 and D3 receptors. A limited SAR study of this series is discussed. In a mitogenesis assay measuring [3H]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D4 receptor, with intrinsic activities ranging from 0 to 35%. Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at 10 mg/kg.
A case report of primary sternal osteomyelitis, a rare clinical entity, is presented. Treatment of primary sternal osteomyelitis is antibiotics and complete debridement of the infected bone and anterior periosteum. If the posterior sternal periosteum is not involved, it should be left intact. The defect can be covered with skeletal muscle flaps, which improves healing and minimizes recurrence. This approach led to a complete and timely cure.
A gas chromatographic-mass spectrometric method is described for the determination of 1-aminocyclopropanecarboxylic acid in mouse urine using the 2,2,3,3-[2H4] isotopolog as an internal standard. Samples (0.1 ml) were extracted using an exchange resin, then derivatized with pentafluoropropanol and pentafluoropropionic anhydride at 100 degrees C for 25 min. Gas chromatography was performed on a (5% phenyl)methylpolysiloxane column and detection was by selected-ion monitoring of M-CO2CH2CF2CF3 fragment ions. The method provided high response linearity (mean r = 0.999) and precision (< 5% coefficient of variation). After orally dosing mice with 1-aminocyclopropanecarboxylic acid (300 mg/kg), 46 and 10% of the dose was excreted unchanged in the 0-24 h and 24-48 h urines, respectively.