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1.
Plant Biol (Stuttg) ; 23(6): 1086-1096, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34263990

ABSTRACT

The establishment and survival of seedlings are critical stages in the life cycle of plants and therefore usually well timed to humid and favourable conditions. Climate projections suggest that the threatened mountain grassland species Arnica montana may be increasingly exposed to drought stress. However, studies that focus on the species' early development are missing. We evaluated impacts of drought-induced stress on A. montana seedlings in their early establishment phase and identified traits that could cause the species' fitness to decline. In a greenhouse experiment, we tested the response of A. montana seedlings to different drought levels (moderate, strong, extreme). To assess their fitness under increasing drought, we evaluated survival of the seedlings based on four senescence stages and measured the performance of above- and belowground morphological and physiological functional traits. Arnica montana seedlings showed high resistance to drought. Senescence accelerated and survival declined only under strong and extreme drought conditions. However, the seedlings' vegetative performance decreased even with moderate drought, as indicated by smaller values of most leaf traits and some root traits. Physiological trait response was less sensitive. Drought stress hinders the establishment and survival of A. montana seedlings. Following the functional trait responses to drought and their association with survival, we suggest declining leaf length, leaf width, and leaf number are sensitive traits that can lead to a decline in performance.


Subject(s)
Arnica , Seedlings , Climate , Droughts , Plant Leaves
2.
Anaesthesist ; 65(4): 267-73, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27043033

ABSTRACT

PURPOSE: Toxic reactions to local anesthetics are rare but potentially lethal. In fact, animal studies and case reports demonstrate that the administration of lipid emulsions after initializing cardiopulmonary resuscitation is a promising treatment option. The aim of this study was to determine how many hospitals in Germany are prepared to treat toxic reactions to local anesthetics with lipid infusion and to identify how often and what type of toxic reactions occur and if treatment was successful. Further, we aimed to elucidate if current guidelines lead to more immediate availability of lipid emulsions in direct proximity to the room where regional anesthesia is performed. METHODS: A standardized survey was sent to 1,305 German hospitals. The main question was whether lipid emulsions are readily available and if published guidelines contributed to this availability. Additionally, we asked whether local anesthetic toxicity had already successfully been treated by lipid emulsions and what type of symptoms were treated. RESULTS: We received replies from n = 509 (39%) hospitals. In 338 (66%) of the responding hospitals, lipid emulsions are readily available. Hospitals with standard operating procedures (SOPs) implemented according to published guidelines have lipids significantly more often immediately available than hospitals with just SOPs (chi-square test of independence, p-value < 0.01). Of all responding hospitals 287 (56%) have implemented a SOP for the treatment of toxic reactions to local anesthetics and 196 (39%) of the hospitals introduced the SOP because of the guidelines. In 28 (6%) of the hospitals, local anesthetic toxicity had already caused cardiac arrest with subsequent cardiopulmonary resuscitation in at least one patient. In 132 (26%) hospitals, local anesthetic toxicity had already been treated by infusing lipid emulsions. Of these hospitals 128 (96%) state this therapeutic approach was successful. Treatment with lipid emulsions was performed frequently after prodromal symptoms 83 (63%) were witnessed. CONCLUSIONS: The majority of surveyed German hospitals are prepared to treat toxic reactions to local anesthetics and published guidelines contributed to this preparedness. The infusion of lipid emulsions is a promising measure to deal with toxic reactions to local anesthetics. Since toxic reactions to local anesthetics are potentially lethal, it seems desirable that lipid emulsions are generally available in routine clinical practice. Currently, the treatment of toxic reactions to local anesthetics is mostly performed in situations (e.g. treatment of prodromal symptoms) that are not recommended by current guidelines. Further research is necessary to better define the future use of lipid emulsions in routine clinical practice.


Subject(s)
Anesthetics, Local/adverse effects , Antidotes/therapeutic use , Fat Emulsions, Intravenous/therapeutic use , Hospitals/statistics & numerical data , Resuscitation/statistics & numerical data , Cardiopulmonary Resuscitation/methods , Germany/epidemiology , Guidelines as Topic , Health Care Surveys , Heart Arrest/chemically induced , Heart Arrest/therapy , Humans , Resuscitation/methods
3.
J Evol Biol ; 29(3): 645-56, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26688295

ABSTRACT

Responses to sexually antagonistic selection are thought to be constrained by the shared genetic architecture of homologous male and female traits. Accordingly, adaptive sexual dimorphism depends on mechanisms such as genotype-by-sex interaction (G×S) and sex-specific plasticity to alleviate this constraint. We tested these mechanisms in a population of Xiphophorus birchmanni (sheepshead swordtail), where the intensity of male competition is expected to mediate intersexual conflict over age and size at maturity. Combining quantitative genetics with density manipulations and analysis of sex ratio variation, we confirm that maturation traits are dimorphic and heritable, but also subject to large G×S. Although cross-sex genetic correlations are close to zero, suggesting sex-linked genes with important effects on growth and maturation are likely segregating in this population, we found less evidence of sex-specific adaptive plasticity. At high density, there was a weak trend towards later and smaller maturation in both sexes. Effects of sex ratio were stronger and putatively adaptive in males but not in females. Males delay maturation in the presence of mature rivals, resulting in larger adult size with subsequent benefit to competitive ability. However, females also delay maturation in male-biased groups, incurring a loss of reproductive lifespan without apparent benefit. Thus, in highly competitive environments, female fitness may be limited by the lack of sex-specific plasticity. More generally, assuming that selection does act antagonistically on male and female maturation traits in the wild, our results demonstrate that genetic architecture of homologous traits can ease a major constraint on the evolution of adaptive dimorphism.


Subject(s)
Cyprinodontiformes/physiology , Models, Genetic , Sexual Behavior, Animal , Age Factors , Animals , Body Size/genetics , Competitive Behavior , Cyprinodontiformes/genetics , Female , Genetic Variation , Genotype , Male , Phenotype , Reproduction/physiology , Sex Characteristics , Sex Ratio
4.
Int J Comput Assist Radiol Surg ; 10(7): 1127-40, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25408305

ABSTRACT

PURPOSE: Minimal invasion computer-assisted neurosurgical procedures with various tool insertions into the brain may carry hemorrhagic risks and neurological deficits. The goal of this study is to investigate the role of computer-based surgical trajectory planning tools in improving the potential safety of image-based stereotactic neurosurgery. METHODS: Multi-sequence MRI studies of eight patients who underwent image-guided neurosurgery were retrospectively processed to extract anatomical structures-head surface, ventricles, blood vessels, white matter fibers tractography, and fMRI data of motor, sensory, speech, and visual areas. An experienced neurosurgeon selected one target for each patient. Five neurosurgeons planned a surgical trajectory for each patient using three planning methods: (1) conventional; (2) visualization, in which scans are augmented with overlays of anatomical structures and functional areas; and (3) automatic, in which three surgical trajectories with the lowest expected risk score are automatically computed. For each surgeon, target, and method, we recorded the entry point and its surgical trajectory and computed its expected risk score and its minimum distance from the key structures. RESULTS: A total of 120 surgical trajectories were collected (5 surgeons, 8 targets, 3 methods). The surgical trajectories expected risk scores improved by 76% ([Formula: see text], two-sample student's t test); the average distance of a trajectory from nearby blood vessels increased by 1.6 mm ([Formula: see text]) from 0.6 to 2.2 mm (243%). The initial surgical trajectories were changed in 85% of the cases based on the expected risk score and the trajectory distance from blood vessels. CONCLUSIONS: Computer-based patient-specific preoperative planning of surgical trajectories that minimize the expected risk of vascular and neurological damage due to incorrect tool placement is a promising technique that yields consistent improvements.


Subject(s)
Neurosurgical Procedures/methods , Stereotaxic Techniques , Surgery, Computer-Assisted/methods , Adult , Aged , Brain/surgery , Child , Child, Preschool , Deep Brain Stimulation/methods , Female , Humans , Imaging, Three-Dimensional , Magnetic Resonance Imaging/methods , Male , Middle Aged , Patient Safety , Retrospective Studies , Young Adult
5.
J Evol Biol ; 26(2): 252-5, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23323999
6.
J Evol Biol ; 25(9): 1800-14, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22827312

ABSTRACT

Local adaptation is often invoked to explain hybrid zone structure, but empirical evidence of this is generally rare. Hybrid zones between two poeciliid fishes, Xiphophorus birchmanni and X. malinche, occur in multiple tributaries with independent replication of upstream-to-downstream gradients in morphology and allele frequencies. Ecological niche modelling revealed that temperature is a central predictive factor in the spatial distribution of pure parental species and their hybrids and explains spatial and temporal variation in the frequency of neutral genetic markers in hybrid populations. Among populations of parentals and hybrids, both thermal tolerance and heat-shock protein expression vary strongly, indicating that spatial and temporal structure is likely driven by adaptation to local thermal environments. Therefore, hybrid zone structure is strongly influenced by interspecific differences in physiological mechanisms for coping with the thermal environment.


Subject(s)
Adaptation, Physiological , Cyprinodontiformes/physiology , Environment , Hybridization, Genetic , Alleles , Animals , Cyprinodontiformes/genetics , Female , Gene Expression Regulation , Gene Frequency , Genetics, Population/methods , Heat-Shock Proteins/analysis , Heat-Shock Proteins/genetics , Hot Temperature , Male , Polymorphism, Single Nucleotide , Population Dynamics , Seasons , Species Specificity , Stress, Physiological , Time Factors , Viviparity, Nonmammalian
7.
Mol Ecol ; 20(2): 342-56, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21210879

ABSTRACT

Natural hybrid zones provide opportunities to study a range of evolutionary phenomena from speciation to the genetic basis of fitness-related traits. We show that widespread hybridization has occurred between two neo-tropical stream fishes with partial reproductive isolation. Phylogenetic analyses of mitochondrial sequence data showed that the swordtail fish Xiphophorus birchmanni is monophyletic and that X. malinche is part of an independent monophyletic clade with other species. Using informative single nucleotide polymorphisms in one mitochondrial and three nuclear intron loci, we genotyped 776 specimens collected from twenty-three sites along seven separate stream reaches. Hybrid zones occurred in replicated fashion in all stream reaches along a gradient from high to low elevation. Genotyping revealed substantial variation in parental and hybrid frequencies among localities. Tests of F(IS) and linkage disequilibrium (LD) revealed generally low F(IS) and LD except in five populations where both parental species and hybrids were found suggesting incomplete reproductive isolation. In these locations, heterozygote deficiency and LD were high, which suggests either selection against early generation hybrids or assortative mating. These data lay the foundation to study the adaptive basis of the replicated hybrid zone structure and for future integration of behaviour and genetics to determine the processes that lead to the population genetic patterns observed in these hybrid zones.


Subject(s)
Biological Evolution , Cyprinodontiformes/classification , Cyprinodontiformes/genetics , Genetic Speciation , Hybridization, Genetic , Animals , Base Sequence , Cyprinodontiformes/physiology , DNA, Mitochondrial/genetics , Female , Genetic Variation , Genotype , Geography , Linkage Disequilibrium , Male , Mexico , Phylogeny , Polymorphism, Single Nucleotide , Reproduction/genetics , Sequence Analysis, DNA
8.
Biol Lett ; 7(2): 229-32, 2011 Apr 23.
Article in English | MEDLINE | ID: mdl-20826470

ABSTRACT

Human-induced environmental change can affect the evolutionary trajectory of populations. In Mexico, indigenous Zoque people annually introduce barbasco, a fish toxicant, into the Cueva del Azufre to harvest fish during a religious ceremony. Here, we investigated tolerance to barbasco in fish from sites exposed and unexposed to the ritual. We found that barbasco tolerance increases with body size and differs between the sexes. Furthermore, fish from sites exposed to the ceremony had a significantly higher tolerance. Consequently, the annual ceremony may not only affect population structure and gene flow among habitat types, but the increased tolerance in exposed fish may indicate adaptation to human cultural practices in a natural population on a very small spatial scale.


Subject(s)
Adaptation, Physiological , Ceremonial Behavior , Paullinia/toxicity , Poecilia/physiology , Animals , Body Size , Drug Tolerance , Female , Humans , Male , Poecilia/anatomy & histology , Religion , Sex Factors , Toxicity Tests
9.
J Evol Biol ; 23(7): 1364-73, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20492091

ABSTRACT

Development consists of growth and differentiation, which can be partially decoupled and can be affected by environmental factors to different extents. In amphibians, variation in the larval environment influences development and causes changes in post-metamorphic shape. We examined post-metamorphic consequences, both morphological and locomotory, of alterations in growth and development. We reared tadpoles of two phylogenetically and ecologically distant frog species (the red-eyed treefrog Agalychnis callidryas and the African clawed frog Xenopus laevis) under different temperatures with ad libitum food supply and under different food levels at a constant temperature. Low temperature and low food levels both resulted in similarly extended larval periods. However, low temperature yielded relatively long-legged frogs with a lower degree of ossification than warm temperature, whereas low food yielded relatively short-legged frogs with a higher degree of ossification than high food levels. Such allometric differences had no effect on locomotor performance of juveniles. Our results provide a basis for understanding the relationship between growth, differentiation and post-metamorphic shape in anurans and help explain many of the discrepancies reported in previous studies.


Subject(s)
Anura/growth & development , Environment , Hindlimb/growth & development , Animals , Anura/anatomy & histology , Diet , Hindlimb/anatomy & histology , Larva/growth & development , Locomotion/physiology , Osteogenesis/physiology , Species Specificity , Temperature , Time Factors
10.
Cerebrovasc Dis ; 26(6): 573-7, 2008.
Article in English | MEDLINE | ID: mdl-18946211

ABSTRACT

BACKGROUND: Emergency treatment of ischemic stroke should ideally be mechanism specific, but acute subtype diagnosis is problematic. Since different subtypes often are associated with specific patterns of neurological deficits, we hypothesize that scores on baseline NIH stroke scale (NIHSS) items may help emergently stratify patients by their probability of having a particular stroke subtype. METHODS: We performed multivariate polytomous logistic regression analyses on 1,281 patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). We tested the predictive value of individual items to the baseline NIHSS exam, and syndromic combinations of those items, in anticipating the TOAST stroke subtype at 3 months adjusting for atrial fibrillation. We then used the most significant NIHSS items to construct a predictive model. RESULTS: The NIHSS items that discriminate between stroke subtypes are language, neglect, visual field and brachial predominance of weakness. Among patients without atrial fibrillation, a normal score for these 4 variables conveys a 46% chance of lacunar stroke, 12% of atherothrombotic stroke and 10% of cardioembolism. This pattern gradually reverses with increased numbers of abnormal responses. Those with abnormalities in all 4 items have a 0.1% chance of lacunar stroke, 50% of atherothrombotic stroke and 39% of cardioembolism. CONCLUSIONS: Language, neglect, visual fields and brachial predominance of weakness in the baseline NIHSS help discriminate between subtypes, particularly between lacunar and nonlacunar strokes. Clinical trials testing interventions aimed to particular stroke mechanisms may use these NIHSS items to emergently stratify patients based on their probability of having a particular stroke subtype.


Subject(s)
Severity of Illness Index , Stroke/classification , Aphasia/etiology , Arm , Atrial Fibrillation/complications , Brain Infarction/diagnosis , Brain Infarction/epidemiology , Brain Ischemia/diagnosis , Brain Ischemia/epidemiology , Cohort Studies , Double-Blind Method , Hemianopsia/etiology , Humans , Intracranial Arteriosclerosis/complications , Intracranial Embolism/diagnosis , Intracranial Embolism/epidemiology , Logistic Models , Muscle Weakness/etiology , Paresis/etiology , Perceptual Disorders/etiology , Predictive Value of Tests , Prospective Studies , Randomized Controlled Trials as Topic/statistics & numerical data , Risk , Stroke/complications , Stroke/epidemiology
11.
J Med Ethics ; 34(10): 717-22, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18827101

ABSTRACT

BACKGROUND: Discussions about medical errors facilitate professional learning for physicians and may provide emotional support after an error, but little is known about physicians' attitudes and practices regarding error discussions with colleagues. METHODS: Survey of faculty and resident physicians in generalist specialties in Midwest, Mid-Atlantic and Northeast regions of the US to investigate attitudes and practices regarding error discussions, likelihood of discussing hypothetical errors, experience role-modelling error discussions and demographic variables. RESULTS: Responses were received from 338 participants (response rate = 74%). In all, 73% of respondents indicated they usually discuss their mistakes with colleagues, 70% believed discussing mistakes strengthens professional relationships and 89% knew at least one colleague who would be a supportive listener. Motivations for error discussions included wanting to learn whether a colleague would have made the same decision (91%), wanting colleagues to learn from the mistake (80%) and wanting to receive support (79%). Given hypothetical scenarios, most respondents indicated they would likely discuss an error resulting in no harm (77%), minor harm (87%) or major harm (94%). Fifty-seven percent of physicians had tried to serve as a role model by discussing an error and role-modelling was more likely among those who had previously observed an error discussion (OR 4.17, CI 2.34 to 7.42). CONCLUSIONS: Most generalist physicians in teaching hospitals report that they usually discuss their errors with colleagues, and more than half have tried to role-model discussions. However, a significant number of these physicians report that they do not usually discuss their errors and some do not know colleagues who would be supportive listeners.


Subject(s)
Attitude of Health Personnel , Faculty, Medical , Internship and Residency , Medical Errors/psychology , Truth Disclosure/ethics , Clinical Competence , Female , Humans , Male , Medical Errors/ethics , Statistics as Topic , Surveys and Questionnaires
12.
Heart ; 94(9): 1181-8, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18070945

ABSTRACT

OBJECTIVE: To compare outcomes after aortic valve replacement (AVR) according to valve type specifically in older patients since valve-related risks are age-dependent; two randomised trials comparing mechanical and bioprosthetic valves found better outcomes with mechanical valves, but the samples were small and the patients were considerably younger than most who undergo AVR. DESIGN: Cohort study. SETTING: 1199 US hospitals. PATIENTS: Patients 65 years and older undergoing AVR during 1991-2003 (n = 307 054) identified through Medicare claims data. MAIN OUTCOME MEASURES: Relative hazard ratios associated with bioprosthetic valves of (1) death (n = 131,719); (2) readmission for haemorrhage (n = 31,186), stroke (n = 25,051) or embolism (n = 5870); (3) reoperation (n = 4216); and (4) death or reoperation (reoperation free survival) in Cox regression analyses adjusting for demographic and clinical factors and hospital-level effects. RESULTS: Overall, 36% of AVR patients received bioprosthetic valves. Bioprosthetic valve recipients were older (77 vs 75 years, p<0.001) and generally had higher comorbidity. Bioprosthetic valve recipients had a slightly lower adjusted hazard ratios of death (HR = 0.97; 95% CI 0.95 to 0.98); readmission for haemorrhage, stroke or embolism (HR = 0.90, 95% CI 0.88 to 0.92); and death or reoperation (HR = 0.97, 95% CI 0.96 to 0.98), but a higher hazard ratio of reoperation (HR = 1.25, 95% CI 1.16 to 1.35). However, overall mortality and complication rates were more than 20 and 10 times higher, respectively, than the overall reoperation rate. CONCLUSIONS: In older patients undergoing AVR, bioprosthetic valve recipients had slightly lower risks of death and complications, but a higher risk of reoperation. Given the low reoperation rate, these data suggest that bioprosthetic valves may be preferred in older patients.


Subject(s)
Aortic Valve Insufficiency/surgery , Aortic Valve/surgery , Bioprosthesis , Heart Valve Prosthesis Implantation/methods , Heart Valve Prosthesis , Age Factors , Aged , Aortic Valve Insufficiency/mortality , Female , Follow-Up Studies , Heart Valve Prosthesis Implantation/mortality , Humans , Male , Postoperative Complications , Proportional Hazards Models , Prosthesis Design , Prosthesis Failure , Recurrence , Reoperation , Survival Rate
13.
Pediatr Cardiol ; 26(4): 396-9, 2005.
Article in English | MEDLINE | ID: mdl-16374689

ABSTRACT

The purpose of this study was to assess the electrocardiogram (ECG) interpretation skills of pediatric residents in a controlled environment and determine if the level of residency training (intern vs senior) improves accuracy. A list of ECG diagnoses was provided to four pediatric residency educators with instructions to categorize each diagnosis as follows: I, all residents; II, the majority of residents, including all senior residents; III, less than the majority of residents; and IV, few residents should be able to interpret correctly. Only those categories that the entire panel believed all residents (category I) or all senior residents (category II) should be able to interpret correctly were included. The test included 17 ECGs: 14 category I and 3 category II. A total of 132 residents participated: 78 interns and 54 seniors. Both groups scored below expected levels. Mean correct score among seniors was 10.9 out of the expected 17 (p < 0.001). Mean correct score for interns was 7.7 out of the expected 14 (p < 0.00l). No difference in ECG interpretation accuracy was found between residency programs. In general, pediatric residents' ECG interpretation skills are less accurate than expected. Although there is a trend toward improvement during training, senior residents fell short of the expectations of the panel. We speculate that focused education in this area will improve resident ECG interpretation and benefit patient care by (1) facilitating referral and treatment of patients with cardiovascular disease and (2) decreasing referrals for erroneous interpretations.


Subject(s)
Clinical Competence/standards , Electrocardiography , Internship and Residency , Heart Diseases/diagnosis , Humans , Reproducibility of Results , United States
14.
J Med Ethics ; 30(5): 499-503, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15467087

ABSTRACT

OBJECTIVE: To describe the frequency of support for terminal sedation among internists, determine whether support for terminal sedation is accompanied by support for physician assisted suicide (PAS), and explore characteristics of internists who support terminal sedation but not assisted suicide. DESIGN: A statewide, anonymous postal survey. SETTING: Connecticut, USA. PARTICIPANTS: 677 Connecticut members of the American College of Physicians. MEASUREMENTS: Attitudes toward terminal sedation and assisted suicide; experience providing primary care to terminally ill patients; demographic and religious characteristics. RESULTS: 78% of respondents believed that if a terminally ill patient has intractable pain despite aggressive analgesia, it is ethically appropriate to provide terminal sedation (diminish consciousness to halt the experience of pain). Of those who favoured terminal sedation, 38% also agreed that PAS is ethically appropriate in some circumstances. Along a three point spectrum of aggressiveness in end of life care, the plurality of respondents (47%) were in the middle, agreeing with terminal sedation but not with PAS. Compared with respondents who were less aggressive or more aggressive, physicians in this middle group were more likely to report having more experience providing primary care to terminally ill patients (p = 0.02) and attending religious services more frequently (p<0.001). CONCLUSIONS: Support for terminal sedation was widespread in this population of physicians, and most who agreed with terminal sedation did not support PAS. Most internists who support aggressive palliation appear likely to draw an ethical line between terminal sedation and assisted suicide.


Subject(s)
Attitude of Health Personnel , Hypnotics and Sedatives/administration & dosage , Medical Staff, Hospital/psychology , Terminal Care/psychology , Analgesia/ethics , Analgesia/methods , Analgesia/psychology , Christianity/psychology , Female , Humans , Male , Middle Aged , Pain, Intractable/drug therapy , Suicide, Assisted/ethics , Suicide, Assisted/psychology , Terminal Care/ethics , Terminal Care/methods , Terminally Ill
16.
J Aerosol Med ; 16(1): 65-73, 2003.
Article in English | MEDLINE | ID: mdl-12737686

ABSTRACT

Polylactic acid (PLA) powders have been used as vector particles to carry pharmaceutical material. Drugs incorporated in the PLA powder can be retained in the lung for a longer period and may be more effective than free-form drugs. A new formulation of L-PLA dry powder, which was easy to disperse in the air, was produced by using a supercritical technology. The L-PLA powder was characterized in terms of physical particle size and aerodynamic size as generated with a Turbuhaler dry powder inhaler (DPI). Electron microscopy analysis of the particles indicated that they were individual particles in bulk form and became aggregate particles after generation by the Turbuhaler. Aerodynamic particle size analysis using both an Aerodynamic Particle Sizer (APS) aerosol spectrometer and Andersen impactor showed that the aerodynamic size decreased as the flow rate in the Turbuhaler increased from 28.3 to 90 L min(-1). Deposition patterns in the human respiratory tract were estimated using a realistic physical replica of human airways. Deposition of the L-PLA was high (80.8%) in the oral airway at 28.3 L min(-1) and an average of 73.4% at flow rates of 60 and 90 L min(-1). In the lung region, the deposition totaled 7.2% at 28.3 L min(-1), 18.3% at 60 L min(-1), and 17.6% at 90 L min(-1). These deposition patterns were consistent with aerodynamic size measurement, which showed 76 to 86% deposition in the USP/EP (US Pharmacopoeia/European Pharmacopoeia) induction port. As the flow rate increased, fewer aggregates were formed resulting in the smaller aerodynamic particles. As a result, more particles penetrated the oral airways and were available for deposition in the lung. Our results showed that L-PLA particles as manufactured by the supercritical technology could be used in a DPI that does not require the use of carrier particles to facilitate aerosol delivery.


Subject(s)
Lactic Acid/administration & dosage , Lung/metabolism , Polymers/administration & dosage , Drug Delivery Systems , Humans , Microspheres , Models, Anatomic , Nebulizers and Vaporizers , Particle Size , Polyesters
17.
Bone Marrow Transplant ; 31(5): 361-9, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12634727

ABSTRACT

Fms-like tyrosine kinase (Flt3L) is a potent stimulator of hematopoietic progenitor cell (HPC) expansion and mobilization; however, this requires 7-10 days of administration. We investigated whether sustained delivery of Flt3L using a poloxamer-based matrix (PG) could accelerate and/or improve the hematopoietic activity of Flt3L in mice. A single injection of PG-Flt3L stimulated significantly more rapid and greater HPC mobilization to the spleen and peripheral blood than the daily injection of Flt3L formulated in saline. Pharmacokinetic analysis demonstrated that the formulation of Flt3L in PG prolonged its elimination (Tbeta) half-life (2.3-fold) and increased its bioavailability (>two fold) and the time to maximum serum concentration (T(max)) (2.7-fold). Further, coadministration of G-CSF and PG-Flt3L allowed lower doses of Flt3L to be active, with significantly greater hematopoietic and mobilization activity, compared to the same total dose of G-CSF, Flt3L or G-CSF and Flt3L formulated in saline. These data demonstrate that formulation of Flt3L in PG significantly accelerates and increases HPC expansion and mobilization. The observation of increased bioactivity by PG-Flt3L in rodents suggests the potential for improved clinical efficacy of Flt3L by reducing the time required for HPC mobilization.


Subject(s)
Hematopoietic Stem Cell Mobilization , Membrane Proteins/administration & dosage , Poloxamer/administration & dosage , Animals , Bone Marrow Cells/drug effects , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Female , Granulocyte Colony-Stimulating Factor/pharmacology , Membrane Proteins/pharmacokinetics , Membrane Proteins/pharmacology , Mice , Mice, Inbred BALB C , Spleen/cytology
18.
Eye (Lond) ; 16(5): 619-21, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12194078

ABSTRACT

PURPOSE: To assess p53 gene expression in pterygia with and without recurrence. The pathogenesis of pterygium has not yet been determined. The most widely recognized etiologic factor is ultraviolet radiation, which leads to degeneration of the conjunctiva. However, pterygium was recently found to have several tumor-like characteristics. The p53 gene is a common marker for neoplasia, and is known to control cell cycle, cell differentiation and apoptosis. In this study we examined the expression of the p53 gene in primary pterygia with and without recurrence, searching for the pathogenesis of this very common lesion and for a prognostic factor for recurrence. METHODS: Immunohistochemical staining using a monoclonal antibody to human p53 (DO-7) was performed on 13 consecutive patients with primary pterygia, four pterygia without recurrence and nine pterygia which recurred during a 12-month follow-up. As a control we used two specimens of normal conjunctiva. RESULTS: Seven of the 13 pterygia specimens (54%) were positive for abnormal p53 expression. There was no difference between the groups with and without recurrence. Two out of four pterygia (50%) without recurrence and five out of nine (55.5%) pterygia with recurrence were positive. No pathological staining was observed in the control specimens. CONCLUSIONS: In this study, abnormal p53 expression was found in pterygial epithelium, suggesting that pterygium could be a result of uncontrolled cell proliferation, and not as a degenerative lesion. There seems to be no connection between abnormal p53 expression and recurrence.


Subject(s)
Genes, p53 , Pterygium/metabolism , Tumor Suppressor Protein p53/metabolism , Antibodies, Monoclonal/immunology , Biomarkers/analysis , Cell Division , Follow-Up Studies , Humans , Immunoenzyme Techniques , Prognosis , Recurrence , Tumor Suppressor Protein p53/immunology
19.
Vaccine ; 20(5-6): 711-23, 2001 Dec 12.
Article in English | MEDLINE | ID: mdl-11738734

ABSTRACT

The potential to generate both a systemic and local immune response makes the mucosal system an attractive site for immunization. However, mucosal administration of protein and peptide antigens generally results in a poor immune response. Successful mucosal vaccination is therefore largely dependent on the development of effective mucosal adjuvants. In this study we have examined the effect of mucosal administration of tetanus toxoid (TT) in the presence of a non-ionic block copolymer, Pluronic F127 (F127), with chitosan or lysophosphatidylcholine (LPC) on the systemic and mucosal immune response. Balb/c mice, immunized intraperitoneally (i.p.) with TT and boosted intranasally (i.n.) with TT in F127/chitosan, demonstrated a significant enhancement in the systemic anti-TT antibody response compared to mice boosted i.n. with TT in PBS or mice boosted i.n. with TT in F127/LPC. We determined the antigen specific IgA response in the nasal and lung washes of these animals and found a significant increase in anti-TT mucosal IgA response in the group boosted with TT in F127/chitosan. Similarly, mice immunized and boosted i.n. with TT in F127/chitosan had a significant enhancement of their systemic anti-TT IgG and mucosal IgA antibody responses compared to the animals immunized and boosted i.n. with TT in PBS or TT in F127/LPC. The results of these studies suggest that F127/chitosan represents a novel mucosal vaccine delivery system, consisting of two components, that appear to exert an additive or synergistic effect on the immune response.


Subject(s)
Chitin/administration & dosage , Immunity, Mucosal/drug effects , Poloxamer/administration & dosage , Tetanus Toxoid/administration & dosage , Adjuvants, Immunologic/administration & dosage , Administration, Intranasal , Animals , Antibody Affinity , Chitin/analogs & derivatives , Chitosan , Dose-Response Relationship, Drug , Drug Synergism , Gels , Immunization, Secondary , Immunoglobulin A/metabolism , Immunoglobulin E/blood , Immunoglobulin G/blood , Immunoglobulin G/classification , Immunoglobulin G/metabolism , Lung/drug effects , Lung/immunology , Mice , Mice, Inbred BALB C , Nasal Mucosa/drug effects , Nasal Mucosa/immunology
20.
Health Serv Res ; 36(5): 959-77, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11666112

ABSTRACT

OBJECTIVES: Compare the discrimination of risk-adjustment models for primary cesarean delivery derived from medical record data and birth certificate data and determine if the two types of models yield similar hospital profiles of risk-adjusted cesarean delivery rates. DATA SOURCES/STUDY SETTING: The study involved 29,234 women without prior cesarean delivery admitted for labor and delivery in 1993-95 to 20 hospitals in northeast Ohio for whom data abstracted from patient medical records and data from birth certificates could be linked. STUDY DESIGN: Three pairs of multivariate models of the risk of cesarean delivery were developed using (1) the full complement of variables in medical records or birth certificates; (2) variables that were common to the two sources; and (3) variables for which agreement between the two data sources was high. Using each of the six models, predicted rates of cesarean delivery were determined for each hospital. Hospitals were classified as outliers if observed and predicted rates of cesarean delivery differed (p < .05). PRINCIPAL FINDINGS: Discrimination of the full medical record and birth certificate models was higher (p < .001) than the discrimination of the more limited common and reliable variable models. Based on the full medical record model, six hospitals were classified as statistical (p < .01) outliers (three high and three low). In contrast, the full birth certificate model identified five low and four high outliers, and classifications differed for seven of the 20 hospitals. Even so, the correlation between adjusted hospital rates was substantial (r = .71). Interestingly, correlations between the full medical record model and the more limited common (r = .84) and reliable (r = .88) variable birth certificate models were higher, and differences in classification of hospital outlier status were fewer. CONCLUSION: Birth certificates can be used to develop cesarean delivery risk-adjustment models that have excellent discrimination. However, using the full complement of birth certificate variables may lead to biased hospital comparisons. In contrast, limiting models to data elements with known reliability may yield rankings that are more similar to rankings based on medical record data.


Subject(s)
Cesarean Section/statistics & numerical data , Medical Audit/methods , Obstetrics and Gynecology Department, Hospital/classification , Practice Patterns, Physicians'/statistics & numerical data , Risk Adjustment , Adult , Birth Certificates , Cohort Studies , Data Collection , Female , Health Services Research , Humans , Medical Records , Models, Statistical , Obstetrics and Gynecology Department, Hospital/statistics & numerical data , Ohio/epidemiology , Pregnancy , Utilization Review
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