Mediation in the Law Curriculum

Cited by Lord Neuberger in ‘Educating Future Mediators’ at the 4th Civil Mediation Council National Conference, May 201

Evaluation of multi-exponential curve fitting analysis of oxygen-quenched phosphorescence decay traces for recovering microvascular oxygen tension histograms

Although it is generally accepted that oxygen-quenched phosphorescence decay traces can be analyzed using the exponential series method (ESM), its application until now has been limited to a few (patho)physiological studies, probably because the reliability of the recovered oxygen tension (pO2) histograms has never been extensively evaluated and lacks documentation. The aim of this study was, therefore, to evaluate the use of the ESM to adequately determine pO2 histograms from phosphorescence decay traces. For this purpose we simulated decay traces corresponding to uni- and bimodal pO2 distributions and recovered the pO2 histograms at different signal-to-noise ratios (SNRs). Ultimately, we recovered microvascular pO2 histograms measured in the rat kidney in a model of endotoxemic shock and fluid resuscitation and showed that the mean microvascular oxygen tension, 〈pO2〉, decreased after induction of endotoxemia and that after 2 h of fluid resuscitation, 〈pO2〉 remained low, but the hypoxic peak that had arisen during endotoxemia was reduced. This finding illustrates the importance of recovering pO2 histograms under (patho)physiological conditions. In conclusion, this study has characterized how noise affects the recovery of pO2 histograms using the ESM and documented the reliability of the ESM for recovering both low- and high-pO2 distributions for SNRs typically found in experiments. This study might therefore serve as a frame of reference for investigations focused on oxygen (re)distribution during health and disease and encourage researchers to (re-)analyze data obtained in (earlier) studies possibly revealing new insights into complex disease states and treatment strategies

Impact of tetanus-diphtheria-acellular pertussis immunization during pregnancy on subsequent infant immunization seroresponses : follow-up from a large randomized placebo-controlled trial

Background: Pertussis immunization during pregnancy results in high pertussis antibody concentrations in young infants but may interfere with infant immune responses to post-natal immunization. Methods: This phase IV, multi-country, open-label study assessed the immunogenicity and safety of infant primary vaccination with DTaP-HepB-IPV/Hib and 13-valent pneumococcal conjugate vaccine (PCV13). Enrolled infants (6\u201314 weeks old) were born to mothers who were randomized to receive reduced-antigen-content diphtheria-tetanus-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) during pregnancy (270/7\u2013366/7 weeks\u2019 gestation) with crossover immunization postpartum. All infants received 2 or 3 DTaP-HepB-IPV/Hib and PCV13 doses according to national schedules. Immunogenicity was assessed in infants pre- and 1 month post-primary vaccination. The primary objective was to assess seroprotection/vaccine response rates for DTaP-HepB-IPV/Hib antigens 1 month post-primary vaccination. Results: 601 infants (Tdap group: 296; control group: 305) were vaccinated. One month post-priming, seroprotection rates were 100% (diphtheria; tetanus), 6598.5% (hepatitis B), 6595.9% (polio) and 6594.5% (Hib) in both groups. Vaccine response rates for pertussis antigens were significantly lower in infants whose mothers received pregnancy Tdap (37.5\u201377.1%) versus placebo (90.0\u201399.2%). Solicited and unsolicited adverse event rates were similar between groups. Serious adverse events occurred in 2.4% (Tdap group) and 5.6% (control group) of infants, none were vaccination-related. Conclusions: Pertussis antibodies transferred during pregnancy may decrease the risk of pertussis infection in the first months of life but interfere with the infant's ability to produce pertussis antibodies, the clinical significance of which remains unknown. Safety and reactogenicity results were consistent with previous experience

Community-Based Outbreaks in Vulnerable Populations of Invasive Infections Caused by Streptococcus pneumoniae Serotypes 5 and 8 in Calgary, Canada

BACKGROUND: Outbreaks of invasive pneumococcal disease (IPD) typically occur within institutions. Beginning in 2005, we detected an increase in serotype (ST) 5 and ST8 IPD cases, predominantly in homeless persons living in an open community. METHODOLOGY/PRINCIPAL FINDINGS: CASPER (Calgary Area S. pneumoniae Epidemiology Research) surveillance study of all IPD (sterile site isolates) in our region (pop ~1,100,000). Interviews and chart reviews of all cases and all isolates phenotypically analyzed and selected isolated tested by multi-locus sequence typing (MLST). CONCLUSIONS/SIGNIFICANCE: During 2005-2007, 162 cases of ST5 IPD and 45 cases of ST8 IPD were identified. The isolates demonstrated phenotypic and genotypic clonality. The ST5 isolates were sequence type (ST) 289 and demonstrated intermediate susceptibility to TMP-SMX. The ST8 isolates were predominantly ST1268, with a susceptible antimicrobial susceptibility profile. Individuals with ST5 IPD were more likely to be middle aged (OR 2.6), homeless (OR 4.4), using illicit drugs(OR 4.8), and asthmatic(OR 2.6). Those with ST8 were more likely to be male (OR 4.4), homeless (OR 2.6), aboriginal (OR7.3), and a current smoker (OR 2.5). Overlapping outbreaks of ST5 and ST8 IPD occurred in an open community in Calgary, Canada and homelessness was a predominant risk factor. Homelessness represents a unique community in which pneumococcal outbreaks can occur

Changes in oxygen partial pressure of brain tissue in an animal model of obstructive apnea

Background: Cognitive impairment is one of the main consequences of obstructive sleep apnea (OSA) and is usually attributed in part to the oxidative stress caused by intermittent hypoxia in cerebral tissues. The presence of oxygen-reactive species in the brain tissue should be produced by the deoxygenation-reoxygenation cycles which occur at tissue level during recurrent apneic events. However, how changes in arterial blood oxygen saturation (SpO2) during repetitive apneas translate into oxygen partial pressure (PtO2) in brain tissue has not been studied. The objective of this study was to assess whether brain tissue is partially protected from intermittently occurring interruption of O2 supply during recurrent swings in arterial SpO2 in an animal model of OSA. Methods: Twenty-four male Sprague-Dawley rats (300-350 g) were used. Sixteen rats were anesthetized and noninvasively subjected to recurrent obstructive apneas: 60 apneas/h, 15 s each, for 1 h. A control group of 8 rats was instrumented but not subjected to obstructive apneas. PtO2 in the cerebral cortex was measured using a fastresponse oxygen microelectrode. SpO2 was measured by pulse oximetry. The time dependence of arterial SpO2 and brain tissue PtO2 was carried out by Friedman repeated measures ANOVA. Results: Arterial SpO2 showed a stable periodic pattern (no significant changes in maximum [95.5 ± 0.5%; m ± SE] and minimum values [83.9 ± 1.3%]). By contrast, brain tissue PtO2 exhibited a different pattern from that of arterial SpO2. The minimum cerebral cortex PtO2 computed during the first apnea (29.6 ± 2.4 mmHg) was significantly lower than baseline PtO2 (39.7 ± 2.9 mmHg; p = 0.011). In contrast to SpO2, the minimum and maximum values of PtO2 gradually increased (p < 0.001) over the course of the 60 min studied. After 60 min, the maximum (51.9 ± 3.9 mmHg) and minimum (43.7 ± 3.8 mmHg) values of PtO2 were significantly greater relative to baseline and the first apnea dip, respectively. Conclusions: These data suggest that the cerebral cortex is partially protected from intermittently occurring interruption of O2 supply induced by obstructive apneas mimicking OSA

Single molecule tracking fluorescence microscopy in mitochondria reveals highly dynamic but confined movement of Tom40

Tom40 is an integral protein of the mitochondrial outer membrane, which as the central component of the Translocase of the Outer Membrane (TOM) complex forms a channel for protein import. We characterize the diffusion properties of individual Tom40 molecules fused to the photoconvertable fluorescent protein Dendra2 with millisecond temporal resolution. By imaging individual Tom40 molecules in intact isolated yeast mitochondria using photoactivated localization microscopy with sub-diffraction limited spatial precision, we demonstrate that Tom40 movement in the outer mitochondrial membrane is highly dynamic but confined in nature, suggesting anchoring of the TOM complex as a whole

Metabolic and endocrine profiles and reproductive parameters in dairy cows under grazing conditions: effect of polymorphisms in somatotropic axis genes

<p>Abstract</p> <p>Background</p> <p>The present study hypothesized that GH-AluI and IGF-I-SnabI polymorphisms do change the metabolic/endocrine profiles in Holstein cows during the transition period, which in turn are associated with productive and reproductive parameters.</p> <p>Methods</p> <p>Holstein cows (Farm 1, primiparous cows, n = 110, and Farm 2, multiparous cows, n = 76) under grazing conditions were selected and GH and IGF-I genotypes were determined. Blood samples for metabolic/endocrine determinations were taken during the transition period and early lactation in both farms. Data was analyzed by farm using a repeated measures analyses including GH and IGF-I genotypes, days and interactions as fixed effects, sire and cow as random effects and calving date as covariate.</p> <p>Results and Discussion</p> <p>Frequencies of GH and IGF-I alleles were L:0.84, V:0.16 and A:0.60, B:0.40, respectively. The GH genotype was not associated with productive or reproductive variables, but interaction with days affected FCM yield in multiparous (farm 2) cows (LL yielded more than LV cows) in early lactation. The GH genotype affected NEFA and IGF-I concentrations in farm 1 (LV had higher NEFA and lower IGF-I than LL cows) suggesting a better energy status of LL cows.</p> <p>There was no effect of IGF-I genotype on productive variables, but a trend was found for FCM in farm 2 (AB cows yielded more than AA cows). IGF-I genotype affected calving first service interval in farm 1, and the interaction with days tended to affect FCM yield (AB cows had a shorter interval and yielded more FCM than BB cows). IGF-I genotype affected BHB, NEFA, and insulin concentrations in farm 1: primiparous BB cows had lower NEFA and BHB and higher insulin concentrations. In farm 2, there was no effect of IGF-I genotype, but there was an interaction with days on IGF-I concentration, suggesting a greater uncoupling somatropic axis in AB and BB than AA cows, being in accordance with greater FCM yield in AB cows.</p> <p>Conclusion</p> <p>The GH and IGF-I genotypes had no substantial effect on productive parameters, although IGF-I genotype affected calving-first service interval in primiparous cows. Besides, these genotypes may modify the endocrine/metabolic profiles of the transition dairy cow under grazing conditions.</p

A Method for Efficient Calculation of Diffusion and Reactions of Lipophilic Compounds in Complex Cell Geometry

A general description of effects of toxic compounds in mammalian cells is facing several problems. Firstly, most toxic compounds are hydrophobic and partition phenomena strongly influence their behaviour. Secondly, cells display considerable heterogeneity regarding the presence, activity and distribution of enzymes participating in the metabolism of foreign compounds i.e. bioactivation/biotransformation. Thirdly, cellular architecture varies greatly. Taken together, complexity at several levels has to be addressed to arrive at efficient in silico modelling based on physicochemical properties, metabolic preferences and cell characteristics. In order to understand the cellular behaviour of toxic foreign compounds we have developed a mathematical model that addresses these issues. In order to make the system numerically treatable, methods motivated by homogenization techniques have been applied. These tools reduce the complexity of mathematical models of cell dynamics considerably thus allowing to solve efficiently the partial differential equations in the model numerically on a personal computer. Compared to a compartment model with well-stirred compartments, our model affords a more realistic representation. Numerical results concerning metabolism and chemical solvolysis of a polycyclic aromatic hydrocarbon carcinogen show good agreement with results from measurements in V79 cell culture. The model can easily be extended and refined to include more reactants, and/or more complex reaction chains, enzyme distribution etc, and is therefore suitable for modelling cellular metabolism involving membrane partitioning also at higher levels of complexity

Oxygen as a Driver of Early Arthropod Micro-Benthos Evolution

BACKGROUND: We examine the physiological and lifestyle adaptations which facilitated the emergence of ostracods as the numerically dominant Phanerozoic bivalve arthropod micro-benthos. METHODOLOGY/PRINCIPAL FINDINGS: The PO(2) of modern normoxic seawater is 21 kPa (air-equilibrated water), a level that would cause cellular damage if found in the tissues of ostracods and much other marine fauna. The PO(2) of most aquatic breathers at the cellular level is much lower, between 1 and 3 kPa. Ostracods avoid oxygen toxicity by migrating to waters which are hypoxic, or by developing metabolisms which generate high consumption of O(2). Interrogation of the Cambrian record of bivalve arthropod micro-benthos suggests a strong control on ecosystem evolution exerted by changing seawater O(2) levels. The PO(2) of air-equilibrated Cambrian-seawater is predicted to have varied between 10 and 30 kPa. Three groups of marine shelf-dwelling bivalve arthropods adopted different responses to Cambrian seawater O(2). Bradoriida evolved cardiovascular systems that favoured colonization of oxygenated marine waters. Their biodiversity declined during intervals associated with black shale deposition and marine shelf anoxia and their diversity may also have been curtailed by elevated late Cambrian (Furongian) oxygen-levels that increased the PO(2) gradient between seawater and bradoriid tissues. Phosphatocopida responded to Cambrian anoxia differently, reaching their peak during widespread seabed dysoxia of the SPICE event. They lacked a cardiovascular system and appear to have been adapted to seawater hypoxia. As latest Cambrian marine shelf waters became well oxygenated, phosphatocopids went extinct. Changing seawater oxygen-levels and the demise of much of the seabed bradoriid micro-benthos favoured a third group of arthropod micro-benthos, the ostracods. These animals adopted lifestyles that made them tolerant of changes in seawater O(2). Ostracods became the numerically dominant arthropod micro-benthos of the Phanerozoic. CONCLUSIONS/SIGNIFICANCE: Our work has implications from an evolutionary context for understanding how oxygen-level in marine ecosystems drives behaviour