Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis

Hereditary hemochromatosis (HH) is a common disorder of iron metabolism caused by mutation in HFE, a gene encoding an MHC class I-like protein. Clinical studies demonstrate that the severity of iron loading is highly variable among individuals with identical HFE genotypes. To determine whether genetic factors other than Hfe genotype influence the severity of iron loading in the murine model of HH, we bred the disrupted murine Hfe allele onto three different genetically defined mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron status and sensitivity to dietary iron loading. Serum transferrin saturations (percent saturation of serum transferrin with iron), hepatic and splenic iron concentrations, and hepatocellular iron distribution patterns were compared for wild-type (Hfe +/+), heterozygote (Hfe +/−), and knockout (Hfe −/−) mice from each strain. Although the Hfe −/− mice from all three strains demonstrated increased transferrin saturations and liver iron concentrations compared with Hfe +/+ mice, strain differences in severity of iron accumulation were striking. Targeted disruption of the Hfe gene led to hepatic iron levels in Hfe −/− AKR mice that were 2.5 or 3.6 times higher than those of Hfe −/− C3H or Hfe −/− C57BL/6 mice, respectively. The Hfe −/− mice also demonstrated strain-dependent differences in transferrin saturation, with the highest values in AKR mice and the lowest values in C3H mice. These observations demonstrate that heritable factors markedly influence iron homeostasis in response to Hfe disruption. Analysis of mice from crosses between C57BL/6 and AKR mice should allow the mapping and subsequent identification of genes modifying the severity of iron loading in this murine model of HH.

Naturally variant autosomal and sex-linked loci determine the severity of iron overload in β2-microglobulin-deficient mice

Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is systemic iron overload. Homozygosity for a mutation in the MHC class I heavy chain paralogue gene HFE has been found to be a primary cause of HH. However, many individuals homozygous for the defective allele of HFE do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the HH phenotype. Mice deficient in the product of the β2-microglobulin (β2M) class I light chain fail to express HFE and other MHC class I family proteins, and they have been found to manifest many characteristics of the HH phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, we performed classical genetic analysis of the iron-loading phenotype in β2M-deficient mice in the context of different genetic backgrounds. Strain background was found to be a major determinant in iron loading. Sex played a role that was less than that of strain background but still significant. Resistance and susceptibility to iron overload segregated as complex genetic traits in F1 and back-cross progeny. These results suggest the existence of naturally variant autosomal and Y chromosome-linked modifier loci that, in the context of mice genetically predisposed by virtue of a β2M deficiency, can profoundly influence the severity of iron loading. These results thus provide a genetic explanation for some of the variability of the HH phenotype.

Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions

Compelling evidence has accumulated over the last several years from our laboratory, as well as others, indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. In our laboratory, chronic constriction injury of the common sciatic nerve, a rat model of neuropathic pain, has been shown to result in activation of central nervous system excitatory amino acid receptors and subsequent intracellular cascades including protein kinase C translocation and activation, nitric oxide production, and nitric oxide-activated poly(ADP ribose) synthetase activation. Similar cellular mechanisms also have been implicated in the development of tolerance to the analgesic effects of morphine. A recently observed phenomenon, the development of “dark neurons,” is associated with both chronic constriction injury and morphine tolerance. A site of action involved in both hyperalgesia and morphine tolerance is in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance may be interrelated at the level of the superficial laminae of the dorsal horn by common neural substrates that interact at the level of excitatory amino acid receptor activation and subsequent intracellular events. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.

S100B up-regulates macrophage production of IL1β and CCL22 and influences severity of retinal inflammation

Funding: This work was supported by funding awards to Dr Isabel Crane from the National Eye Research Centre, Bristol, UK (Grant ref. SCIAD 058); and NHS Grampian Endowment Trust (Grant ref. 10/16). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Self-Injurious Behavior And Its Relationship To Eating Disorder Symptom Severity

Widely held clinical assumptions about self-harming eating disorder patients were tested in this project. Specifically, the present study had two aims: (1) to confirm research that suggests patients with self-injurious behavior exhibit greater severity in eating disorder symptomology; and (2) to document the treatment course for these patients (e.g. reported change in eating disorder attitudes, beliefs, and behaviors) from admission to discharge. Data from 43 participants who received treatment at a Partial Hospitalization Program (PHP) for Eating Disorders were used in the current study. The length of treatment required for study inclusion reflected mean lengths of stay (Williamson, Thaw, & Varnardo-Sullivan, 2001) and meaningful treatment lengths in prior research (McFarlane et al., 2013; McFarlane, Olmsted, & Trottier, 2008): five to eight weeks. Scores on the Eating Disorder Inventory-III (Garner, 2004) at the time of admission and discharge were compared. These results suggest that there are no significant differences between eating disordered patients who engage in self-injury and those who do not in terms of symptom severity or pathology at admission. The results further suggest that patients in both groups see equivalent reductions in symptoms from admission to discharge across domains and also share non-significant changes in emotional dysregulation over the course of treatment. Importantly, these results also suggest that general psychological maladjustment is higher at discharge for eating disordered patients who engage in self-injury.

Social determinants and health effects of low and high severity intimate partner violence

PURPOSE: We sought to analyze whether the sociodemographic profile of battered women varies according to the level of severity of intimate partner violence (IPV), and to identify possible associations between IPV and different health problems taking into account the severity of these acts. METHODS: A cross-sectional study of 8,974 women (18-70 years) attending primary healthcare centers in Spain (2006-2007) was performed. A compound index was calculated based on frequency, types (physical, psychological, or both), and duration of IPV. Descriptive and multivariate procedures using logistic regression models were fitted. RESULTS: Women affected by low severity IPV and those affected by high severity IPV were found to have a similar sociodemographic profile. However, divorced women (odds ratio [OR], 8.1; 95% confidence interval [CI], 3.2-20.3), those without tangible support (OR, 6.6; 95% CI, 3.3-13.2), and retired women (OR, 2.7; 95% CI, 1.2-6.0) were more likely to report high severity IPV. Women experiencing high severity IPV were also more likely to suffer from poor health than were those who experienced low severity IPV. CONCLUSIONS: The distribution of low and high severity IPV seems to be influenced by the social characteristics of the women involved and may be an important indicator for estimating health effects. This evidence may contribute to the design of more effective interventions.

Successional stage after land abandonment modulates fire severity and post-fire recovery in a Mediterranean mountain landscape

This study analyses the effect of successional stage after farmland terrace abandonment on post-fire plant recovery in a Mediterranean landscape. Specific objectives of the study were to (1) compare fuel characteristics and fire severity in three successional stages after farmland abandonment – dry grassland, dense shrubland and pine stands; (2) analyse the effect of pre-fire successional stage and fire severity on vegetation recovery and (3) analyse the relative vulnerability (i.e. potential for ecosystem shift and soil degradation) to wildfires of the successional stages. We assessed 30 abandoned terraces (15 unburned and 15 burned), with diverse successional stages, on the Xortà Range (south-east Spain). Post-fire recovery was measured 1, 4 and 7 years after fire. The successional stages varied in aboveground biomass, litter amount, vertical structure and continuity of plant cover, and flammability. Dry grassland showed the lowest fire severity, whereas no differences in severity were found between shrubland and pine stands. One year after fire, plant cover was inversely related to fire severity; this relationship attenuated with time after fire. Post-fire recovery of pine stands and shrubland led in both cases to shrublands, contributing to landscape homogenisation. The pine stands showed the largest changes in composition due to fire and the lowest post-fire plant recovery – a sign of high vulnerability to fire.

Capsaicin for post-surgical neuropathic peripheral pain – calculation of allodynia area

Poster apresentado no Congresso O Norte da Anestesia, 19-21 Novembro 2015, Hotel Ipanema Park, Porto, Portugal.

Using linked data to evaluate severity and outcome of injury by type of object struck (first object struck only) for motor vehicle crashes in Connecticut.

Federal Highway Administration, Washington, D.C.

The development and evaluation of a prototype grade severity rating system. Final report.

Federal Highway Administration, Washington, D.C.

Tri-level study: modification. Task 1: final report on potential benefits of various improvements in vehicle systems in preventing accidents or reducing their severity. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Training program for accident investigation and coding in the National Crash Severity Study. Final report.

National Highway Traffic Safety Administration, Washington, D.C.