Pulmonary availability of isotretinoin in rats after inhalation of a powder aerosol

Repeated oral administration of chemopreventive retinoids such as isotretinoin over extended periods of time is associated with intolerable systemic toxicity. Here isotretinoin was formulated as a powder aerosol, and its delivery to the lungs of rats was studied with the aim to explore the possibility of minimizing adverse effects associated with its oral administration. Rats received isotretinoin orally (0.5, 1 or 10 mg kg–1) or by inhalation (theoretical dose ~1 or ~10 mg kg–1) in a nose-only inhalation chamber. Isotretinoin was quantitated by high-pressure liquid chromatography in plasma and lung tissue. The ratios of mean area of concentration-vs-time curve (AUC) values in the lungs over mean AUCs in the plasma for isotretinoin following single or repeated aerosol exposure surpassed those determined for the oral route by factors of between two (single low-dose) and five (single high-dose). Similarly, the equivalent ratios for the maximal peak concentrations in lungs and plasma obtained after aerosol exposure consistently exceeded those seen after oral administration, suggesting that lungs were exposed to higher isotretinoin concentrations after aerosol inhalation than after oral administration of similar doses. Repeated high doses of isotretinoin by inhalation resulted in moderate loss of body weight, but microscopic investigation of ten tissues including lung and oesophagus did not detect any significant aerosol-induced damage. The results suggest that administration of isotretinoin via powder aerosol inhalation is probably superior to its application via the oral route in terms of achieving efficacious drug concentrations in the lungs. © 2000 Cancer Research Campaig

Statin Therapy Alters Lipid Storage in Diabetic Skeletal Muscle

While statins significantly reduce cholesterol levels and thereby reduce the risk of cardiovascular disease, the development of myopathy with statin use is a significant clinical side-effect. Recent guidelines recommend increasing inclusion criteria for statin treatment in diabetic individuals; however, the impact of statins on skeletal muscle health in those with diabetes (who already suffer from impairments in muscle health) is ill-defined. Here we investigate the effects of Fluvastatin treatment on muscle health in wild-type and streptozotocin (STZ)-induced diabetic mice. Wild-type and STZ-diabetic mice received diet enriched with 600 mg/kg Fluvastatin or control chow for 24 days. Muscle morphology, intra and extracellular lipid levels, and lipid transporter content was investigated. Our findings indicate that short-term Fluvastatin administration induced a myopathy that was not exacerbated by the presence of STZ-induced diabetes. Fluvastatin significantly increased ectopic lipid deposition within the muscle of STZ-diabetic animals, findings that were not seen with diabetes or statin treatment alone. Consistent with this observation, only Fluvastatin-treated diabetic mice downregulated protein expression of lipid transporters FAT/CD36 and FABPpm in their skeletal muscle. No differences in FAT/CD36 or FABPpm mRNA content were observed. Altered lipid compartmentalization resultant of a downregulation in lipid transporter content in STZ-induced diabetic skeletal muscle was apparent in the current investigation. Given the association between ectopic lipid deposition in skeletal muscle and the development of insulin-resistance, our findings highlight the necessity for more thorough investigations into the impact of statins in humans with diabetes

Histopathologic findings in malignant peripheral nerve sheath tumor predict response to radiotherapy and overall survival

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and poorly understood malignant neoplasm. Even in the setting of multimodal therapy, the clinical course of MPNST is frequently marked by metastatic conversion and poor overall prognosis, with optimal treatment paradigms for this rare tumor unknown. METHODS: We reviewed the medical records and histopathology of 54 consecutive patients who were treated at University of California San Francisco between 1990 and 2018. RESULTS: Our cohort consisted of 24 male and 30 female patients (median age 38 years). Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) sarcoma grading criteria segregated patients into groups with differences in overall survival (OS) ( CONCLUSIONS: Our results lend support to the FNCLCC sarcoma grading criteria as a prognostic scheme for MPNST, although few cases of grade 1 were included. Further, we identify increased Ki-67 labeling as a strong predictor of poor OS from MPNST. Finally, we identify a subset of MPNSTs with a predictive immunohistochemical profile that has improved local control with adjuvant radiotherapy. These data provide insights into the grading and therapy for patients with MPNST, although further studies are needed for independent validation

Identifying the effect of climate variability on communal conflict through randomization

publishedVersio

Use of sonic tomography to detect and quantify wood decay in living trees.

Premise of the studyField methodology and image analysis protocols using acoustic tomography were developed and evaluated as a tool to estimate the amount of internal decay and damage of living trees, with special attention to tropical rainforest trees with irregular trunk shapes.Methods and resultsLiving trunks of a diversity of tree species in tropical rainforests in the Republic of Panama were scanned using an Argus Electronic PiCUS 3 Sonic Tomograph and evaluated for the amount and patterns of internal decay. A protocol using ImageJ analysis software was used to quantify the proportions of intact and compromised wood. The protocols provide replicable estimates of internal decay and cavities for trees of varying shapes, wood density, and bark thickness.ConclusionsSonic tomography, coupled with image analysis, provides an efficient, noninvasive approach to evaluate decay patterns and structural integrity of even irregularly shaped living trees

Environmental changes and violent conflict

This letter reviews the scientific literature on whether and how environmental changes affect the risk of violent conflict. The available evidence from qualitative case studies indicates that environmental stress can contribute to violent conflict in some specific cases. Results from quantitative large-N studies, however, strongly suggest that we should be careful in drawing general conclusions. Those large-N studies that we regard as the most sophisticated ones obtain results that are not robust to alternative model specifications and, thus, have been debated. This suggests that environmental changes may, under specific circumstances, increase the risk of violent conflict, but not necessarily in a systematic way and unconditionally. Hence there is, to date, no scientific consensus on the impact of environmental changes on violent conflict. This letter also highlights the most important challenges for further research on the subject. One of the key issues is that the effects of environmental changes on violent conflict are likely to be contingent on a set of economic and political conditions that determine adaptation capacity. In the authors' view, the most important indirect effects are likely to lead from environmental changes via economic performance and migration to violent conflict. © 2012 IOP Publishing Ltd

A New Paradigm for Large Earthquakes in Stable Continental Plate Interiors

Large earthquakes within stable continental regions (SCR) show that significant amounts of elastic strain can be released on geological structures far from plate boundary faults, where the vast majority of the Earth's seismic activity takes place. SCR earthquakes show spatial and temporal patterns that differ from those at plate boundaries and occur in regions where tectonic loading rates are negligible. However, in the absence of a more appropriate model, they are traditionally viewed as analogous to their plate boundary counterparts, occuring when the accrual of tectonic stress localized at long-lived active faults reaches failure threshold. Here we argue that SCR earthquakes are better explained by transient perturbations of local stress or fault strength that release elastic energy from a pre-stressed lithosphere. As a result, SCR earthquakes can occur in regions with no previous seismicity and no surface evidence for strain accumulation. They need not repeat, since the tectonic loading rate is close to zero. Therefore, concepts of recurrence time or fault slip rate do not apply. As a consequence, seismic hazard in SCRs is likely more spatially distributed than indicated by paleoearthquakes, current seismicity, or geodetic strain rates

Rates, risk factors & methods of self harm among minority ethnic groups in the UK: a systematic review

<p>Abstract</p> <p>Background</p> <p>Studies suggest that the rates of self harm vary by ethnic group, but the evidence for variation in risk factors has not been synthesised to inform preventive initiatives.</p> <p>Methods</p> <p>We undertook a systematic literature review of research about self harm that compared at least two ethnic groups in the United Kingdom.</p> <p>Results</p> <p>25 publications from 1765 titles and abstracts met our inclusion criteria. There was higher rate of self harm among South Asian women, compared with South Asian men and White women. In a pooled estimate from two studies, compared to their white counterparts, Asian women were more likely to self harm (Relative Risk 1.4, 95%CI: 1.1 to 1.8, p = 0.005), and Asian men were less likely to self harm (RR 0.5, 95% CI: 0.4 to 0.7, p < 0.001). Some studies concluded that South Asian adults self-harm impulsively in response to life events rather than in association with a psychiatric illness. Studies of adolescents showed similar methods of self harm and interpersonal disputes with parents and friends across ethnic groups. There were few studies of people of Caribbean, African and other minority ethnic groups, few studies took a population based and prospective design and few investigated self harm among prisoners, asylum seekers and refugees.</p> <p>Conclusion</p> <p>This review finds some ethnic differences in the nature and presentation of self harm. This argues for ethnic specific preventive actions. However, the literature does not comprehensively cover the UK's diverse ethnic groups.</p