Oxygen - a limiting factor for brain recovery

Effective brain metabolism is highly dependent on a narrow therapeutic window of oxygen. In major insults to the brain (e.g., intracerebral hemorrhage), a slight decrease in oxygen supply, as occurs in a hypobaric environment at high altitude, has devastating effects on the injured brain tissue. Conversely, increasing brain oxygenation, by the use of hyperbaric oxygen therapy, can improve brain metabolism and its dependent regenerative processes.     

The role of previously unmeasured organic acids in the pathogenesis of severe malaria

IntroductionSevere falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria.MethodsIn this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death.ResultsPatients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean±SD) was elevated in severe malaria (8.2 mEq/L±4.5) and severe sepsis (8.6 mEq/L±7.7) compared with uncomplicated malaria (6.0 mEq/L±5.1) and encephalopathy (6.6 mEq/L±4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6–7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5–7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).ConclusionsNewly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1023-5) contains supplementary material, which is available to authorized users.     

The hepatitis C virus (HCV)-Trimera mouse: a model for evaluation of agents against HCV.

The lack of small-animal models that are suitable for evaluation of agents used to treat infection with hepatitis C virus (HCV) severely hinders the assessment of potential new therapies for the disease. This study created such a model, termed the "HCV-Trimera" model. The HCV-Trimera model was developed by using lethally irradiated mice, reconstituted with SCID mouse bone marrow cells, in which human liver fragments infected ex vivo with HCV had been transplanted. Viremia (positive-strand HCV RNA levels) in HCV-Trimera mice peaked at approximately day 18 after liver transplantation, and an infection rate of 85% was reached. Viral replication in liver grafts was evidenced by the presence of specific negative-strand HCV RNA. The usefulness of this model for evaluation of anti-HCV agents was demonstrated by the ability of a small molecule (an HCV internal ribosomal entry site inhibitor) and an anti-HCV human monoclonal antibody (HCV AB(XTL)68) to reduce virus loads in HCV-Trimera mice in a dose-dependent manner.     

Altered Endothelial Function in Asymptomatic Male Adolescents with Type 1 Diabetes

Objective. While adult men and women with diabetes experience similar rates of cardiovascular disease, early microvascular complications show significant gender differences during adolescence. The goal of this study was to determine whether a gender contrast in a preclinical stage of atherosclerosis, or endothelial dysfunction, is present in pediatric diabetic patients. Methods. Reactive hyperemia‐peripheral arterial tonometry (RH‐PAT), a noninvasive method to assess endothelial dysfunction, was used. Measurements were performed at rest and after hyperemia in 20 diabetic subjects and 20 age‐ and gender‐matched nondiabetics, aged 12–16 years. Confounding risk factors for endothelial dysfunction, including smoking, obesity, and hypertension, were excluded. Results. RH‐PAT was lower for male diabetic subjects vs. controls (n = 12, 1.60 ± 0.32 vs. 1.92 ± 0.28, P < .001). RH‐PAT was similar in female diabetic patients vs. controls. Male and females with type 1 diabetes subjects had equivalent metabolic control (HbA1C 7.48 ± 1.0 vs. 7.51 ± 0.9) and lipid profiles. No difference was observed in age, HbA1C, and diabetes duration, between male and female diabetic subjects. However, diabetic female patients had a greater body mass index (24.2 ± 2.5 vs. 20.6 ± 2.0, P = .003) and were more mature in pubertal status as compared with diabetic male patients. Conclusion. Endothelial dysfunction was present in adolescent male diabetic subjects as measured using RH‐PAT. Considering that endothelial dysfunction is reversible, early detection of this process may have theurapeutic and prognostic implications in this young age group.     

Economic evaluation of hormonal therapies for postmenopausal women with estrogen receptor–positive early breast cancer in Canada

Background

Aromatase inhibitor (ai) therapy has been subjected to numerous cost-effectiveness analyses. However, with most ais having reached the end of patent protection and with maturation of the clinical trials data, a re-analysis of ai cost-effectiveness and a consideration of ai use as part of sequential therapy is desirable. Our objective was to assess the cost-effectiveness of the 5-year upfront and sequential tamoxifen (tam) and ai hormonal strategies currently used for treating patients with estrogen receptor (er)–positive early breast cancer.

Methods

The cost-effectiveness analysis used a Markov model that took a Canadian health system perspective with a lifetime time horizon. The base case involved 65-year-old women with er-positive early breast cancer. Probabilistic sensitivity analyses were used to incorporate parameter uncertainties. An expected-value-of-perfect-information test was performed to identify future research directions. Outcomes were quality-adjusted life-years (qalys) and costs.

Results

The sequential tam–ai strategy was less costly than the other strategies, but less effective than upfront ai and more effective than upfront tam. Upfront ai was more effective and less costly than upfront tam because of less breast cancer recurrence and differences in adverse events. In an exploratory analysis that included a sequential ai–tam strategy, ai–tam dominated based on small numerical differences unlikely to be clinically significant; that strategy was thus not used in the base-case analysis.

Conclusions

In postmenopausal women with er-positive early breast cancer, strategies using ais appear to provide more benefit than strategies using tam alone. Among the ai-containing strategies, sequential strategies using tam and an ai appear to provide benefits similar to those provided by upfront ai, but at a lower cost.     

Multiple Myeloma and Atopic Eczema in an Adult

Multiple myeloma is the fourteenth cause of cancer-related death. The symptoms of myeloma are mostly nonspecific, and there is significant delay between the first symptoms and diagnosis of myeloma. Atopic eczema is a common chronic inflammatory skin disease associated with dysregulation of the immune system. It generally develops in early childhood but can also occur in adults. Eczema is associated with a variety of hematological and solid malignancies, and possibly multiple myeloma. We report a patient with eczema that developed 5 years before the diagnosis of multiple myeloma but was mistaken for psoriasis.Key Words: Multiple myeloma, Atopic eczema, Early symptoms, Diagnostic criteria     

Collagenous matrix supported by a 3D-printed scaffold for osteogenic differentiation of dental pulp cells

Objective

A systematic characterization of hybrid scaffolds, fabricated based on combinatorial additive manufacturing technique and freeze-drying method, is presented as a new platform for osteoblastic differentiation of dental pulp cells (DPCs).