Prognostic significance of peak oxygen consumption ≤ 10 ml/kg/min in heart failure: Context vs. criteria

Background

Both heart failure (HF) treatment and management may distort or enhance the predictive accuracy of low peak oxygen consumption (pVO₂ ≤ 10 ml/kg/min), blurring the identification of specific patients in whom heart transplantation (HT) could make a clinical difference. The aim of this study was to re-evaluate the prognostic significance of pVO₂ ≤ 10 ml/kg/min in systolic HF in light of changes in medical treatment and management.

Methods

Two-year outcomes were compared across the “millennium dawn” (MD) between two HF cohorts with pVO₂ ≤ 10 ml/kg/min and gas exchange ratio > 1.10: 116 patients were recorded between 1994 and 1999 (pre-MD: mean pVO₂ 8.6 ± 1.1 ml/kg/min) and 90 between 2001 and 2008 (post-MD: mean pVO₂ 8.8 ± 1.0 ml/kg/min). Cardiac-related death was considered an event and event censoring was interrupted at 24 months for surviving patients.

Results

Patients across the MD had the same age, NYHA class, left ventricular ejection fraction and pVO₂ (pre-MD: mean pVO₂ 8.6 ± 1.1; post-MD: mean pVO₂ 8.8 ± 1.0 ml/kg/min: NS). Seventy-one patients (34%) died: 51 (44%) in the pre-MD and 20 (22%) in the post-MD group (p < 0.01). The post-MD group showed a better mean 1-year (83% vs. 68%; χ² = 5.17, p = 0.0229) and 2-year survival (77% vs. 56%; χ² = 8.87, p = 0.0029) compared to pre-MD patients.

Conclusions

Two-year outcome of HF patients with pVO₂ ≤ 10 ml/kg/min has significantly improved in the post-MD era, suggesting the HT indication should not rely on a single CPET parameter, rather on a multifactorial clinical approach.     

Effect of an Aluminum Hydroxide-Magnesium Hydroxide Combination Drug on Adhesion,IL-8 Inducibility,and Expression of HSP60 by Helicobacter pylori

Background: Co-magaldrox (Maalox®) is used world-wide as an antacid and as a cytoprotective agent for gastritis and peptic ulcer diseases. We examined the effects of co-magaldrox on Helicobacter pylori. Methods: Adhesion of H. pylori to human gastric epithelial cells (MKN45) was evaluated by flow cytometry. Morphologic changes in H. pylori caused by co-magaldrox were determined by scanning electron microscopy. Induction of interleukin-8 (IL-8) from MKN45 cells was examined with enzyme-linked immunosorbent assay, and the intracellular and extracellular expression of heat-shock protein 60 (HSP60) was analyzed with sodium dodecyl sulphate-polyacrylamide gel electrophoresis and flow cytometry. Results: Adhesion of H. pylori to MKN 45 cells was significantly inhibited by 1.25%-5% co-magaldrox. H. pylori aggregated with co-magaldrox according to an electron microscopic examination. IL-8 secretion from MKN45 cells after H. pylori infection was also inhibited by co-magaldrox. Extracellular expression of HSP60 on the surface of H. pylori was decreased after treatment with co-magaldrox, whereas the intracellular synthesis of HSP60 was not. HSP60-induced IL-8 secretion was significantly inhibited by co-magaldrox in a dose-dependent manner. Conclusions: These results show that co-magaldrox suppressed the expression of the following virulence factors: adhesion, IL-8 inducibility, and expression of extracellular HSP60. Therefore, co-magaldrox is a potent anti-H. pylori and cytoprotective drug.     

Idiopathic pneumonia syndrome with thrombotic microangiopathy-related changes after allogeneic hematopoietic stem cell transplantation

Idiopathic pneumonia syndrome (IPS), defined as widespread alveolar injury, is a severe complication of hematopoietic stem cell transplantation (HSCT) and a clinical syndrome with variable histopathologic correlates and multiple etiologies. Transplantation-associated thrombotic microangiopathy (TMA) is another severe complication of HSCT. TMA occurs when endothelial injury causes thrombosis and fibrin deposition in the organ microcirculation. We present a case of IPS with TMA-related changes in the lungs following HSCT. A 54-year-old woman underwent an allogeneic HSCT for refractory multiple myeloma. During transplantation, cyclosporine was administered for prophylaxis against graft-versus-host disease, but she developed respiratory failure after she was weaned off the drug. A computed tomography scan revealed ground-glass attenuation and reticular opacity in the bilateral whole-lung fields. Bronchoscopy indicated no evidence of infection, and IPS was diagnosed. High-dose steroids and etanercept were ineffective, and she died 1 month after the onset of IPS. Autopsy revealed diffuse alveolar damage, and stenosis or obstruction due to intimal thickening and thrombi resulting from endothelial injury in the arterioles of both lungs. We retrospectively diagnosed TMA based on the histological and clinical findings. To our knowledge, this is the first report suggesting the possible role of TMA in the clinical course of IPS.     

Nuclear medical PET-study in the causal relationship between mastication and brain function in human evolutionary and developmental processes

The principal author (Kubote 1995, 1997, 1998, 1999, 2000a, b) has proposed that chewing food well from infancy will lead to a clear-headed and robust person, following which the same concept has been presented to the general public by the mass media. Unfortunately, however, there does not yet seem to be any direct evidence to support this claim. It is thus necessary to review mastication from the standpoint of the new concept of evidence-based medicine (EBM) and to create a new direction in medicodental research and treatment from the viewpoint of human evolution, because the causal relationship between mastication and brain function has never been clarified either in fossil science research or in the modern scientific bibliography.

To confirm the human historical fossil record in regard to the causal relationship between the development of mastication and brain function in human evolutionary processes, the effect of gum chewing on brain reaction was examined in humans by means of a positron-emission tomography (PET) camera (Momose et al. 1997) after an antecubital intravenous injection of H₂¹⁵O.

Powerful activation of the cortical cells was demonstrated in multiple cortical areas involving the marginal areas of the bilateral central sulci of the cerebral cortex (Fig. 1), and the activated areas coincided with our previous results in region of interest (ROI) analysis (Momose et al. 1887). Three-dimensionally, numerous cortical cells were shown to form nuclei on relief maps (Fig. 2).

As diets and feeding habits changed in a stepwise manner from frugivorous to omnivorous via herbivorous and carnivorous over the lengthy progress of evolution, the brain concomitantly grew and the cranial capacity gradually increased in volume from 500 cm³, food from plant sources to animal sources (700 cm³), and then to both (1500 cm³), during the human evolutionary and developmental processes.

Gradual increases in the cranial capacity of human fossils during the developmental stage have been demonstrated also by PET images of the human brain acquired by means of a PET camera and an antecubital intravenous injection of H₂¹⁵O during mastication that showed powerful activation of cortical cells in multiple areas. It could be concluded that human fossils give us concrete information on how to feed our children in the modern human life style from infancy to adulthood, so that we should bring children up by adhering to images of the principal feeding habits discovered during this research on human evolutionary and developmental processes.     

Pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in cynomolgus monkeys

Mirabegron is a novel β₃-adrenoceptor agonist developed for the treatment of overactive bladder. To clarify the relationship between the pharmacological effects of mirabegron in monkeys and the clinical efficacy in patients with overactive bladder, the effect of mirabegron on bladder function was evaluated using cynomolgus monkeys. Quantitative PCR revealed that mRNA expression of β₃-adrenoceptors was most abundant (98 %) among β-adrenoceptor subtypes in the bladder of cynomolgus monkeys. Mirabegron, which showed selective and potent agonistic activity on monkey β₃-adrenoceptors expressed in Chinese hamster ovary cells with EC₅₀ value of 32 nmol/L and intrinsic activity of 0.8, induced concentration-dependent relaxation of bladder smooth muscle strips isolated from cynomolgus monkeys with EC₅₀ values of 120 nmol/L in 20 mmol/L KCl stimulation and 43 nmol/L under 9.81 mN resting tension. In conscious cynomolgus monkeys, mirabegron decreased micturition frequency at oral doses of 1 and 3 mg/kg and increased mean volume voided per micturition at an oral dose of 3 mg/kg. Plasma concentration at which bladder function improved in the cynomolgus monkeys was similar to that at the clinically effective dose in patients with overactive bladder. These data suggest that the relaxant function in monkey bladder is mainly mediated by β₃-adrenoceptors similar to that in the human bladder and mirabegron showed efficacy on the bladder functions of the same parameters in clinical evaluation endpoints.     

Microcapsulation of DNA and the adsorption of toxic substances

This study reports on deoxyribonucleic acid (DNA) immobilization in a microcapsule and the adsorption of toxic substances. Salmon testes DNA was immobilized using a microencapsulation method and the immobilization efficiency of DNA, stability of microcapsulated DNA and adsorption properties of toxic substances were investigated under various experimental conditions. This study succeeded in immobilizing over 90% of DNA in the DNA dosage based on the thymine base and the microcapsulation of DNA showed high reproducibility for immobilization efficiency. Immobilized DNA in the microcapsules did not leak, regardless of the salt concentration and pH values in the external aqueous phase. Microcapsulated DNA could selectively adsorb toxic substances that have a planar structure. Based on these results, it was shown that the microcapsulated DNA is a good adsorbent for toxic substances and the microcapsulation method is useful for immobilizing DNA in a polymer matrix.     

Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties

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Multiplex genomic profiling of non–small cell lung cancers from the LETS phase III trial of first-line S-1/carboplatin versus paclitaxel/carboplatin: results of a West Japan Oncology Group study

Archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected from advanced NSCLC patients enrolled in LETS phase III trial comparing first-line S-1/carboplatin with paclitaxel/carboplatin and subjected to multiplex genotyping for 214 somatic hotspot mutations in 26 genes (LungCarta Panel) and 20 major variants of ALK, RET, and ROS1 fusion genes (LungFusion Panel) with the Sequenom MassARRAY platform. MET amplification was evaluated by fluorescence in situ hybridization. A somatic mutation in at least one gene was identified in 48% of non–squamous cell carcinoma and 45% of squamous cell carcinoma specimens, with EGFR (17%), TP53 (11%), STK11 (9.8%), MET (7.6%), and KRAS (6.2%). Mutations in EGFR or KRAS were associated with a longer or shorter median overall survival, respectively. The LungFusion Panel identified ALK fusions in six cases (2.5%), ROS1 fusions in five cases (2.1%), and a RET fusion in one case (0.4%), with these three types of rearrangement being mutually exclusive. Nine (3.9%) of 229 patients were found to be positive for de novo MET amplification. This first multiplex genotyping of NSCLC associated with a phase III trial shows that MassARRAY-based genetic testing for somatic mutations and fusion genes performs well with nucleic acid derived from FFPE specimens of NSCLC tissue.     

Use of colony-stimulating factor in patients with ovarian cancer receiving paclitaxel and carboplatin in Japan

Objective

To assess the use of colony-stimulating factors (CSFs) in patients with ovarian cancer who receive adjuvant paclitaxel and carboplatin chemotherapy in clinical practice and to assess whether the frequency of CSF use differs among hospitals in Japan.

Methods

CSF use in patients with ovarian cancer who received first-line paclitaxel and carboplatin was analyzed retrospectively using data from the Japanese hospitalization payment system.

Results

A total of 1,050 patients at 104 hospitals were identified. The median age was 60 years (range, 22 to 88 years). Of these, 163 patients (15.5%) were diagnosed with neutropenia and 134 patients (12.8%) received CSFs. Among the patients who received CSFs, 125 (93%) received them for the treatment of neutropenia without fever and 1 received them for febrile neutropenia. In total, CSFs were administered for 272 cycles of chemotherapy. Among them, CSFs were used as treatment for neutropenia without fever in 259 cycles (95%), as prophylaxis (primary or secondary) in 12 cycles (4%), and as treatment for febrile neutropenia in 1 cycle. Among hospitals, a median of 4.0% of patients received CSFs with an interquartile range of 25% (Q1, 0%; Q3, 25%). A logistic random effects model showed that the variation in the proportion of patients receiving CSFs among the 104 hospitals was 2.0 (p<0.001), suggesting that the use of CSFs varied across hospitals.

Conclusion

Most patients received CSFs for neutropenia without fever. Standardized and evidence-based use of CSFs is critically required among hospitals in Japan.     

Aneurysm expansion after stent-graft placement in the absence of endoleak

Sixty-three patients with thoracic or abdominal aortic aneurysms were treated with endovascular stent-grafts. No endoleak was identified at any interval of follow-up in 58 patients. In four of them (7%), the aneurysms expanded by 10 mm or more during follow-up and additional interventions were required. Aneurysm expansion was caused by inappropriate sealing at the aneurysmal necks in two patients and transgraft seroma in the other two. Although some aneurysm expansion could be avoided by proper patient selection and accurate placement of stent-grafts, it seems difficult to predict aneurysm expansion in most cases.