Aging‐ and vascular‐related pathologies

Our aging population is set to grow considerably in the coming decades. In fact, the number of individuals older than 65 years will double by 2050. This projected increase in people living with extended life expectancy represents an inevitable upsurge in the presentation of age‐related pathologies. However, our current understanding of the impact of aging on a number of biological processes is unfortunately inadequate. Cardiovascular, cerebrovascular, and neurodegenerative diseases are particularly prevalent in the elderly population. Intriguingly, these pathologies are all associated with vascular dysfunction, suggesting that the process of aging can induce structural and functional impairments in vascular networks. Together with elevated cell senescence, pre‐existing comorbidities, and the emerging concept of age‐associated inflammatory imbalance, impaired vascular functions can significantly increase one's risk in acquiring age‐related diseases. In this short review, we highlight some current clinical and experimental evidence of how biological aging contributes to three vascular‐associated pathologies: atherosclerosis, stroke, and Alzheimer's disease.     

Pre‐transplant comorbidity burden and post‐transplant chronic graft‐versus‐host disease

The Haematopoietic Cell Transplantation‐Comorbidity Index (HCT‐CI) was designed as a predictor of non‐relapse mortality after HCT. Chronic graft‐versus‐host disease (GVHD) contributes to mortality after HCT. Here, we investigated whether the HCT‐CI could predict development of chronic GVHD or post‐chronic GVHD mortality. We retrospectively analysed data from 2909 patients treated with allogeneic HCT for malignant and non‐malignant haematological conditions at four institutions. In Cox regression models adjusted for potential confounders, increasing HCT‐CI was not statistically significantly associated with the development of chronic GVHD [hazard ratio (HR) = 1·02, P = 0·34]. Yet, the index was associated with an increased risk of non‐relapse mortality (HR = 1·29, P < 0·0001) as well as overall mortality (HR = 1·25, P < 0·001) following the development of chronic GVHD. The association between HCT‐CI and post‐chronic GVHD mortality was similar regardless of donor type or stem cell source. HCT‐CI scores could be incorporated in the design of clinical trials for treatment of chronic GVHD.     

Periplogenin‐3‐O‐ ‐D‐Glucopyranosyl ‐(1→6)‐ ‐D‐Glucopyaranosyl‐ ‐(1→4) ‐D‐Cymaropyranoside,Isolated from Aegle marmelos Protects Doxorubicin Induced Cardiovascular Problems and Hepatotoxicity in Rats

Doxorubicin is a common chemotherapeutic anticancer drug. Its use is associated with adverse effects including cardiotoxicity. Several therapeutics interventions have been attempted to reduce the toxicity and to improve the efficacy of the drug. However, on phytochemicals very few investigations have been made. In the present study we have evaluated the potential of a cardenolide, periplogenin, isolated from the leaves of Aegle marmelos in protecting the doxorubicin induced cardiotoxicity and lipid peroxidation (LPO) in rats. Doxorubicin induced cardiac and hepatotoxicity were characterized by marked biochemical changes including an increase in serum creatine kinase–MB (CK–MB), glutamate‐pyruvate transaminase (SGPT), and tissue LPO, with a decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). It also increased the levels of different serum lipids, but decreased the amount of high‐density lipoprotein (HDL). Cotherapy of the test cardenolide and doxorubicin for 4 weeks reversed all these adverse effects. However, out of three different concentrations (12.5, 25, and 50 mg/kg p.o.) of the test periplogenin, 25 mg/kg appeared to be most effective. When its efficacy was compared with that of vitamin E (α‐tocopherol) the isolated compound exhibited a better therapeutic potential. The isolated periplogenin from the leaves of A. marmelos could potentially inhibit doxorubicin‐induced cardiovascular problems in rats. However, its moderate dose was found to be most effective.     

RET‐rearranged non‐small‐cell lung cancer and therapeutic implications

First‐line tyrosine kinase inhibitors are standard of care for non‐small‐cell lung cancers (NSCLC) harbouring an epidermal growth factor receptor mutation, anaplastic lymphoma kinase fusion or c‐ros oncogene 1 rearrangement. Other targetable oncogenic drivers have been identified but testing for these is neither funded nor commonly performed in Australia. Using a case example, we discuss the importance of considering several other genomic aberrations in our population, such as rearrangements in the RET proto‐oncogene, which occur in 1–2% of lung adenocarcinoma. New oncogenic drivers and corresponding targeted agents are constantly being discovered; these will continue to refine the treatment of non‐small‐cell lung cancer in the era of precision medicine.     

Electrocardiographic T‐ and U‐Wave Discordance

Background: Abundant information has been reported regarding the U wave, which almost entirely has been focused on U waves in isolation. There has been little investigation of discordant T and U waves. Methods: Of 18,750 consecutively recorded electrocardiograms, 143 patients were categorized resulting in three groups. Group A: 53 patients with negative T waves and positive U waves (Type I Discordance); Group B: 26 patients with positive T waves and negative U waves (Type II Discordance); and Group C: 63 patients with negative T and negative U waves. Each patient's chart was reviewed for relevant clinical, laboratory, and medical history. Results: Coronary disease was slightly more common in Group A (64%) than in Group B (46%) (P = 0.174; ns). Coronary disease in Group C was extremely common (88%; P <0.001). Hypertension in the two discordant groups was similar: Group A (60%) versus Group B (58%) (P = ns), Group C was significantly higher (88%) (P <0.001). Left ventricular hypertrophy was 49% in Group A and 58% in Group B (P = ns), but Group C was significantly higher at 70% (P = 0.038). Conclusions: This appears to be the first investigation of the associations of discordant T and U waves. We found that the significance of any U wave is not independent of their respective T wave. In addition, we propose that the U wave not be analyzed in isolation, but rather with respect to its T wave.     

Feasibility and acceptability of CD‐ROM‐based cognitive‐behavioural treatment for binge‐eating disorder

We compared preliminary feasibility and acceptability of CD‐ROM‐delivered CBT for overweight individuals with binge‐eating disorder (BED) to 10 weekly group CBT sessions (Group) and to a waiting list control (WL). Attrition was numerically greater in the Group than the CD‐ROM condition; although only Group differed significantly from WL in dropout rates. Those in the CD‐ROM condition reported continued use of their CD‐ROM after treatment. Also, the majority of WL participants elected to receive CD‐ROM over Group treatment at the end of the waiting period. Preliminarily, no significant differences emerged across the active treatment groups on most outcome measures. However, there was a significantly greater decline in binge days in the two active groups relative to WL. CD‐ROM appears to be an acceptable and at least initially preferred method of CBT delivery for overweight individuals with BED. Copyright © 2007 John Wiley & Sons, Ltd and Eating Disorders Association.     

Adenoma‐like and non‐adenoma‐like dysplasia‐associated lesion or mass in ulcerative colitis

Ulcerative colitis (UC) patients have an increased risk of colorectal cancer. UC has two general patterns of dysplasia, which are commonly classified as adenoma‐like dysplasia‐associated lesion or mass (DALM) and non‐adenoma‐like DALM. The latter has a high risk of concurrent malignancy and often requires a colectomy. Unfortunately, non‐adenoma‐like DALMs sometimes have endoscopic features similar to those of adenoma‐like DALMs. Therefore, new endoscopic techniques to distinguish between these two kinds of DALM have been proposed.     

N‐Methyl‐d‐Aspartate Induces Cortical Hyperemia through Cortical Spreading Depression‐Dependent and ‐Independent Mechanisms in Rats

Objective: N‐methyl‐d ‐aspartate (NMDA) is a powerful cerebrovascular dilator in vivo. Cortical spreading depression (CSD) has recently been shown to contribute to the pial arteriolar dilation in mice. Our main aim was to examine the participation of CSD in the overall cerebrovascular response to NMDA in the rat. Methods: Anesthetized Wistar rats (eight weeks old) were equipped with a closed cranial window to allow topical application of NMDA (10^?5–10^?3 M) to the parietal cortex. Cortical blood flow (CoBF) under and outside the cranial window was simultaneously monitored by using a two‐channel laser‐Doppler flowmeter. CSDs were detected by recording the changes in the cortical DC potential. Results: Concentrations of 10^?4 and 10^?3 M of NMDA evoked single CSDs associated with rapid, transient hyperemia, followed by a sustained, but reduced, increase in CoBF. The latency and magnitude of the CoBF responses were dose dependent. The higher dose resulted in shorter latency (100±5* vs. 146±11 seconds, *P<0.05; mean±standard error of the mean) and larger overall flow response (77±12* vs. 28±3% from baseline) under, but not outside, the cranial window. Conclusions : NMDA elicits dose‐dependent increases in CoBF that are composed of CSD‐dependent and ‐independent components in rats.     

Over‐expression of Toll‐like receptors and their ligands in small‐for‐size graft

Aim: Toll‐like receptors (TLRs) participate in several physiological and pathological processes of transplantation, including inflammation and allograft rejection, but the expression of TLRs and their ligands remains undetermined in small‐for‐size graft transplantation. Methods: A non‐arterialized partial liver transplantation model was used. The expression of TLR2 and TLR4 mRNA and protein, CD14 and Myeloid Differentiation‐2 (MD‐2) mRNA, as well as TLR2 and TLR4 exogenous ligands (endotoxin) and endogenous ligands [heat shock protein (HSP) 60 and 70] were assessed. The signaling pathways induced by TLR2 and TLR4 were also assessed. Results: In small‐for‐size liver graft, the expression of mRNA and protein of TLR2 and TLR4, CD14 and MD‐2 mRNA, as well as endogenous ligands of TLR2 and TLR4 such as HSP60 and HSP70 was quickly and significantly increased after reperfusion, and reached a peak at 3 h after reperfusion. The levels of exogenous ligands (endotoxin) were increased and reached a peak at 6 h after reperfusion. The appearance of TLR2 and TLR4 mRNA was accompanied by increased HSP 60 and 70 mRNA within 24 h after reperfusion. In the small‐for‐size group, the peak levels of TLRs and their endogenous ligands appeared earlier than those in the full size group; the peak levels of TLRs and their endogenous and exogenous ligands were higher than those in the full size group. Conclusion: TLR2 and TLR4, as well as their endogenous and exogenous ligands were activated in small‐for‐size liver graft transplantation.     

Step‐by‐step StentBoost‐guided small vessel stenting using the self‐expandable sparrow stent‐in‐wire

A 56 year‐old woman underwent percutaneous coronary intervention for a lesion in a small mid‐left anterior descending coronary artery (reference vessel diameter by quantitative coronary angiography: 2.11 mm) with a novel drug‐eluting stent specifically designed for small vessels, the CardioMind Sparrow stent delivery system. This is a self‐expandable sirolimus‐eluting nitinol stent directly mounted into a 0.014‐inch coronary guidewire. The stent has a very thin strut thickness (67 micron), limiting its radiopacity. A specific X‐ray stent‐enhancing visualization technique, “StentBoost”, allowed clear visualization and understanding of the steps needed for an appropriate release and deployment of the aforementioned stent. © 2008 Wiley‐Liss, Inc.