Chronic sildenafil lowers transpulmonary gradient and improves cardiac output allowing successful heart transplantation

INTRODUCTION: For patients undergoing heart transplantation, an elevated pulmonary vascular resistance (PVR) increases mortality in the early post-heart transplant period. This study aimed to assess the effects of chronic sildenafil administration on the PVR, transpulmonary gradient (TPG), and cardiac output (CO) in patients with heart failure awaiting heart transplantation. METHOD: The data from serial right heart catheterizations (RHC) of six patients were analyzed. All patients demonstrated a reaction to the vasodilators glyceryl trinitrate or inhaled iloprost at initial RHC before commencing sildenafil. A follow-up RHC was performed as required to guide management. RESULTS: The average total daily dose of sildenafil was 100 mg for a period of 68+/-58 days (4-145). The average TPG at baseline was 23.7 mmHg and fell in 4 of the 6 patients (67%) with an average reduction of 4.5+/-7.3 mmHg (-5 to 14). The average PVR at baseline was 571 dyn s cm(-5) and fell in 5 of 6 patients (83%), with an average reduction of 167+/-266 dyn s cm(-5) (74-518). The CO at baseline was 3.95 L/min and rose in 5 of 6 patients (83%) with an average improvement of 0.58 L/min (-1.1 to 1.3). The mean pulmonary capillary wedge pressure (MPCWP) at baseline was 26.3 mmHg and fell in 5 of 6 patients (83%) with an average fall of 5.5 mmHg (-1 to 17). Four of the six patients achieved a final TPG<15 mmHg, which we consider to be acceptable for orthotopic heart transplantation, average 11 mmHg (8 to 13). Three of these patients have already undergone successful, uncomplicated heart transplantation. CONCLUSION: Chronic sildenafil use is safe and effective in reducing an elevated TPG and PVR in patients with heart failure requiring heart transplantation and allows patients to be transplanted who may otherwise have been excluded because of pulmonary hypertension.     

Postconditioning protects human atrial muscle through the activation of the RISK pathway

Ischemic postconditioning (IPost) has been demonstrated to reduce myocardial injury in patients undergoing primary coronary angioplasty for an acute myocardial infarction.Pre-clinical animal studies suggest that pro-survival protein kinases of the Reperfusion Injury Salvage Kinase (RISK) pathway such as Akt and Erk1/2 mediate the cardioprotective effect of IPost.Whether IPost can protect human myocardial tissue ex vivo and whether it recruits the RISK pathway in human myocardium are both not known. To investigate this, atrial appendages were harvested from patients undergoing cardiac surgery. From these samples atrial trabeculae were isolated and mounted on a superperfusion apparatus and subjected to 90 min of hypoxia followed by 120 min of reoxygenation at the end of which function expressed as a percentage of the recovery of baseline contractile function was determined.Atrial trabeculae were randomized to control, hypoxic preconditioning (HPre), hypoxic postconditioning comprising either four 30-s (HPost-30) or 60-s (HPost-60) episodes of alternating hypoxia and reoxygenation, and HPost in the presence or absence of UO126 (a MEK1/2 inhibitor) or LY294002 (a PI3K inhibitor).HPre and HPost-60 improved the recovery of baseline contractile function (45.4±3.2% with HPre and 45.2±2.2% with HPost-60 vs 26.7±2.1 % in control: N≥ 6/group: P<0.05), whereas HPost-30 failed to cardioprotect (28.3±3.4% with HPost-30 vs 26.7±2.1 % in control: N≥ 6/group: P>0.05). The cardioprotective effect of HPost-60 was abolished in the presence of either LY (28.1±2.5% with HPost-60+LY vs 45.2±2.2% with HPost-60: N≥ 6/group: P<0.05) or UO (32.7±1.8% with HPost-60+UO vs 45.2±2.2% with HPost-60:N=7/group: P<0.05). The kinase inhibitors alone had no effect on functional recovery (28.2±3.6% with LY and 30.1±4.8% with UO vs 26.7±2.1 % in control: N≥ 5/group: P>0.05). In conclusion, we demonstrate for the first time that postconditioning protects human myocardium ex vivo and that this effect is dependent on the activation of the RISK pathway.     

A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level

Background

Serum creatinine (S_CR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in S_CR level is explicable by genetic factors.

Methods

We performed a meta-analysis of genome-wide association studies of S_CR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with S_CR (candidate loci) were replicated in two additional population-based samples ('replication cohorts').

Results

After the discovery meta-analysis, 29 loci were selected for replication. Association between S_CR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 × 10^-6 and 1.7 × 10^-4, respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 × 10^-3). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated.

Conclusions

While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABA_A receptors in the regulation of the glomerular basement membrane and a possible interaction between GABA_Areceptors and synaptotagmin-I at the podocyte level.     

Generation of a panel of antibodies against proteins encoded on human chromosome 21

Background  

Down syndrome (DS) is caused by trisomy of all or part of chromosome 21. To further understanding of DS we are working with a mouse model, the Tc1 mouse, which carries most of human chromosome 21 in addition to the normal mouse chromosome complement. This mouse is a model for human DS and recapitulates many of the features of the human syndrome such as specific heart defects, and cerebellar neuronal loss. The Tc1 mouse is mosaic for the human chromosome such that not all cells in the model carry it. Thus to help our investigations we aimed to develop a method to identify cells that carry human chromosome 21 in the Tc1 mouse. To this end, we have generated a panel of antibodies raised against proteins encoded by genes on human chromosome 21 that are known to be expressed in the adult brain of Tc1 mice     

Organ messenger ribonucleic acid and plasma proteome changes in the adjuvant-induced arthritis model: responses to disease induction and therapy with the estrogen receptor-beta selective agonist ERB-041

Two receptors [estrogen receptor (ER)alpha and ERbeta] mediate the manifold effects of estrogens throughout the body. Although a clear role has been established for ERalpha in the classical effects of estrogen activity, the physiological role of ERbeta is less well understood. A small-molecule ERbeta selective agonist, ERB-041, has potent antiinflammatory activity in the Lewis rat model of adjuvant-induced arthritis. To characterize the response of target organs and pathways responsible for this antiinflammatory effect, mRNA expression profiling of the spleen, lymph node, and liver was performed, in conjunction with a global analysis of the plasma proteome. We find that the expression of a large number of genes and proteins are altered in the disease model and the majority of these are partially or fully reversed by ERB-041 treatment. Regulated pathways include the acute-phase response, eicosanoid synthesis, fatty acid metabolism, and iron metabolism. In addition, many of the regulated genes and proteins are known to be dysregulated in human rheumatoid arthritis, providing further evidence that the manifestations of the Lewis rat adjuvant-induced arthritis model bear similarity to the human disease.     

Future research on dementia relating to culturally and linguistically diverse communities

About one in five older Australians were born overseas. However, there has been very little information published in Australia or internationally about dementia in persons from culturally and linguistically diverse (CALD) backgrounds. This limits our ability to plan for and provide evidence‐based medical care, social care and aged care services to persons from CALD backgrounds. This paper describes challenges to conducting CALD dementia research; these include sampling, having valid instruments and costs. Nine key research recommendations in the areas of epidemiology, community knowledge, carers, service delivery, screening and assessment, medical management, residential aged care and minority CALD reached by consensus by an expert group are presented. The paper closes with some strategies to encourage CALD research. The material presented here will provide guidance for future research endeavours.     

Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses

We previously demonstrated that olfactory cultures from individuals with schizophrenia had increased cell proliferation compared to cultures from healthy controls. The aims of this study were to (a) replicate this observation in a new group of individuals with schizophrenia, (b) examine the specificity of these findings by including individuals with bipolar I disorder and (c) explore gene expression differences that may underlie cell cycle differences in these diseases. Compared to controls (n = 10), there was significantly more mitosis in schizophrenia patient cultures (n = 8) and significantly more cell death in the bipolar I disorder patient cultures (n = 8). Microarray data showed alterations to the cell cycle and phosphatidylinositol signalling pathways in schizophrenia and bipolar I disorder, respectively. Whilst caution is required in the interpretation of the array results, the study provides evidence indicating that cell proliferation and cell death in olfactory neuroepithelial cultures is differentially altered in schizophrenia and bipolar disorder.     

Dosing via gavage or diet for reproduction studies: a pilot study using two fat-soluble compounds-hexachlorobenzene and aroclor 1254.

The choice of a dosing route for in vivo toxicological tests is often dictated by practical constraints. Reproduction studies are particularly challenging in this regard since the determination of no-effect levels and allowable daily intakes from reproduction data encompasses exposure of the dam to the test xenobiotic prior to pregnancy, during gestation and during lactation. The fetus/infant can be exposed to the xenobiotic as well as the dam's metabolic products of the test xenobiotic during gestation and lactation. We initiated a series of two-litter, pilot reproduction studies with Sprague-Dawley and Fischer 344 rats to specifically ascertain the amount of xenobiotic and its metabolites ingested by the nursing neonate on lactation days 4, 7, 12, 17 and 21, when its dam received the xenobiotic via its diet or by gavage. The xenobiotics studied in this initial series of experiments were hexachlorobenzene (HCB) and Aroclor(R) 1254 (polychlorinated biphenyls; PCBs). The dams were dosed for 28 days, mated to untreated males and then remated approximately 2 weeks after weaning their first litter to a second untreated male. Dietary levels of 10 ppm HCB or 10 ppm PCBs, and gavage doses of 0.9 mg HCB or 0.8 mg PCBs/kg body weight/day were chosen and resulted in similar doses of HCB and PCBs per unit of the body weight of the dam during the premating period. There were no apparent toxicological effects regarding the dam nor were any of the reproduction parameters (feed consumption, dam weight, litter size, pup weight, external anomalies and day 4 viability index) significantly different from control values. Following impregnation, the body weight of the dam increased appreciably during gestation, but its feed consumption increased only slightly. During lactation, the dam's feed consumption increased markedly while its body weight increased slightly. Consequently, when dams received the xenobiotic in their diet they consumed slightly less xenobiotic per unit of body weight during gestation when compared to the gavaged dams, whereas the situation was dramatically reversed during lactation. While the greater consumption of xenobiotic by the dietary-dosed dams during lactation did result in more HCB (P相似文献   

Successful management of both early and delayed-onset neurological deficit following extent II thoracoabdominal aneurysm repair.

INTRODUCTION: Delayed-onset paraplegia is an uncommon but devastating complication of thoracoabdominal aneurysm repair. REPORT: We report the successful use of repeat cerebrospinal fluid drainage in the management of both immediate- and delayed-onset (21 days) paraplegia in the same patient undergoing open Type II thoracoabdominal aneurysm repair. DISCUSSION: Few studies have looked specifically at preventing delayed onset of symptoms. We advocate continued attention to blood pressure management and hydration for the duration of hospital stay and recommend repeat CSF drainage if symptoms occur.