Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI.

Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk. SUMMARY: Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions.

Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel.

The impact of topical antiretrovirals for pre-exposure prophylaxis on humoral responses following HIV infection is unknown. Using a binding antibody multiplex assay, we investigated HIV-specific IgG and IgA responses to envelope glycoproteins, p24 Gag and p66, in the genital tract (GT) and plasma following HIV acquisition in women assigned to tenofovir gel (n=24) and placebo gel (n=24) in the CAPRISA 004 microbicide trial to assess if this topical antiretroviral had an impact on mucosal and systemic antibody responses. Linear mixed effect modeling and partial least squares discriminant analysis was used to identify multivariate antibody signatures associated with tenofovir use. There were significantly higher response rates to gp120 Env (P=0.03), p24 (P=0.002), and p66 (P=0.009) in plasma and GT in women assigned to tenofovir than placebo gel at multiple time points post infection. Notably, p66 IgA titers in the GT and plasma were significantly higher in the tenofovir compared with the placebo arm (P<0.05). Plasma titers for 9 of the 10 HIV-IgG specificities predicted GT levels. Taken together, these data suggest that humoral immune responses are increased in blood and GT of individuals who acquire HIV infection in the presence of tenofovir gel.

Role of long-term mechanical circulatory support in patients with advanced heart failure.

Advanced heart failure represents a small proportion of patients with heart failure that possess high-risk features associated with high hospital readmission rates, significant functional impairment and mortality. Identification of those who have progressed to, or are near a state of advanced heart failure should prompt referral to a service that offers therapies in mechanical circulatory support (MCS) and cardiac transplantation. MCS has grown as a management strategy in the care of these patients, most commonly as a bridge to cardiac transplantation. The predominant utilisation of MCS is implantation of left ventricular assist devices (LVAD), which have evolved significantly in their technology and application over the past 15-20 years. The technology has evolved to such an extent that Destination Therapy is now being utilised as a strategy in management of advanced heart failure in appropriately selected patients. Complication rates have decreased with VAD implantation, but remain a significant consideration in the decision to implant a device, and in the follow up of these patients.

Analysis of T cell responses to chimpanzee adenovirus vectors encoding HIV gag-pol-nef antigen.

Adenoviruses have been shown to be both immunogenic and efficient at presenting HIV proteins but recent trials have suggested that they may play a role in increasing the risk of HIV acquisition. This risk may be associated with the presence of pre-existing immunity to the viral vectors. Chimpanzee adenoviruses (chAd) have low seroprevalence in human populations and so reduce this risk. ChAd3 and chAd63 were used to deliver an HIV gag, pol and nef transgene. ELISpot analysis of T cell responses in mice showed that both chAd vectors were able to induce an immune response to Gag and Pol peptides but that only the chAd3 vector induced responses to Nef peptides. Although the route of injection did not influence the magnitude of immune responses to either chAd vector, the dose of vector did. Taken together these results demonstrate that chimpanzee adenoviruses are suitable vector candidates for the delivery of HIV proteins and could be used for an HIV vaccine and furthermore the chAd3 vector produces a broader response to the HIV transgene.

Outcomes of simultaneous heart-kidney and lung-kidney transplantations: the Australian and New Zealand experience.

BACKGROUND: Heart or lung transplantation alone in individuals with significant pre-existing renal impairment results in high mortality and morbidity. Simultaneous heart-kidney (SHK) or simultaneous lung-kidney (SLK) transplantation may be considered in patients with dual organ failure not suitable for single organ transplantation. AIM: We aimed to outline the Australian and New Zealand experience of SHK and SLK transplantations, focussing on patient characteristics and survival. METHODS: We analysed all SHK and SLK transplants performed in four centres across Australia and New Zealand between 1990 and 2014. RESULTS: Over the study period, 35 SHK and 3 SLK transplants were performed across 4 transplant centres. Mean age at transplantation for SHK transplants was 45 years, and for SLK transplant was 27 years. The most common aetiology of renal failure was glomerulonephritis. Most SHK transplant patients (77%) required renal replacement therapy prior to transplantation, with only one of the three patients undergoing SLK transplant, dialysis dependent. One-year survival for the cohort was 79%, which is lower than reported for single organ transplantation. However, 5- and 10-year survivals of 76% and 68%, respectively, were comparable. Isolated renal graft loss was seen in five patients, with only one patient successfully re-transplanted and the rest commencing dialysis. CONCLUSION: The Australian and New Zealand experience of SHK and SLK includes 38 patients with a high 1-year mortality, but excellent 5- and 10-year survivals. Based on this, it seems reasonable to continue to offer combined organ transplantation to select patients with dual organ failure.

Seizure management at Auckland City Hospital Emergency Department between July and December 2009: time for a change?

AIMS: To assess the management of epileptic seizures and status epilepticus in adult patients at Auckland City Hospital emergency department. This information will form the basis of future seizure management protocols and further research on the management of status epilepticus. METHODS: The prehospital and acute hospital management of all adult seizure patients seen between 1 July 2009 and 31 December 2009 was reviewed with respect to seizure type, presence of first seizure, pre-existing epilepsy diagnosis and disposition from the emergency department. RESULTS: Two hundred and fifty-five seizure events were identified in 227 patients. Nineteen patients presented twice during the study period and three patients presented three or more times. Generalised seizures were much more common than focal seizures. There were 75 presentations with first seizure (29.4%). Thirty-seven patients (49.3%) with a first seizure received treatment with an anti-epileptic drug. Status epilepticus occurred on 12 occasions (4.7%) with only three patients receiving lorazepam as treatment. The majority of seizure patients were managed by emergency department staff (58.4%) while general medicine (17.6%) and neurology (11.8%) teams managed fewer patients. Phenytoin was used in 56 patients (22%) with the majority (n= 43) receiving intravenous phenytoin. Many of the patients who received intravenous phenytoin were not subsequently discharged on that medication (46%). CONCLUSIONS: More patients than would be expected received treatment after their first seizure. Phenytoin was a widely used anti-epileptic drug. There was a wide variability in the management of status epilepticus, and intravenous lorazepam was underutilised.

Medically refractory neurosarcoidosis treated with infliximab.

Neurosarcoidosis can worsen despite standard immunosuppressive therapy, a situation for which there is no established medical management. We present three cases of medically refractory neurosarcoidosis treated with infliximab. All three patients showed a clinical response to this treatment and side effects were limited. A summary of reported cases of neurosarcoidosis treated with infliximab is included. This case series supports a role for infliximab in the treatment of patients with medically refractory neurosarcoidosis.

Outcomes following de novo CNI-free immunosuppression after heart transplantation: a single-center experience.

Renal impairment at the time of heart transplantation complicates the choice of subsequent immunosuppressive therapy. Calcineurin (CNI)-free regimens utilizing proliferation signal inhibitors (PSI) may mitigate against nephrotoxicity in this group; however, their effectiveness remains unclear. We present our 7-year experience with de novo CNI-free, PSI-based immunosuppression after heart transplantation. Of the 152 patients transplanted between July 1999 and July 2006, de novo immunosuppression regimens were 49 CNI-free, PSI-based, 88 CNI, 15 combination of CNI+PSI. Pretransplant creatinine clearance improved within 6 months in the PSI group (0.69 +/- 0.34 mL/s vs. 1.00 +/- 0.54 mL/s, p < 0.05) but not the CNI (1.32 +/- 0.54 mL/s vs. 1.36 +/- 0.53 mL/s, p = ns) or CNI+PSI (1.20 +/- 0.24 mL/s vs. 1.20 +/- 0.41 mL/s, p = ns) groups. The PSI group had more episodes of early (

Doublecortin expression in the normal and epileptic adult human brain.

Mesial temporal lobe epilepsy (MTLE) is a neurological disorder associated with spontaneous recurrent complex partial seizures and hippocampal sclerosis. Although increased hippocampal neurogenesis has been reported in animal models of MTLE, increased neurogenesis has not been reported in the hippocampus of adult human MTLE cases. Here we showed that cells expressing doublecortin (Dcx), a microtubule-associated protein expressed in migrating neuroblasts, were present in the hippocampus and temporal cortex of the normal and MTLE adult human brain. In particular, increased numbers of Dcx-positive cells were observed in the epileptic compared with the normal temporal cortex. Importantly, 56% of Dcx-expressing cells in the epileptic temporal cortex coexpressed both the proliferative cell marker, proliferating cell nuclear antigen and early neuronal marker, TuJ1, suggesting that they may be newly generated neurons. A subpopulation of Dcx-positive cells in the epileptic temporal cortex also coexpressed the mature neuronal marker, NeuN, suggesting that epilepsy may promote the generation of new neurons in the temporal cortex. This study has identified, for the first time, a novel population of Dcx-positive cells in the adult human temporal cortex that can be upregulated by epilepsy and thus, raises the possibility that these cells may have functional significance in the pathophysiology of epilepsy.

MRI of sporadic Creutzfeldt-Jakob disease.

The key MRI findings in five cases of sporadic Creutzfeldt-Jakob disease (CJD) are illustrated with four 'definite' and one 'probable' according to World Health Organization criteria. Close attention to fluid-attenuation inversion recovery and diffusion-weighted imaging sequences are important for diagnosis, noting especially restricted diffusion in cortical and deep grey matter. Our study and those of others show predominant cortical, caudate and thalamic involvement. This pattern is highly sensitive and specific for the diagnosis. Fluid-attenuation inversion recovery and diffusion-weighted imaging signal abnormality becomes progressively more extensive and bilateral as disease progresses, but may become less pronounced in end-stage disease because of atrophy.

Dermatofibrosarcoma protuberans, magnetic resonance imaging and pathological correlation.

Dermatofibrosarcoma protuberans (DFSP) is a rare slow-growing soft tissue tumour which characteristically occurs on the chest, head and neck regions. Typical histologic features include monomorphous spindle-shaped cells arranged in a storiform pattern on a background of fibrous stroma. The tumour has a propensity for local invasion and high recurrence rate. While the imaging features are not pathognomonic of the tumour, the characteristic location and shape should prompt inclusion in the differential diagnostic list.

Adult neurogenesis in mesial temporal lobe epilepsy: a review of recent animal and human studies.

Mesial temporal lobe epilepsy (mTLE) is a neurological condition characterized by the occurrence of spontaneous recurrent seizures originating from mesial structures involving the hippocampus within the temporal lobe. This condition is often associated with pathological features in the hippocampus such as neuronal cell loss, widening of the granule cell layer, astrogliosis and mossy fibre spouting. At present, the mechanisms underlying these pathological features are unclear. However, recent advances in adult neurogenesis studies in mTLE animals and patients suggest that newly generated neurons may contribute to the pathogenesis of ongoing epileptogenesis. This article will review the recent animal and human studies on adult neurogenesis in mTLE and discuss how these results suggests that adult endogenous neurogenesis may not always be reparative in the mTLE and may be targeted in new therapeutic strategies for mTLE.

Differential mechanisms for T lymphocyte recruitment in normal and neoplastic human gastric mucosa.

Worldwide, gastric adenocarcinoma (GC) is the second most common cause of death from malignant disease. The reason why immune responses are unable to clear the tumour is not fully understood, although aberrant lymphocyte recruitment to the tumour site might be one factor. Therefore, we investigated the homing phenotype of mucosal T lymphocytes in GC, compared to tumour-free mucosa. We could detect significantly decreased frequencies of mucosal homing alpha4beta7+ T cells in the tumour tissues and increased frequencies of L-selectin+ T cells. This was probably due to the correlated decrease in MAdCAM-1 positive and increase in PNAd positive blood vessels in the tumour mucosa. There were also fewer CXCR3+ T lymphocytes in the tumour tissue. These findings provide evidence that endothelial cells within tumours arising at mucosal sites do not support extravasation of typical mucosa-infiltrating T cells. This may be of major relevance for future immunotherapeutic strategies for treatment of GC.

Detection of focal cerebral hemisphere lesions using the neurological examination.

OBJECTIVE: To determine the sensitivity and specificity of clinical tests for detecting focal lesions in a prospective blinded study. METHODS: 46 patients with a focal cerebral hemisphere lesion without obvious focal signs and 19 controls with normal imaging were examined using a battery of clinical tests. Examiners were blinded to the diagnosis. The sensitivity, specificity, and positive and negative predictive values of each test were measured. RESULTS: The upper limb tests with the greatest sensitivities for detecting a focal lesion were finger rolling (sensitivity 0.33 (95% confidence interval, 0.21 to 0.47)), assessment of power (0.30 (0.19 to 0.45)), rapid alternating movements (0.30 (0.19 to 0.45)), forearm rolling (0.24 (0.14 to 0.38)), and pronator drift (0.22 (0.12 to 0.36)). All these tests had a specificity of 1.00 (0.83 to 1.00). This combination of tests detected an abnormality in 50% of the patients with a focal lesion. In the lower limbs, assessment of power was the most sensitive test (sensitivity 0.20 (0.11 to 0.33)). Visual field defects were detected in 10 patients with a focal lesion (sensitivity 0.22 (0.12 to 0.36)) and facial weakness in eight (sensitivity 0.17 (0.09 to 0.31)). Overall, the examination detected signs of focal brain disease in 61% of the patients with a focal cerebral lesion. CONCLUSIONS: The neurological examination has a low sensitivity for detecting early cerebral hemisphere lesions in patients without obvious focal signs. The finger and forearm rolling tests, rapid alternating movements of the hands, and pronator drift are simple tests that increase the detection of a focal lesion without greatly increasing the length of the examination.

Down-regulation of epithelial IL-8 responses in Helicobacter pylori-infected duodenal ulcer patients depends on host factors, rather than bacterial factors.

Helicobacter pylori infection is one of the most common gastrointestinal infections worldwide. Although the majority of the infected individuals remain asymptomatic carriers of the bacteria, approximately 15% develop peptic ulcers, which are most prevalent in the duodenum. H. pylori induce a vigorous immune response which, however, fails to clear the infection. Instead, the chronic inflammation that arises in the infected gastroduodenal mucosa may be involved in the development of H. pylori-associated peptic ulcers. We have previously shown that duodenal ulcer (DU) patients have a significantly lower epithelial cytokine, e.g. IL-8, response in the duodenum than asymptomatic (AS) carriers. In this study we have further investigated the mechanisms behind this finding, i.e. whether it can be explained by bacterial factors, down-regulation of epithelial cytokine production by regulatory T cells, or an impaired ability of the duodenal epithelium in DU patients to produce cytokines. Gastric AGS, and intestinal T84 epithelial cell lines were stimulated with H. pylori strains isolated from DU patients and AS carriers, respectively. All strains were found to induce comparable cytokine and cytokine receptor expression in epithelial cells. Regulatory T cells (CD4+ CD25(high)), isolated from human peripheral blood and cocultured with H. pylori stimulated AGS cells, were found to slightly suppress H. pylori-induced epithelial cytokine production. Furthermore, primary cultures of duodenal epithelial cells from DU patients were found to produce markedly lower amounts of cytokines than epithelial cells isolated from AS carriers. These results suggest that the lower epithelial cytokine responses in the duodenum of DU patients, which may be of importance for the pathogenesis of H. pylori-induced duodenal ulcers, most likely can be explained by host factors, i.e. mainly a decreased ability of the duodenal epithelium to produce cytokines, but possibly partly also down-regulation by regulatory T cells.

Cerebral melioidosis.

Two cases of cerebral melioidosis are presented to illustrate the clinical presentation and progress and to highlight the radiological features.

Increased long-term mortality in heart failure due to sleep apnoea is not yet proven.

Previous small-scale studies of the effect of sleep-disordered breathing (SDB) on prognosis in congestive heart failure (CHF) are either lacking or conflicting. The aim of this study was to assess the impact of the presence and type of SDB on mortality in a patient group with severe CHF referred to a specialised heart failure centre. Out of 78 patients ((mean +/- SD) 53 +/- 9 yrs, left ventricular ejection fraction 19.9 +/- 7.2% and pulmonary capillary wedge pressure 16.5 +/- 8.3 mmHg) followed-up over a median period of 52 months, 29% had no apnoea (CHF-N), 28% had obstructive sleep apnoea (CHF-OSA) and 42% had central sleep apnoea (CHF-CSA). At 52 months, their overall mortality was 40%, and combined mortality and transplantation was 72%. Mortality rates were similar between the three apnoea groups. Survivors had a similar prevalence of SDB (71%) as the nonsurvivors (70%). Although a significant increase in mortality was evident at 500 days in those patients with either CHF-SDB or CHF-CSA as compared with CHF-N, this was not significant at final follow-up (52 months) using Kaplan Meier analysis. Multivariate analysis identified transplantation but not SDB type or severity as a significant predictor of survival. In conclusion, sleep-disordered breathing impacts upon early (500 day), but not long-term (52 month), mortality in a specialised heart failure centre.