Noradrenergic neuromodulation in ageing and disease.

The locus coeruleus (LC) is a small brainstem structure located in the lower pons and is the main source of noradrenaline (NA) in the brain. Via its phasic and tonic firing, it modulates cognition and autonomic functions and is involved in the brain's immune response. The extent of degeneration to the LC in healthy ageing remains unclear, however, noradrenergic dysfunction may contribute to the pathogenesis of Alzheimer's (AD) and Parkinson's disease (PD). Despite their differences in progression at later disease stages, the early involvement of the LC may lead to comparable behavioural symptoms such as preclinical sleep problems and neuropsychiatric symptoms as a result of AD and PD pathology. In this review, we draw attention to the mechanisms that underlie LC degeneration in ageing, AD and PD. We aim to motivate future research to investigate how early degeneration of the noradrenergic system may play a pivotal role in the pathogenesis of AD and PD which may also be relevant to other neurodegenerative diseases.

The effect of dexmedetomidine on postoperative behaviour change in children: a randomised controlled trial.

Children may develop changes in their behaviour following general anaesthesia. Some examples of negative behaviour include temper tantrums and nightmares, as well as sleep and eating disorders. The aim of this study was to determine whether dexmedetomidine reduces the incidence of negative behaviour change after anaesthesia for day case surgery in children aged two to seven years. Children were randomly allocated to one of three groups: a premedication group received 2 mg.kg-1 intranasal dexmedetomidine; an intra-operative group received 1 mg.kg-1 intravenous dexmedetomidine; and a control group. The primary outcome was the incidence of negative behaviour on postoperative day 3 using the Post-Hospitalisation Behaviour Questionnaire for Ambulatory Surgery (PHBQ-AS) and the Strength and Difficulties Questionnaire (SDQ). Secondary outcomes included: the incidence of negative behaviour on postoperative days 14 and 28; anxiety at induction; emergence delirium; pain; length of recovery and hospital stay; and any adverse events. The data for 247 patients were analysed. Negative behaviour change on postoperative day 3 was similar between all three groups when measured with the PHBQ-AS (47%, 44% and 51% respectively; adjusted p=0.99) and the SDQ (median scores 7.5, 6.0 and 8.0 respectively; adjusted p=0.99). The incidence of negative behaviour in the group who received dexmedetomidine intra-operatively was less at postoperative day 28 (15% compared with 36% in the dexmedetomidine premedication group and 41% in the control group, p<0.001). We conclude that dexmedetomidine does not reduce the incidence of negative behaviour on postoperative day 3 in two to seven-year olds having day case procedures.

Intensity-Modulated Radiotherapy With a Simultaneous Integrated Boost in Rectal Cancer.

AIMS: Dose-response curves suggest that higher doses of radiotherapy improve the complete response rate in rectal cancer. The UK adopted the EXPERT trial dose and fractionation, 45 Gy in 25 fractions to the pelvis with a sequential 9 Gy in five fractions to the gross tumour, in patients where the aim was to maximise the complete response. In the Oxford University Hospital NHS Foundation Trust (Oxford, UK) we deliver a biological equivalent dose (BED5) in selected patients using intensity-modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) in 25 fractions. We carried out a retrospective analysis of our series to: (i) document the toxicity of this protocol; (ii) ascertain whether dose constraints from RTOG 0822 were appropriate; (iii) assess the response. MATERIALS AND METHODS: The demographics and treatment details for all consecutive patients treated with this protocol were collected using electronic systems. Patients received 45 Gy to the elective nodes and 52 Gy using a SIB to the gross tumour with capecitabine chemotherapy using IMRT or RapidArc plans. Acute toxicity was collected prospectively during weekly reviews. For the purpose of this study, a dedicated gastrointestinal radiologist reviewed all baseline and post-treatment magnetic resonance images and assigned a magnetic resonance tumour regression grade (mrTRG). RESULTS: Seventy-one patients were identified. Seventy completed radiotherapy with a median overall treatment time of 34 days (range 32-36 days); 67.6% received full-dose chemotherapy, with 21.2% receiving a reduced dose. There was a 4.2% incidence of grade 3+ non-haematological toxicity and 1.5% grade 3 + haematological toxicity. 4.2% were admitted during their radiotherapy, with one death due to a pelvic abscess. The RTOG 0822 constraints were achieved in ≥75% of cases, other than the high-dose bladder constraint. mrTRG 1-2 was seen in 47.8%, with mrTRG 1 seen in 23.9%. CONCLUSIONS: We suggest that our protocol shows acceptable acute toxicity, with promising mrTRG results, and could be adopted by centres as an IMRT equivalent dose for EXPERT dose and fractionation.

Neoadjuvant radiotherapy in rectal cancer - less is more?

AIM: There is significant international variation in the use of neoadjuvant radiation prior to total mesorectal excision. The MERCURY group advocate selective neoadjuvant chemoradiotherapy (CRT). We have performed a retrospective, single-centre study of patients treated with CRT, where only the circumferential resection margin is threatened, with the aim of identifying whether a more selective approach to CRT provides acceptable local relapse rates (LRRs). METHOD: All consecutive patients who underwent radical surgery for rectal adenocarcinoma over a 5-year period (2007-2012) in the Oxford University Trust were considered. Electronic hospital systems were reviewed to obtain patient and tumour demographics, treatment and follow-up information. All patients were classified into risk categories according to National Institute for Health and Care Excellence guidance. Data were analysed using Microsoft Excel and R. RESULTS: Two hundred and seventy-two patients were identified: 123, 89 and 60 in the high-, intermediate- and low-risk categories, respectively. Seventy-nine per cent of those in the high-risk group, 6% in the intermediate and 5% in the low-risk group underwent CRT. The overall 5-year LRR and distant recurrence rate (DRR) were 5.2% and 17.8%, respectively. The 5-year LRR for those who went straight to surgery was 2.0% and for those who had neoadjuvant CRT it was 7.4%. The DRR for these two groups was 8.5% and 18.9%, respectively. CONCLUSION: Our series demonstrates that the use of CRT only in margin-threatening tumours, results in an exceptionally low LRR for those without margin-threatening disease. In routine clinical care, this strategy can minimize the significant morbidity of multimodal treatment and allow earlier introduction of systemic therapy to minimize distant recurrence.

The treatment of all MRI-defined low rectal cancers in a single expert centre over a 5-year period: is there room for improvement?

AIM: Outcomes following treatment for low rectal cancer still remain inferior to those for upper rectal cancer. A clear definition of 'low' rectal cancer is lacking and consensus is more likely using a definition based on MRI criteria. This study aimed to determine disease presentation and treatment outcome of low rectal cancer based on a strict anatomical definition. METHOD: A low rectal cancer was defined as one with a lower border below the pelvic attachment of the levator muscles on sagittal MRI. One hundred and eighty consecutive patients with tumours defined by this criterion between 2006 and 2011 were identified from a prospectively managed departmental database. RESULTS: One hundred and eighteen patients (66%) underwent curative resection and 12 (7%) palliative resection. Eleven patients (6%) were entered into a 'watch and wait' (W&W) protocol; 10 others (5%) were not fit to undergo any operation. Some 26 patients (14%) had nonresectable local or metastatic disease. An R0 resection was the most important factor influencing survival after curative surgery. R+ resections occurred in 12% of non-abdominoperineal excisions, 11% of abdominoperineal excisions and 47% of extended resections. Overall survival was similar in the curative resections compared with the W&W patients. In 23 of the 96 (24%) treated with neoadjuvant chemoradiotherapy there was a persistent clinical or a pathological complete response. CONCLUSION: In curative resections, a clear margin is the most important determinant of survival. In 24% of the patients treated with neoadjuvant chemoradiotherapy, surgery could potentially have been avoided. There is scope for improvement in the treatment of locally advanced rectal cancers.

Chemokine-adjuvanted electroporated DNA vaccine induces substantial protection from simian immunodeficiency virus vaginal challenge.

There have been encouraging results for the development of an effective HIV vaccine. However, many questions remain regarding the quality of immune responses and the role of mucosal antibodies. We addressed some of these issues by using a simian immunodeficiency virus (SIV) DNA vaccine adjuvanted with plasmid-expressed mucosal chemokines combined with an intravaginal SIV challenge in rhesus macaque (RhM) model. We previously reported on the ability of CCR9 and CCR10 ligand (L) adjuvants to enhance mucosal and systemic IgA and IgG responses in small animals. In this study, RhMs were intramuscularly immunized five times with either DNA or DNA plus chemokine adjuvant delivered by electroporation followed by challenge with SIVsmE660. Sixty-eight percent of all vaccinated animals (P<0.01) remained either uninfected or had aborted infection compared with only 14% in the vaccine naïve group. The highest protection was observed in the CCR10L chemokines group, where six of nine animals had aborted infection and two remained uninfected, leading to 89% protection (P<0.001). The induction of mucosal SIV-specific antibodies and neutralization titers correlated with trends in protection. These results indicate the need to further investigate the contribution of chemokine adjuvants to modulate immune responses and the role of mucosal antibodies in SIV/HIV protection.

Transanal endoscopic microsurgery for rectal cancer.

Since its introduction in the 1980s, total mesorectal excision (TME) has been the standard surgical technique for treating rectal cancer. This procedure involves removing the rectum and the surrounding envelope of fat along the plane of the mesorectal fascia. Resecting this embryological unit reduces the local recurrence rate by removing all local lymph nodes, including those with occult metastatic disease; however, this surgery is associated with mortality and morbidity. Complications include incontinence for patients given an anastomosis, long-term stoma formation, and sexual and bladder dysfunction. Local excision of rectal cancer using the transanal endoscopic microsurgery (TEM) technique is associated with fewer complications, and therefore, is used as an alternative in specific circumstances. We outline the technique, its indications, imaging appearances and complications.

CD4 T-cell cytokine correlates of diagnostic tests for latent tuberculous infection in HIV-1-infected subjects.

SETTING: Public human immunodeficiency virus (HIV) clinic and tuberculosis (TB) clinics in Kampala, Uganda. OBJECTIVE: To examine TB-specific CD4 T-cell single and polyfunctional cytokine correlates of clinical diagnostic tests for latent tuberculous infection (LTBI) in HIV-1-infected subjects. DESIGN: Thirty antiretroviral therapy-naïve HIV-1-infected adults without active TB disease underwent clinical tuberculin skin test (TST), interferon-gamma release assay (IGRA), and in vitro flow cytometry analysis on cells stimulated with purified protein derivative (PPD) and TB antigens early secreted antigenic target 6 + culture filtrate protein 10 (EC) for frequencies of interleukin (IL) 2, IL-17, interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) expressing cells. RESULTS: PPD-specific CD4 T-cell expression of TNF-α and IFN-γ was higher in the TST-positive than in the TST-negative group. EC-specific CD4 T-cell expression of TNF-α and IL-2 was higher in the TST+ group than in the TST- group. Expression of both PPD and EC-specific expression of IL-2, IFN-γ and TNF-α were greater in IGRA-positive than in IGRA-negative subjects. The TST+ group exhibited greater polyfunctionality than the TST- group. All cytokine combinations that contained TNF-α correlated strongly with TST size. CONCLUSION: While IL-2, IFN-γ and TNF-α correlate with clinical tests of LTBI, TNF-α is the dominant cytokine correlating with both TST size and magnitude of IGRA response.

How useful is endorectal ultrasound in the management of early rectal carcinoma?

INTRODUCTION: Endorectal ultrasonography (EUS) is used to T stage early rectal tumours and select patients to whom transanal endoscopic microsurgery (TEM) could be offered. Published papers have shown that EUS can have good accuracy, but there is little literature on how EUS influences patient management. The study aim is to ascertain the value of EUS in the management of early rectal tumours. METHODS: Patients with adenomas/early rectal carcinoma being considered for TEM were prospectively studied. Each patient underwent EUS. The surgeon recorded the expected T stage, confidence level of the T stage and management plan for each patient on a proforma before and after the ultrasound result was revealed. Comparison was made between the ultrasound stage and final pathological stage where available. RESULTS: Ninety-six patients were referred over 2 years. Nine were out of reach of the rigid probe and were excluded. Proformas were completed on 53/87 patients (age range 28-87 years, mean age 66 years, 30 males/23 females). Forty-eight patients had a pathological report to compare with the EUS T stage. Ultrasound agreed with the pathological T staging in 43 patients (90%). Patient management was changed in five patients. In 30% of (16/53) patients, EUS increased the confidence level for T staging. CONCLUSION: Although EUS has a high accuracy in predicting the T stage of early rectal cancers, it never changes the management plan for lesions thought to be benign. It seldom changes the pre-operative selection process when clinical examination is considered with other imaging modalities (MRI/CT). EUS should be reserved for answering specific questions in difficult cases rather than for all patients.

Antiparkinsonian potential of targeting group III metabotropic glutamate receptor subtypes in the rodent substantia nigra pars reticulata.

BACKGROUND AND PURPOSE: Increased firing of the glutamatergic pathway between the subthalamic nucleus and substantia nigra pars reticulata (SNpr) contributes to the abnormal firing of motor circuits and subsequent motor deficits seen in Parkinson's disease. Broad spectrum agonist-induced activation of presynaptic group III metabotropic glutamate (mGlu) receptors within the SNpr reduced glutamate release and reversed akinesia in the reserpine-treated rat model of Parkinson's disease. Here, we have sought to identify which subtypes of group III mGlu receptor in the SNpr were responsible for these beneficial effects. EXPERIMENTAL APPROACH: The ability of the mGlu(4) positive allosteric modulator, N-phenyl-7-(hydroxyminocyclopropa[b]chromen-1a-carboxamide) (PHCCC), the mGlu(7) allosteric agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) and the mGlu(8) -selective agonist (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] to inhibit KCl-evoked [(3) H]-D-aspartate release was examined in vitro in rat nigral prisms. Reversal of akinesia in reserpine-treated rats was also assessed following intranigral injection of these agents. KEY RESULTS: PHCCC and AMN082 inhibited [(3) H]-D-aspartate release by 42% and 53%, respectively when given alongside a sub-threshold concentration of the broad spectrum group III agonist, L-2-amino-4-phosphonobutyrate (L-AP4; 1 µM). In contrast (S)-3,4-DCPG failed to inhibit [(3) H]-D-aspartate release. All three agents also reversed reserpine-induced akinesia although only the effects of PHCCC and AMN082 were inhibited by pre-treatment with the group III antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG). CONCLUSIONS AND IMPLICATIONS: These findings reveal that targeting SNpr mGlu(4) or mGlu(7) receptors, but not mGlu(8) receptors, provided relief from akinesia in the reserpine-treated rat model of Parkinson's disease, most likely reflecting inhibition of excess glutamate release in this region.

Laxative-free CT colonography.

OBJECTIVES: The aim of this study was to determine if the introduction of faecal tagging to CT colonography (CTC) made the examination easier to tolerate or reduced the number of false-positives. METHODS: Our department changed bowel preparation for CT colonography from Picolax (Ferring Pharmaceuticals Ltd, London, UK) to Gastrografin (Bracco Diagnostics Inc, Princeton, NJ) only with a modified diet. Questionnaires were given to a subgroup of patients within these cohorts. The numbers of false-positives were compared between two cohorts before and after this change. false-positives were defined as lesions reported on CT that were not confirmed by subsequent endoscopic examination. Polyps were matched if they were in the same or adjacent segments, and were within 5 mm of the reported size. RESULTS: 412 patients were identified from the Picolax cohort, and 116 from the Gastrografin cohort. 62 patients in each group completed questionnaires. Gastrografin produced less diarrhoea; 34% had five or more bowel motions in the previous day and night, compared with 77% for Picolax (p<0.001), although more patients found drinking it unpleasant compared with Picolax (85% reported drinking Picolax as "easy" vs 61% for Gastrografin; p=0.002). Picolax produced more non-diagnostic examinations, although this difference was not statistically significant. There was not a significant reduction in the numbers of false-positives (2 out of 112 for Gastrografin group, 14 out of 389 for the Picolax group; p=0.54). CONCLUSION: Switching from Picolax to Gastrografin as a CTC preparation technique produced less diarrhoea, but did not reduce the number of false-positives.

Negative effects of habitat loss on survival of migrant Warblers in a forest mosaic.

Habitat loss and fragmentation in forested landscapes often negatively affect animal abundance; however, whether these factors also affect fitness is not well known. We hypothesized that observed decreases in bird occurrence and abundance in landscapes with harvested forests are associated with reduced apparent survival of adults. We defined apparent survival as an estimate of survival that accounts for an imperfect resighting probability, but not permanent emigration (i.e., dispersal). We examined the association between spatially extensive habitat loss and apparent survival of males of 2 Neotropical migrant species, Blackburnian Warbler (Dendroica fusca) and Black-Throated Green Warbler (D. virens), over 7 years in the Greater Fundy Ecosystem, New Brunswick, Canada. We estimated apparent survival among and within breeding seasons. We quantified amount of habitat in the context of individual species. In this landscape, boundaries between land-cover types are gradual rather than clearly identifiable and abrupt. Estimated apparent within-season survival of both species decreased as a function of amount of habitat within a 2000-m radius; survival was approximately 12 times (95% CI 3.43-14) greater in landscapes with 85% habitat than in landscapes with 10% habitat. Apparent annual survival also decreased as a function of amount of habitat within a 100-m radius. Over the range of habitat amount, apparent annual survival decreased 15% (95% CI 7-29%) as the amount of habitat decreased. Our results suggest that reduced species occurrence in landscapes with low proportions of habitat is due partly to lower apparent survival at these sites. This mechanism operates both directly (i.e., via effects on mortality or dispersal during breeding) and possibly through indirect effects during the nonbreeding season. Habitat loss was associated not only with a lower number of individuals, but also with lower survival of those individuals.

Polyfunctional Mycobacterium tuberculosis-specific effector memory CD4+ T cells at sites of pleural TB.

Pleural tuberculosis (TB) is a common presentation of Mycobacterium tuberculosis (MTB) infection, and despite spontaneous resolution remains a strong risk factor for reactivation pulmonary TB in a majority of individuals. This study was undertaken to further understand the characteristics of immune cells at sites of pleural TB. A significant shift toward memory CD4+ T cells with an effector phenotype and away from naïve CD4+ T cells in pleural fluid as compared to blood mononuclear cells was found. These data suggest that effector T cells are capable of migrating to sites of active TB infection and/or the differentiation to effector phenotype T cells in situ is highly amplified. Using multi-parameter flow cytometry analysis, a significant portion of MTB-specific CD4+ T cells in the pleural space were polyfunctional demonstrating two, three or four simultaneous functions including IFN-gamma, IL-2, TNF-alpha, and or MIP-1 alpha production. A greater proportion of these polyfunctional cells were of effector memory rather than central memory phenotype. The role of these polyfunctional MTB-specific CD4+ T cells at sites of pleural TB requires further study.

Adenovirus-based vaccines: comparison of vectors from three species of adenoviridae.

In order to better understand the broad applicability of adenovirus (Ad) as a vector for human vaccine studies, we compared four adenovirus (Ad) vectors from families C (Ad human serotype 5 [HAdV-5; here referred to as AdHu5]), D (HAdV-26; here referred to as AdHu26), and E (simian serotypes SAdV-23 and SAdV-24; here referred to as chimpanzee serotypes 6 and 7 [AdC6 and AdC7, respectively]) of the Adenoviridae. Seroprevalence rates and titers of neutralizing antibodies to the two human-origin Ads were found to be higher than those reported previously, especially in countries of sub-Saharan Africa. Conversely, prevalence rates and titers to AdC6 and AdC7 were markedly lower. Healthy human adults from the United States had readily detectable circulating T cells recognizing Ad viruses, the levels of which in some individuals were unexpectedly high in response to AdHu26. The magnitude of T-cell responses to AdHu5 correlated with those to AdHu26, suggesting T-cell recognition of conserved epitopes. In mice, all of the different Ad vectors induced CD8(+) T-cell responses that were comparable in their magnitudes and cytokine production profiles. Prime-boost regimens comparing different combinations of Ad vectors failed to indicate that the sequential use of Ad vectors from distinct families resulted in higher immune responses than the use of serologically distinct Ad vectors from the same family. Moreover, the transgene product-specific antibody responses induced by the AdHu26 and AdC vectors were markedly lower than those induced by the AdHu5 vector. AdHu26 vectors and, to a lesser extent, AdC vectors induced more potent Ad-neutralizing antibody responses. These results suggest that the potential of AdHu26 as a vaccine vector may suffer from limitations similar to those found for vectors based on other prevalent human Ads.

Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease.

BACKGROUND AND PURPOSE: Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson's disease (PD). This study aimed to establish whether activation of pre-synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD. EXPERIMENTAL APPROACH: Broad-spectrum group III mGlu receptor agonists, O-phospho-l-serine (l-SOP) and l-2-amino-4-phosphonobutyrate (l-AP4), were assessed for their ability to inhibit KCl-evoked [(3)H]-d-aspartate release in rat nigral prisms or inhibit KCl-evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine-treated rats was assessed following intranigral injection of l-SOP and l-AP4. Finally, the neuroprotective effect of 7 days' supra-nigral treatment with l-AP4 was examined in 6-hydroxydopamine (6-OHDA)-lesioned rats. KEY RESULTS: l-SOP and l-AP4 inhibited [(3)H]-d-aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). l-SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l-SOP and l-AP4 into the SNpr reversed reserpine-induced akinesia. Following administration above the SNpc, l-AP4 provided neurochemical, histological and functional protection against 6-OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects. CONCLUSIONS AND IMPLICATIONS: These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects.

Thresholds in forest bird occurrence as a function of the amount of early-seral broadleaf forest at landscape scales.

Recent declines in broadleaf-dominated, early-seral forest globally as a function of intensive forest management and/or fire suppression have raised concern about the viability of populations dependent on such forest types. However, quantitative information about the strength and direction of species associations with broadleaf cover at landscape scales are rare. Uncovering such habitat relationships is essential for understanding the demography of species and in developing sound conservation strategies. It is particularly important to detect points in habitat reduction where rates of population decline may accelerate or the likelihood of species occurrence drops rapidly (i.e., thresholds). Here, we use a large avian point-count data set (N = 4375) from southwestern and northwestern Oregon along with segmented logistic regression to test for thresholds in forest bird occurrence as a function of broadleaf forest and early-seral broadleaf forest at local (150-m radius) and landscape (500-2000-m radius) scales. All 12 bird species examined showed positive responses to either broadleaf forest in general, and/or early-seral broadleaf forest. However, regional variation in species response to these conditions was high. We found considerable evidence for landscape thresholds in bird species occurrence as a function of broadleaf cover; threshold models received substantially greater support than linear models for eight of 12 species. Landscape thresholds in broadleaf forest ranged broadly from 1.35% to 24.55% mean canopy cover. Early-seral broadleaf thresholds tended to be much lower (0.22-1.87%). We found a strong negative relationship between the strength of species association with early-seral broadleaf forest and 42-year bird population trends; species most associated with this forest type have declined at the greatest rates. Taken together, these results provide the first support for the hypothesis that reductions in broadleaf-dominated early-seral forest due to succession and intensive forest management have led to population declines of constituent species in the Pacific northwestern United States. Forest management treatments that maintain or restore even small amounts of broadleaf vegetation could mitigate further declines.

Radiological detection of post-oesophagectomy anastomotic leak - a comparison between multidetector CT and fluoroscopy.

The purpose of this study was to directly compare CT with fluoroscopy for the diagnosis of occult anastomotic leak following oesophagectomy. Patients undergoing oesophagectomy and gastric conduit formation for the treatment of oesophageal cancer were eligible for inclusion. Imaging was performed 6-8 days post-operatively. Patients underwent multislice CT examination of the chest and abdomen with a bolus of oral contrast, followed by fluoroscopic water-soluble contrast swallow (with subsequent use of barium if this was normal). The studies were reviewed by a consultant radiologist, who was blinded to the results of the other modality. Images were reported as showing "no leak", "possible leak" or "definite leak". The presence of mediastinal gas or fluid or extraluminal contrast at CT was recorded. The clinical outcome after reinstituition of oral intake was used as a reference standard. Patient preference for modality was recorded. 52 patients were recruited. Four were found to have leak on CT and fluoroscopy. 11 had possible leak at CT, but normal fluoroscopy: 2 of these had a leak confirmed later, whereas 9 had no leak. 37 had normal CT and fluoroscopy findings, and remained clinically well. The sensitivity, specificity, positive and negative predictive values were 100%, 80%, 40% and 100%, respectively, for CT, and 67%, 100%, 100% and 96%, respectively, for fluoroscopy. The positive predictive value of mediastinal air, air/fluid and extraluminal contrast were 25%, 75% and 50%, respectively. 35 patients found CT more tolerable. In conclusion, CT was better tolerated and more sensitive but less specific than fluoroscopy for detecting occult anastomotic leak.

An evidence-based review for the management of cystic pancreatic lesions.

The incidental finding of pancreatic cysts is becoming more common because of the increased use of cross-sectional imaging. As a result, the perspective from historical series of symptomatic patients is not always applicable to the current cohort of patients with cystic lesions in their pancreas. In this review, the characteristic radiological features that aid diagnosis are highlighted, and the complementary role of different imaging methods and the appropriate use of tissue sampling are identified. Based on the literature regarding the diagnostic role of imaging in characterizing cystic pancreatic lesions, it is possible to recommend a practical imaging algorithm for the diagnosis of cystic pancreatic lesions.

Expansion of activated human naïve T-cells precedes effector function.

Naïve T-cells divide and mature, both functionally and phenotypically, upon stimulation through the T-cell receptor. Although much is known about the overall changes that occur in naïve cells upon TCR stimulation, and the different memory/effector populations that arise following stimulation, the relationship between cell division and functional and phenotypical changes that occur after activation is poorly understood. Here, we examine the early stages of human naïve and antigen-experienced T-cell activation, and the relationship between cell division and acquisition of effector function during the transition from resting antigen-experienced or naïve T-cells into effector cells. Stimulated naïve T-cells proliferate prior to acquisition of effector function, as measured by cytokine production and expression of effector-associated cell surface molecules. Additionally, we show that interlukin-7 (IL-7) can drive proliferation of naïve T-cells without TCR:MHC peptide interactions. IL-7 alone does not, however, drive the proliferation of antigen-experienced T-cells. Memory T-cells will divide in response to exogenous IL-7 but only in the presence of naïve T-cells and IL-2. This study contributes to the current understanding of the mechanistic differences between naïve and memory T-cell responses by defining the functional and phenotypic changes that occur to T-cells after stimulation.

Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection.

Human immunodeficiency virus (HIV)-specific T-cell responses are thought to play a key role in viral load decline during primary infection and in determining the subsequent viral load set point. The requirements for this effect are unknown, partly because comprehensive analysis of total HIV-specific CD4(+) and CD8(+) T-cell responses to all HIV-encoded epitopes has not been accomplished. To assess these responses, we used cytokine flow cytometry and overlapping peptide pools encompassing all products of the HIV-1 genome to study total HIV-specific T-cell responses in 23 highly active antiretroviral therapy naïve HIV-infected patients. HIV-specific CD8(+) T-cell responses were detectable in all patients, ranging between 1.6 and 18.4% of total CD8(+) T cells. HIV-specific CD4(+) T-cell responses were present in 21 of 23 patients, although the responses were lower (0.2 to 2.94%). Contrary to previous reports, a positive correlation was identified between the plasma viral load and the total HIV-, Env-, and Nef-specific CD8(+) T-cell frequency. No correlation was found either between viral load and total or Gag-specific CD4(+) T-cell response or between the frequency of HIV-specific CD4(+) and CD8(+) T cells. These results suggest that overall frequencies of HIV-specific T cells are not the sole determinant of immune-mediated protection in HIV-infection.