Anomalous quantized plateaus in two-dimensional electron gas with gate confinement.

Quantum information can be coded by the topologically protected edges of fractional quantum Hall (FQH) states. Investigation on FQH edges in the hope of searching and utilizing non-Abelian statistics has been a focused challenge for years. Manipulating the edges, e.g. to bring edges close to each other or to separate edges spatially, is a common and essential step for such studies. The FQH edge structures in a confined region are typically presupposed to be the same as that in the open region in analysis of experimental results, but whether they remain unchanged with extra confinement is obscure. In this work, we present a series of unexpected plateaus in a confined single-layer two-dimensional electron gas (2DEG), which are quantized at anomalous fractions such as 9/4, 17/11, 16/13 and the reported 3/2. We explain all the plateaus by assuming surprisingly larger filling factors in the confined region. Our findings enrich the understanding of edge states in the confined region and in the applications of gate manipulation, which is crucial for the experiments with quantum point contact and interferometer.

Extensive mucocutaneous, oesophageal and otic lichen planus secondary to nivolumab therapy.

We report a 73-year-old female with metastatic renal cell carcinoma who developed a widespread lichenoid reaction following nivolumab treatment. The timeline of the reaction strongly correlated with the nivolumab treatment and subsequent cessation. Our patient had cutaneous, mucosal, otic, ophthalmic and oesophageal involvement, demonstrating the potentially extensive nature of lichenoid reactions to anti-programmed cell death receptor-1 (anti-PD1) therapies. Although lichenoid reactions to anti-PD1 therapies are now well recognized, there have been no previous reports of otic or oesophageal involvement in the literature. Although cutaneous lichenoid reactions do not tend to be severe or treatment limiting, more widespread systemic lichenoid reactions are challenging to manage, particularly in the context of malignancy. This very unusual case highlights the importance of considering involvement beyond the skin in all lichenoid skin reactions.

3/2 fractional quantum Hall plateau in confined two-dimensional electron gas.

Even-denominator fractional quantum Hall (FQH) states, such as 5/2 and 7/2, have been well known in a two-dimensional electron gas (2DEG) for decades and are still investigated as candidates of non-Abelian statistics. In this paper, we present the observation of a 3/2 FQH plateau in a single-layer 2DEG with lateral confinement at a bulk filling factor of 5/3. The 3/2 FQH plateau is quantized at [Formula: see text] within 0.02%, and can survive up to 300 mK. This even-denominator FQH plateau may imply intriguing edge structure and excitation in FQH system with lateral confinement. The observations in this work demonstrate that understanding the effect of the lateral confinement on the many-body system is critical in the pursuit of important theoretical proposals involving edge physics, such as the demonstration of non-Abelian statistics and the realization of braiding for fault-tolerant quantum computation.

Gene and Protein Expression of Chemokine (C-C-Motif) Ligand 19 is Upregulated in Unstable Carotid Atherosclerotic Plaques.

OBJECTIVE/BACKGROUND: The aim was to investigate the expression of genes associated with carotid plaque instability and their protein products at a local and systemic level. METHODS: Carotid plaques from 24 patients undergoing carotid endarterectomy (CEA) were classified as stable or unstable using clinical, histological, ultrasound, and transcranial Doppler criteria, and compared using whole genome microarray chips. Initial results of differentially expressed genes were validated by quantitative reverse transcriptase polymerase chain reaction in an independent group of 96 patients undergoing CEA. The protein product of genes significantly differentially expressed between patients with stable and unstable plaques were analysed by plaque immunohistochemistry and serum protein quantification by enzyme-linked immunosorbent assay on a further independent cohort. RESULTS: Expression of chemokine (c-c-motif) ligand 19 (CCL19) was significantly upregulated in plaques from patients with clinically unstable disease (p < .001). Cathepsin G expression was upregulated in histologically unstable plaques (p = .04). Serum concentration of CCL19 was significantly higher in patients with clinically unstable plaques (p = .02). Immunohistochemical staining for CCL19 demonstrated positive staining in histologically and clinically unstable plaques (p = .03). CCL19 also co-localised with CD3+ T-cell lymphocytes in the core region, around where CCL19 was expressed. CONCLUSIONS: CCL19 is significantly overexpressed in patients with unstable carotid atherosclerotic plaques and may be a possible novel biomarker for identifying high-risk patients in whom more urgent intervention may be indicated.

Tracheal agenesis, a frightening scenario.

OBJECTIVE: This paper discusses three cases of tracheal agenesis that presented within a six-week period to the Norfolk and Norwich University Hospital. By reviewing the available literature on tracheal agenesis, the report aims to outline a protocol for future prenatal and postnatal management. METHODS: A case series and a literature review. RESULTS: Three cases of tracheal agenesis presented in the classical manner, with respiratory distress and unsuccessful intubation following delivery. A literature review confirmed that prenatal diagnosis requires future innovation; survival is rare and is predominately reliant on intubation of the oesophagus when a patent tracheoesophageal fistula is present. In most cases, tracheal agenesis represents part of the 'VATER' association: vertebral defects, anal atresia, tracheoesophageal fistula with oesophageal atresia, and radial or renal dysplasia. Complex, multiple-stage surgical procedures have been described; however, no survival to adolescence is documented. CONCLUSION: There is a call for improved prenatal diagnosis to allow both adequate counselling of parents and preparation for multi-specialty management at delivery. In addition, these cases highlight the ongoing need for improved congenital anomaly data within the UK, with currently only 49 per cent of England's births being registered.

Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques.

Nine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, the Mycobacterium bovis BCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4ß1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.

Identification of high-risk Dukes B colorectal cancer by microRNA expression profiling: a preliminary study.

AIM: MicroRNAs (miRNAs) from tumour tissue and common gene mutations were studied to determine whether they predict the development of metastasis in patients with Dukes B colorectal cancer. METHOD: Patients who underwent curative resection for Dukes B colorectal cancer who subsequently developed distant metastatic disease at some stage in the following 5 years ('high-risk B') were compared with case-matched controls of Dukes A, Dukes B (no metastases, 'low-risk B') and Dukes C patients without any detectable metastasis at 5 years of follow-up. MiRNAs from tumour and adjacent normal tissue and common gene mutations (KRAS, BRAF, PIK3CA) in primary cancer tissue were analysed to identify prognostic tissue markers for the development of metastasis in patients with Dukes B colorectal cancer. RESULTS: Expression of miR-15b and miR-135b was significantly downregulated (P < 0.001) in 'high-risk B' tumours compared with Dukes A, 'low-risk B' and C without metastasis. No significant differences were noted for mutation status and the development of metastasis. CONCLUSION: The study suggests that the development of metastasis in Dukes B tumours may be predictable based on the miRNA expression of miR-15b and miR-135b. This requires further study on a much larger cohort.

Identification of patients with a histologically unstable carotid plaque using ultrasonic plaque image analysis.

OBJECTIVES: In patients with carotid stenosis the risk of stroke is highest in the first few days after onset of symptoms and it is low in asymptomatic patients. The ability to identify patients with a high (or low) probability of having a histologically unstable plaque might become a complimentary method that can refine the indications for surgical intervention. METHODS: Two histopathologists, using validated American Heart Association criteria, independently graded plaques harvested during carotid endarterectomy. Preoperative Duplex images were independently assessed for juxtaluminal black area, plaque type, plaque area, and grey-scale median (GSM) following image normalization. Logistic regression analysis was then performed to create a model for predicting predominantly histologically unstable or stable plaques. RESULTS: A total of 126 patients were included in the study. Based on the presence and extent of histological features including haemorrhage, thrombus, fibrous tissue, lipid core, inflammation, neovascularity, foam cells, and cap rupture, 39 plaques were graded as predominantly stable, while 87 were predominantly unstable. Unstable plaques were associated with a plaque area >95 mm(2) (OR 4.15; 95% CI 1.34-12.8 p = .009), a juxtaluminal black area >6 mm(2) (OR 2.77; 95% CI 1.24 to 6.17 p = .01) and a GSM <25 (OR 3.76; 95% CI 1.14-12.39). Logistic regression indicated that patients with the first two features had a 90% probability of having a histologically unstable plaque. The model was used to calculate the probability of having an unstable plaque in each patient. The receiver operating characteristic curve using the p value was 0.68 (95% CI 0.59-0.78). CONCLUSIONS: Computerized plaque analysis has the potential to identify patients with histologically unstable carotid plaques. This model requires validation, but offers the potential to influence patient selection for emergency interventions and the monitoring of medical therapy.

Beyond pregnancy--the neglected burden of mortality in young women of reproductive age in Bangladesh: a prospective cohort study.

OBJECTIVE: To describe proportionate mortality and causes of death unrelated to pregnancy. DESIGN: Prospective cohort study. SETTING: Rural northwest Bangladesh. POPULATION: A cohort of 133,617 married women of reproductive age. METHODS: Verbal autopsies were conducted for women who died whilst under surveillance in the cohort trial. Physician-assigned causes of death based on verbal autopsies were used to categorise deaths. MAIN OUTCOME MEASURES: The proportion of deaths due to non-communicable diseases, infectious diseases, injury or pregnancy. RESULTS: Of the 1107 deaths occurring among women between 2001 and 2007, 48% were attributed to non-communicable diseases, 22% to pregnancy, 17% to infections, 9% to injury and 4% to other causes. CONCLUSIONS: Although focus on pregnancy-related mortality remains important, more attention is warranted on non-communicable diseases among women of reproductive age.

Differential expression of p16(INK4A) and cyclin D1 in benign and malignant salivary gland tumors: a study of 44 Cases.

Salivary gland tumors (SGT) are a heterogeneous group of lesions. There is conflicting data concerning the molecular events involving the tumour suppressor retinoblastoma protein (pRb) pathway in these tumors. Few studies examined the alterations in components of the Rb pathway by immunohistochemical (IHC) methods in benign and malignant SGTs. Furthermore, recent evidence implicates human papillomavirus (HPV) in mucoepidermoid carcinoma (MEC) carcinogenesis. The purpose of our study is to examine p16(INK4A) and cyclin D1 expression in a variety of benign and malignant salivary gland tumors, and to investigate p16(INK4A) expression as a surrogate marker for HPV infection in MEC. Our series includes 30 malignant tumors [14 MEC, 6 acinic cell carcinomas (ACC), 5 polymorphous low grade adenocarcinomas (PLGA), 5 (AdCC)] and 14 benign tumors (4 benign cysts, 5 Warthin tumors and 5 pleomorphic adenomas (PA). All cases were tested by IHC for p16(INK4A) and cyclin D1. Testing for HPV wide spectrum (HPV-WS) was performed by in situ hybridization in all MEC cases. Staining intensity was recorded semi quantitatively (on a scale from 0 to 4+). Fisher's exact test and Pearson X2 test with a p < 0.05 were used. Cyclin D1 and p16(INK4A) are expressed similarly in malignant and benign tumors (p = 0.146 and p = 0.543, respectively). None of the MEC cases showed nuclear reactivity for HPV-WS. Statistical analysis showed positive correlation between cyclin D1 and p16(INK4A) expression. Our findings suggest that p16(INK4A) overexpression is likely secondary to cyclin D1 gene upregulation or amplification. Further molecular studies are warranted.

The impact of potential islet precursor cells on islet autotransplantation outcomes.

Islet autotransplant patients represent excellent subjects to assess the posttransplant impact of islet precursors, as chronic pancreatitis (CP) causes an elevation of ductal cells, pancreatic precursors cells, and hormone-positive acinar cells. The relationship between these cell types and autograft outcomes should be more apparent than would be the case in the context of an allograft program with confounding immunological variables. To improve diabetic control following total pancreatectomy for CP, nonpurified islets were autotransplanted into the liver. Pancreas specimens were recovered from 23 patients and stained for antigens including: insulin, glucagon, cytokeratin 19, cytokeratin 7, and PDX-1. In line with previous reports, the prevalence of ductal cells, non-islet endocrine cells and non-islet PDX-1-expressing cells was significantly higher in CP glands compared with normal pancreata. When correlating follow-up data (i.e., fasting and stimulated C-peptide/glucose levels and HbA1c%) with pancreas immunoreactivity, high levels of ductal cells, non-islet PDX-1-positive cells, and non-islet glucagon-positive cells were associated with superior outcomes, detectable up to 2 years posttransplant. To conclude, the acinar parenchyma and ductal epithelium of the CP pancreas show an upregulation of both endocrine and pre-endocrine cell types, which appear to have a positive effect on islet graft outcomes in autotransplantation setting.

Features of unstable carotid plaque during and after the hyperacute period following TIA/stroke.

BACKGROUND: The aim was to test the hypothesis that histologically unstable carotid plaque features were more prevalent in patients undergoing carotid endarterectomy (CEA) in the acute period after onset of symptoms and that the plaque would assume more stable histological characteristics as the delay from the most recent event increased. METHODS: Seven histological features of plaque instability (haemorrhage, large lipid core, chronic plaque inflammation, chronic cap inflammation, marked vascularity, cap rupture and many foam cells) were independently quantified and then correlated with recency of symptoms in patients undergoing CEA. RESULTS: In patients undergoing CEA ≤14 days of their last event, 87/119 (73%) exhibited ≥5/7 unstable histological plaque features, compared with 22/40 (55%) of patients undergoing delayed surgery (P = 0.048). As expected, there was a sustained decline in the prevalence of unstable plaque features in 61 patients undergoing surgery between days 7-28. However, there was then a marked increase in the prevalence of plaque haemorrhage (59% up to 65%), large lipid core (41% up to 78%), chronic plaque inflammation (71% up to 91%), cap rupture (35% up to 39%), many foam cells (24% up to 43%) and marked vascularity (71% up to 91%) in 23 patients undergoing CEA after 29 days had elapsed. CONCLUSION: Patients undergoing surgery ≤14 days had a significantly higher overall burden of high risk plaque features compared with those undergoing delayed CEA. However, the secondary upsurge across a range of unstable plaque features in patients undergoing CEA after ≥29 days had elapsed suggests that the relationship between recency of symptoms and plaque histology is more complex than had been anticipated in previous studies.

Histologically unstable asymptomatic carotid plaques have altered expression of genes involved in chemokine signalling leading to localised plaque inflammation and rupture.

BACKGROUND: Many studies have evaluated histological and gene expression profiles in TIA/stroke patients after onset of symptoms, but there is limited understanding as to how these plaque related features interact before symptom onset. In particular, no studies have evaluated differential gene expression in histologically unstable (vs stable plaques) in neurologically asymptomatic patients. METHODS: Nine asymptomatic patients had their plaques scored blindly by two independent Histopathologists using the AHA plaque scoring system. RNA extracted from the plaques was hybridised onto a whole genome microarray. Analysis was performed using GenomeStudio (v1.0) and the DAVID bioinformatics resource (v6.7). RESULTS: Three plaques were histologically unstable (Grade 2/3), while six were stable (Grade 0/1). 346 differentially expressed genes (>1.3 fold, P < 0.05) were identified (293 down-regulated and 53 up-regulated) between stable and unstable plaques. Genes related to chemokine and protein signalling (pro-inflammatory/pro-apoptotic) were identified to have high enrichment scores (>1.3) and were significantly up-regulated in unstable (asymptomatic) plaques. CONCLUSION: The findings confirm the intuitively held belief that changes in chemokine and protein signalling may be associated with acute plaque disruption and precede the onset of symptoms. Once validated, these genes could therefore become targets for innovative medical treatments in the future or could help identify asymptomatic patients with histologically unstable plaques that would benefit from surgical intervention.

Adequacy of lymph node harvesting in colorectal cancer management: improving standards, ensuring quality.

OBJECTIVE: The aim of this study was to determine the adequacy of nodal sampling in resection specimens for colorectal carcinoma in a Jamaican population. METHODS: The pathology records of all patients who underwent operation for colorectal carcinoma at the University Hospital of the West Indies (UHWI) during the five-year period, 2003-2007, were reviewed. Pertinent clinical and pathologic data were obtained and analysed. RESULTS: One hundred and ninety-one patients were identified with M:F ratio of 1.1:1 and a mean age of 66 years. There were 119 (63%) left-sided lesions and 70 (37%) right-sided lesions. Stage T3N0 lesions were the most common and accounted for 41.1% of cases. The predominant histologic type was adenocarcinoma (99.5%) with the majority being moderately differentiated. The mean number of nodes sampled in node-negative cases was 13.8 +/- 9.75 nodes for right-sided lesions and 10.64 +/- 7.25 nodes for left-sided lesions (p = 0.05, CI 95%). The adequacy of nodal sampling was acceptable in cases of N0 right-sided carcinomas but was unsatisfactory in cases of N0 left-sided carcinomas. More importantly, however in two cases from the right and 10 cases from the left, two or fewer nodes were harvested. CONCLUSION: This review suggests the need for re-examination of the adequacy of surgical resection and/or nodal sampling technique for colorectal cancer resection specimens, given the importance of nodal status in determining the need for adjuvant therapy. Less than adequate node sampling should not be accepted by the reporting pathologist or attending surgeon as this has important prognostic implications.

Patients with recurrent ischaemic events from carotid artery disease have a large lipid core and low GSM.

OBJECTIVES: The aim of the current study was to determine whether computerised ultrasound plaque analysis could identify features predictive of an increased risk of early recurrent events after symptom onset. METHODS: Between August 2008 and December 2010, 158 consecutive symptomatic patients undergoing carotid endarterectomy (CEA) had their plaques harvested at CEA and then independently scored for markers of histological plaque instability. Duplex ultrasound images recorded prior to CEA were independently assessed using the Iconsoft software. RESULTS: One hundred and fifty eight recently symptomatic patients underwent CEA with 118 (75%) undergoing their operation within 14 days of their most recent clinical event. Twenty (12.7%) suffered a recurrent cerebral ischaemic event following admission to the vascular unit and before undergoing CEA. Using multivariate stepwise analysis; lipid core (OR 4.00, 95% CI 1.07 to 14.83, P = 0.042) and a low GSM (OR 6.21, 95% CI 1.86 to 20.4, P = 0.003) were independently associated with recurrent cerebrovascular events. CONCLUSION: Within a cohort of patients presenting with recent onset cerebral ischaemic events undergoing CEA, the plaques of patients with recurrent events following admission to hospital had evidence a large lipid core and a low GSM.

Microwave ablation of the liver: a description of lesion evolution over time and an investigation of the heat sink effect.

AIM: Microwave ablation has been successfully used to treat unresectable liver tumours for many years. However, despite its widespread use, there seems to be a relative paucity of experimental data regarding lesion evolution and the effects of any surrounding vasculature on ablation morphology. The aim of this study was to investigate the principal pathological changes in the liver following microwave ablation, in particular the heat sink effect. In addition we carefully reviewed the available literature to provide an overview of all relevant pathological studies. METHODS: Microwave ablation was carried out on male rats at various distances from the hilum. Histological (H&E) and immunocytochemical (caspase 3) analyses of the lesion were performed at various time points; 0, 4, 24, 48  hours, 2 weeks and 1 month. A literature review was carried out using Medline, Embase and the Cochrane database to identify all relevant histological studies. RESULTS: The lesion underwent complete coagulative necrosis and was extremely regular at the ablation edge with no evidence of any influence from surrounding blood vessels at all time points. H&E and caspase 3 results were consistent and microwave caused little collateral damage outside the intended ablation zone. CONCLUSION: This study suggests that microwave ablation is extremely concise and is minimally affected by the heat sink effect. Comparative investigations with other treatment modalities are required.

The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models.

Heat shock protein 90 (Hsp90) is an emerging target for cancer therapy due to its important role in maintaining the activity and stability of key oncogenic signaling proteins. We show here that the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion protein, presumed to be the oncogenic driver in about 5% of patients with non-small cell lung cancer (NSCLC), is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504. We find EML4-ALK to be more sensitive to Hsp90 inhibition than either HER2 or mutant epidermal growth factor receptor (EGFR) with an inhibitory concentration (IC)(50) for protein degradation in the low nanomolar range. This degradation leads to a potent inhibition of downstream signaling pathways and to the induction of growth arrest and apoptosis in cells carrying the EML4-ALK fusion. To generate a causative link between the expression of EML4-ALK and sensitivity to IPI-504, we introduced an EML4-ALK cDNA into HEK293 cells and show that the expression of the fusion protein sensitizes cells to IPI-504 both in vitro and in vivo. In a xenograft model of a human NSCLC cell line containing the ALK rearrangement, we observe tumor regression at clinically relevant doses of IPI-504. Finally, cells that have been selected for resistance to ALK kinase inhibitors retain their sensitivity to IPI-504. We have recently observed partial responses to administration of IPI-504 as a single agent in a phase 2 clinical trial in patients with NSCLC, specifically in patients that carry an ALK rearrangement. This study provides a molecular explanation for these clinical observations.

Acute computed tomography findings in patients with acute confusion of non-traumatic aetiology.

BACKGROUND: A retrospective review was undertaken of all patients referred for computed tomography (CT) scans of the head for acute onset of confusion, not consequent on head trauma, during the period June 1, 2004 to May 31, 2007. METHOD: Data were obtained by Microsoft Word search of the reports of the Radiology Department of the University Hospital of the West Indies, Kingston, Jamaica. Two hundred and twenty-one patients were reviewed: 103 men and 118 women. The mean age of the sample was 64 years; 168 patients (76%) were 50 years old or older. RESULT: Computed tomography scans were reported normal in 170 (76.9%) patients; 45 patients (20.4%) had definite acute intracranial CT findings. Findings were equivocal in three patients (1.4%) and unavailable for three (1.4%); 23.2% and 15.6% of patients above and below the age of 50 years respectively showed acute abnormalities on CT The most common acute finding on CT scan was an ischaemic infarct (68%). Other abnormalities included intracerebral haemorrhage and metastases 6.2% each, toxoplasmosis and primary brain tumour 4.2% each and subdural haematoma and meningitis 2.1% each. The diagnoses of toxoplasmosis were made based on appearances typical of toxoplasmosis on CT scans in patients whose request stated that they were HIV positive. CONCLUSION: In the sample reviewed, most patients who presented with acute confusion were above the age of 50 years. Overall, 20.4% of patients from all age groups had acute abnormalities on CT with a relative higher proportion, 23.2% versus 15.6% of those over 50 years, having acute pathology. The most common abnormality was an ischaemic infarct. This finding is similar to that in developed countries and unlike that seen in other developing countries where infectious aetiologies predominate.