Presenting symptoms and long-term survival in head and neck cancer.

OBJECTIVES: To assess how type and number of symptoms are related to survival in patients with head and neck cancer. DESIGN: Patients were followed up for over 10 years from the Scottish Audit of Head and Neck Cancer (national cohort of head and neck cancer patients in Scotland 1999-2001). September 2013, cohort was linked to national mortality data. First, second and third presenting symptoms were recorded at diagnosis. SETTING: National prospective audit-Scotland. PARTICIPANTS: A subset of 1589 patients, from the original cohort of 1895, who had cancer arising from one of the four main subsites; larynx, oropharynx, oral cavity and hypopharynx. MAIN OUTCOME MEASURES: Median survival in relation to patients' presenting symptoms. RESULTS: A total of 1146 (72%) males and 443 (28%) females, mean age at diagnosis 64 years (13-95). There was a significant difference in survival in relation to the number of the patient's presenting symptoms; one symptom had a median survival of 5.3 years compared with 1.1 years for three symptoms. Patients who presented with weight loss had a median survival of 0.8 years, compared to 4.2 years if they did not (P < .001). Patients who presented with hoarseness had a median survival of 5.9 years compared to 2.6 years without (P < .001). There was no significant difference in long-term survival for patients who presented with an ulcer, compared to those that did not (P = .105). CONCLUSIONS: This study highlights the importance of patients' presenting symptoms, giving valuable information in highlighting appropriate "red flag" symptoms and subsequent treatment planning and prognosis.

Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population.

Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH. In this study, the carrier frequency for five RTEL1 mutations that occurred in individuals of Ashkenazi Jewish descent was investigated in order to advise on including them in existing clinical mutation panels for this population. Our screening showed that the carrier frequency for c.3791G>A (p.R1264H) was higher than expected, 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population. Haplotype analyses suggested the presence of a common founder. We recommend that the c.3791G>A RTEL1 mutation be considered for inclusion in carrier screening panels in the Ashkenazi population.

Common genetic variants in the 9p21 region and their associations with multiple tumours.

BACKGROUND: The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers. METHODS: We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9-32.8 Mb) in eight case-control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SNP analyses for each study separately, adjusting for study-specific covariates. We combined SNP results across studies by fixed-effect meta-analyses and a newly developed subset-based statistical approach (ASSET). Gene-based P-values were obtained by the minP method using the Adaptive Rank Truncated Product program. We adjusted for multiple comparisons by Bonferroni correction. RESULTS: Rs3731239 in cyclin-dependent kinase inhibitors 2A (CDKN2A) was significantly associated with ESCC (P=7 × 10(-6)). The CDKN2A-ESCC association was further supported by gene-based analyses (Pgene=0.0001). In the meta-analyses by ASSET, four SNPs (rs3731239 in CDKN2A, rs615552 and rs573687 in CDKN2B and rs564398 in CDKN2BAS) showed significant associations with ESCC and EC (P<2.46 × 10(-4)). One SNP in MTAP (methylthioadenosine phosphorylase) (rs7023329) that was previously associated with melanoma and nevi in multiple genome-wide association studies was associated with CRC, CA and OS by ASSET (P=0.007). CONCLUSION: Our data indicate that genetic variants in CDKN2A, and possibly nearby genes, may be associated with ESCC and several other tumours, further highlighting the importance of 9p21.3 genetic variants in carcinogenesis.

Dissociation of explicit and implicit long-term memory consolidation in semantic dementia: a case study.

We report a case study of a semantic dementia patient, whose episodic memory consolidation was tested over a 2-month period. The results reveal that despite early retention of information, the patient lost all explicit information of the newly learnt material after 2 weeks. By contrast, he retained implicit word information even after a 4-week delay. These findings highlight the critical time window of 2-4 weeks in which newly learnt information should be re-encoded in rehabilitations studies. The results also indicate that learnt information can be still accessed with implicit retrieval strategies when explicit retrieval fails.

Worldwide genetic structure in 37 genes important in telomere biology.

Telomeres form the ends of eukaryotic chromosomes and are vital in maintaining genetic integrity. Telomere dysfunction is associated with cancer and several chronic diseases. Patterns of genetic variation across individuals can provide keys to further understanding the evolutionary history of genes. We investigated patterns of differentiation and population structure of 37 telomere maintenance genes among 53 worldwide populations. Data from 898 unrelated individuals were obtained from the genome-wide scan of the Human Genome Diversity Panel (HGDP) and from 270 unrelated individuals from the International HapMap Project at 716 single-nucleotide polymorphism (SNP) loci. We additionally compared this gene set to HGDP data at 1396 SNPs in 174 innate immunity genes. The majority of the telomere biology genes had low to moderate haplotype diversity (45-85%), high ancestral allele frequencies (>60%) and low differentiation (FST<0.10). Heterozygosity and differentiation were significantly lower in telomere biology genes compared with the innate immunity genes. There was evidence of evolutionary selection in ACD, TERF2IP, NOLA2, POT1 and TNKS in this data set, which was consistent in HapMap 3. TERT had higher than expected levels of haplotype diversity, likely attributable to a lack of linkage disequilibrium, and a potential cancer-associated SNP in this gene, rs2736100, varied substantially in genotype frequency across major continental regions. It is possible that the genes under selection could influence telomere biology diseases. As a group, there appears to be less diversity and differentiation in telomere biology genes than in genes with different functions, possibly due to their critical role in telomere maintenance and chromosomal stability.

Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study.

BACKGROUND: There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case-control studies suggested an association between short blood telomere length (TL) and increased RCC risk. METHODS: We conducted a large population-based case-control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001). CONCLUSION: These data do not support the hypothesis that blood TL is associated with RCC. This population-based case-control study is, to our knowledge, the largest investigation to date of TL and RCC.

Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity.

Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.

Orbitofrontal dysfunction discriminates behavioral variant frontotemporal dementia from Alzheimer's disease.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) patients show prefrontal cortex dysfunction and atrophy. METHODS: We investigated whether executive function in conjunction with prefrontal cortex atrophy discriminates bvFTD and Alzheimer's disease (AD) patients efficiently at presentation. RESULTS: AD and bvFTD patients were distinguishable by 89.5% on their performance of 3 executive tasks: the Hayling Test of Inhibitory Control, Digit Span Backward and Letter Fluency. Similarly, scan ratings showed that orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex regions distinguish both patient groups. More importantly, employing the Hayling error score in conjunction with the OFC atrophy rating showed that 92% of patients can be correctly classified into bvFTD and AD. CONCLUSION: A combination of OFC and disinhibition measures appears to be a powerful diagnostic tool in differentiating bvFTD from AD patients in this preliminary study.

The integral membrane protein, ponticulin, acts as a monomer in nucleating actin assembly.

Ponticulin, an F-actin binding transmembrane glycoprotein in Dictyostelium plasma membranes, was isolated by detergent extraction from cytoskeletons and purified to homogeneity. Ponticulin is an abundant membrane protein, averaging approximately 10(6) copies/cell, with an estimated surface density of approximately 300 per microns2. Ponticulin solubilized in octylglucoside exhibited hydrodynamic properties consistent with a ponticulin monomer in a spherical or slightly ellipsoidal detergent micelle with a total molecular mass of 56 +/- 6 kD. Purified ponticulin nucleated actin polymerization when reconstituted into Dictyostelium lipid vesicles, but not when a number of commercially available lipids and lipid mixtures were substituted for the endogenous lipid. The specific activity was consistent with that expected for a protein comprising 0.7 +/- 0.4%, by mass, of the plasma membrane protein. Ponticulin in octylglucoside micelles bound F-actin but did not nucleate actin assembly. Thus, ponticulin-mediated nucleation activity was sensitive to the lipid environment, a result frequently observed with transmembrane proteins. At most concentrations of Dictyostelium lipid, nucleation activity increased linearly with increasing amounts of ponticulin, suggesting that the nucleating species is a ponticulin monomer. Consistent with previous observations of lateral interactions between actin filaments and Dictyostelium plasma membranes, both ends of ponticulin-nucleated actin filaments appeared to be free for monomer assembly and disassembly. Our results indicate that ponticulin is a major membrane protein in Dictyostelium and that, in the proper lipid matrix, it is sufficient for lateral nucleation of actin assembly. To date, ponticulin is the only integral membrane protein known to directly nucleate actin polymerization.

Cancer waiting times: what is the value of a lymphoma waiting time?

BACKGROUND AND AIM: Waiting times for patients with lymphoma have been reported across the United Kingdom since 2005. Lymphoma however, is not a single disease but a wide spectrum of lymphoid tumours that range from the most malignant to the most indolent, from highly curable to incurable. We now question the value of the current system that reports lymphoma waiting time on a quarterly basis and makes no allowance for the different types of lymphoma. METHOD: Four hundred and sixty nine cases of lymphoma were registered in the west of Scotland in 2004. Complete datasets were available on 428. Patient demographic data, subtypes of lymphoma, biopsy site and referral urgency data were linked to the waiting times analysis for 2004 for the three subtypes, Lymphoma (HL), Diffuse Large B Cell (DLBC) and follicular Non Hodgkin Lymp (NHL). RESULTS: Patients with HL were younger, more likely to receive urgent referral and have a diagnosis made from neck node biopsy than the other two groups. Patients with DLBC NHL however had the shortest interval between presentation and the start of treatment and were subsequently more likely to receive treatment within 62 days than patients with either follicular NHL (p < 0.001) or HL (p < 0.05). CONCLUSION: Lymphoma subtype is a major factor determining the rate of progress from presentation to the start of treatment, hence the waiting time.

Cervical lymphadenopathy resulting in a diagnosis of lymphoma.

BACKGROUND AND AIMS: Currently there is no protocol in the west of Scotland for the investigation of a patient with a lymph node in the neck which might contain lymphoma. The aim of this audit was to examine the current management of these patients. METHODS: Data were collected on 112 patients diagnosed as having lymphoma from a neck node biopsy within a 12 month period from 1st November 2004 to 31st October 2005. Biopsy data were collected in combination with the first point of consultation, investigations used to arrive at diagnosis and any associated complications. RESULTS: Eighty seven percent of patients underwent excision biopsy with complications noted in 7%. Fine needle aspiration cytology (FNAC) was carried out in 60% of which 34% were ultrasound guided. Core biopsy was carried out in 17% of which 63% were ultrasound guided, Forty-five percent of patients were first referred to ear, nose and throat (ENT) surgery, 17% to general surgery, 14% to haematology, 13% to general medicine and 11% to other specialties. CONCLUSION: This audit shows that there was a wide range of first points of consultation and diagnostic procedures used. It is recommended that there should be access for all patients with cervical lymphadenopathy to a weekly neck lump clinic with standardised protocols for lymphoma diagnosis. This should ensure that patients are diagnosed accurately and treated in a timely manner.

Thinking outside the box: re-evaluating the approach to penetrating cardiac injuries.

INTRODUCTION: Penetrating cardiac injuries are infrequent but highly lethal. To address these injuries, cardiopulmonary bypass and cardiothoracic surgery availability are required for Level I trauma center verification. However, acute care surgeons are more readily available for this time-sensitive injury. The purpose of this study was to review an acute care surgery-based experience with penetrating cardiac trauma at an urban Level 1 trauma center. Our hypothesis was that care provided solely by acute care surgeons was both safe and effective for this patient population. METHODS: All patients with injuries to the 'cardiac box' following penetrating thoracic trauma were identified from 2005-2010. Demographic and injury related data were obtained. The types and location of cardiac injury, as well as patient outcomes, were determined from operative reports. RESULTS: 1701 patients with penetrating chest trauma were admitted during the study period. 260 patients were identified as having high-risk injuries and were included in the review. 37 patients underwent resuscitative thoracotomy, with a survival rate of 8 %. 76 patients (29 %) suffered a cardiac injury. 72 % of these patients had a preoperative FAST exam, which had a sensitivity and specificity of 56.5 and 82.5 % respectively. 82 % underwent a pericardial window, which had a positive predictive value of 81.4 %. 61 % (n = 46) of the patients with a cardiac injury survived, while the overall death rate in this cohort was 21 %. No patients in the cohort required cardiopulmonary bypass for emergent repair of cardiac injury and acute care surgeons performed all cases. CONCLUSION: Penetrating injury to the heart is highly lethal and time-sensitive. Increasingly, FAST and subxyphoid pericardial window are relied upon to make the diagnosis in patients arriving in varying stages of shock to the resuscitation room. Acute care surgeons are the most appropriate surgeons to care for these injuries and provide safe and effective care.

Effect of risk factors on exercise capacity in NIDDM.

Exercise capacity has been used as a noninvasive parameter for predicting cardiovascular events. It is known that diabetic patients have an impaired exercise capacity when compared with nondiabetic age-matched control subjects, but the risk factors associated with this impairment have not been thoroughly analyzed. A total of 453 male and female NIDDM patients who underwent graded exercise testing with expired gas analysis were studied to determine the possible influences of demographic and cardiac risk factors on exercise capacity. Univariate and multiple linear regression analyses were performed on baseline patient characteristics with respect to peak oxygen consumption (VO2). In the regression analyses, African-American race was strongly associated with a decrease in peak VO2; the difference in means between African-Americans and other subjects for men was -2.50 ml.kg-1.min-1 (-4.28, -0.07, 95% CI) (P < 0.006) and for women was -2.96 ml.kg-1.min-1 (-4.45, -1.47) (P < 0.0002). Univariate analyses revealed that African-American subjects had increased prevalence, longer duration, and higher systolic and diastolic hypertension than the non-Hispanic and Hispanic whites. Other independent predictors of peak VO2 (reported as change in peak VO2 in milliliters per kilogram per minute) were BMI (men: -0.39 kg/m2 [-0.52, -0.29], P < 0.0001; women: -0.39 kg/m2 [-0.48, -0.31], P < 0.0001), age (men: -0.16/year [-0.23, -0.09], P < 0.0001; women: -0.17/year [-0.24, -0.11], P < 0.0001), baseline resting systolic blood pressure (men: -0.03/mmHg [-0.06, -0.01], P < 0.05; women: -0.03/mmHg (-0.06, -0.01)f1p4< 0.05), and pack-years smoking (men: -0.04/pack-years [-0.04, -0.01], P < 0.01; women: -0.04/pack-years [-0.07, -0.01], P < 0.0001). Thus, in this large NIDDM study, weight loss, smoking cessation, and aggressive blood pressure control, particularly in African-Americans with NIDDM, would appear to be important in improving exercise capacity and potentially improving the increased cardiovascular mortality associated with an impaired exercise capacity.

Urinary albumin excretion as a predictor of diabetic retinopathy, neuropathy, and cardiovascular disease in NIDDM.

OBJECTIVE: The relationship between urinary albumin excretion (UAE) and diabetic complications in NIDDM has not been studied in a large American population. The demonstrated relationship between increased UAE and the development of retinopathy, nephropathy, and neuropathy in IDDM makes this an important issue to also be studied in NIDDM patients. RESEARCH DESIGN AND METHODS: A large population study of 947 NIDDM patients living predominantly in a metropolitan area was undertaken. Three categories of UAE, namely, normal albuminuria (< 20 micrograms/min), microalbuminuria (20-200 micrograms/min), and overt albuminuria (> 200 micrograms/min) were compared with 1) retinopathy as assessed by stereoscopic fundus photographs; 2) cardiovascular disease as assessed by a history of cardiac disease or stroke; ischemic changes on exercise treadmill testing; Q wave myocardial infarction; Estes, Sokolow, or Cornell criteria for left ventricular hypertrophy; positive Rose questionnaire for angina; and an abnormal Doppler exam for peripheral vascular disease; and 3) neuropathy as assessed by neurological symptom and disability scores, autonomic function testing, and quantitative sensory exams involving thermal and vibratory sensation. Selected patient characteristics were then evaluated to determine their effects on the presence of diabetic complications using univariate analyses. Multiple logistic regression analyses were then performed to determine the independent effect of UAE on these diabetic complications. RESULTS: chi 2 analyses revealed that UAE was significantly associated with the presence of retinopathy (P < 0.001), neuropathy (P < 0.001), and cardiovascular disease (P < 0.001). In the multiple logistic regression analyses, UAE had strong independent associations with retinopathy, neuropathy, and cardiovascular disease. CONCLUSIONS: Thus, increasing UAE in this large NIDDM population in the U.S. was associated with an increased prevalence of diabetic retinopathy, neuropathy, and cardiovascular disease. This suggests that UAE may be more than an indicator of renal disease in NIDDM patients and, in fact, may reflect a state of generalized vascular damage occurring throughout the body. Prospective studies in NIDDM patients are needed to determine the predictive effect of UAE and the effect of decreasing UAE on future diabetic micro- and macrovascular complications.

Normal development and effects of deafferentation on the morphology of superior collicular neurons projecting to the lateral posterior nucleus in hamster.

Visually responsive neurons in the superficial layers of the hamster's superior colliculus (SC) can be divided into distinct morphological and functional classes. In the preceding paper (Mooney et al., '91), we showed that neonatal enucleation has only slight and insignificant effects upon the structural characteristics of cells within a given class, but results in a significant reduction of neurons (narrow and widefield vertical cells) with dorsally directed dendritic arbors. In an effort to determine whether this change reflected differential transneuronal degeneration of these cell types or alterations in the dendritic arbors of surviving cells, this study re-examined this issue by restricting the analysis to a specific and relatively homogeneous subpopulation of superficial layer neurons, those that project to the lateral posterior nucleus (LP). Physiological recordings demonstrated that most (64.7%) tecto-LP cells in neonatally enucleated hamsters develop somatosensory receptive fields. The combination of retrograde tracing and injection of cells with Lucifer yellow in a fixed slice preparation demonstrated that nearly 75% of tecto-LP cells in normal adult hamsters are widefield vertical cells while less than 25% of the neurons filled in neonatally enucleated adults are in this class. Most of the tecto-LP cells in the neonatally enucleated adult hamsters were either horizontal cells (19.5%), giant stellate cells (24.6%), or had dendrites that were directed only toward the deep SC laminae (10.3%). Differential enucleation-induced cell death could not account for all of these changes. Tecto-LP neurons were retrogradely labelled with the carbocyanine dye, Di-I, in hamsters on postnatal day (P-) 0 (the day of birth) through P-10. As early as P-0, most retrogradely labelled neurons could be identified as either widefield (44.6%) or narrowfield (18.9%) vertical cells. These results, when considered together with those from the normal adult and neonatally enucleated adult hamsters, support the conclusion that neonatal eye removal results in a reorganizaton of the dendritic arbors of some collicular neurons that have already undergone considerable development at the time of the lesion.

Correlations between the receptive field properties and morphology of neurons in the deep layers of the hamster's superior colliculus.

Extracellular and intracellular recording, receptive field mapping, and intracellular HRP injection techniques were used to define the morphological classes of cells in the deep laminae of the hamster's superior colliculus and to determine whether there are any correlations between the structural and functional characteristics of these neurons. A total of 110 neurons were characterized and reconstructed. Of these, 23.6% (N = 26) were visual, 60% (N = 66) were somatosensory, 0.9% (N = 1) were bimodal (visual-somatosensory), and 15.4% (N = 17) were unresponsive. Of the somatosensory neurons, 72.7% (N = 48) were low threshold, 4.5% (N = 3) had a wide dynamic range, 9.1% (N = 6) responded only to noxious stimulation, and 13.6% (N = 9) had complex somatosensory receptive fields. Deep layer cells were divided into eight morphological classes. These classes were multipolar cells (26.4%, N = 29), bipolar cells (9.1%, N = 10), widefield vertical cells (7.3%, N = 8), horizontal cells (13.6%, N = 15), stellate cells (10.9%, N = 12), ventrally directed cells (5.5%, N = 6), sparse radial cells (17.3%, N = 19), and small sparse radial cells (6.4%, N = 7). Four cells (3.6%) did not fit into this classification scheme. Univariate and multivariate analyses of variance of properties such as soma area, number of branch points, total dendritic length, and volume and orientation of dendritic arbor indicated that these classes were significantly different. However, chi 2 analysis and multivariate analysis of variance indicated no significant relationships between morphological class and either laminar location or receptive field type. There was a significant positive relationship between the possession of dendrites that extended into the superficial laminae and visual responsivity.