Identification of novel candidate autoantibodies in Alzheimer's disease.

BACKGROUND AND PURPOSE: Accumulated failures in Alzheimer's disease (AD) clinical trials have highlighted an urgent need to identify additional biomarkers involved in AD. Recently, mounting evidence reported that autoantibodies are ubiquitous in human sera. However, it is unknown whether autoantibodies are upregulated in amyloid-tau biomarker-confirmed AD. METHODS: A total of 40 subjects with mild dementia (Clinical Dementia Rating = 1) were stratified into AD (n = 16) and non-AD (n = 24) groups according to their cerebrospinal fluid levels of tau and Aß42 . Their sera were collected and analyzed using a microarray containing > 1600 potential human autoantigens. Autoantibodies that were present exclusively in the AD group were identified and selected using the penetrance-based fold change method with the following criteria: penetrance fold change(AD)  ≥ 2, frequency(AD)  ≥ 15% and frequency(non-AD)  = 0%. RESULTS: All controls and samples passed the quality control criteria and were further used for biomarker analysis. Six autoantibodies with elevated responses to the following autoantigens were found exclusively in the AD group: nucleosome assembly protein 1-like 3 (31.3%, 5/16 subjects) and microtubule-associated protein 4, pantothenic acid kinase 3, phosphoinositide-3-kinase regulatory subunit 1, protein tyrosine phosphatase type IVA member 1 and SRY (sex-determining region Y)-box 15 (all 18.8%, 3/16 subjects). CONCLUSIONS: Although some identified autoantigens are linked to AD and cognitive dysfunction, the increased autoantibody levels have not been reported in AD. Autoantibodies may provide deeper insights into the pathogenesis of AD and serve as diagnostic biomarkers; their corresponding antigens can be further studied to assess their potential as therapeutic targets.

Clinical outcome of head and neck cancer patients: a comparison between ENT patients referred via the 2 weeks wait pathway and alternative routes in the UK health system.

2 weeks wait (2ww) referral was intended to improve cancer outcomes in the UK. However, a previous study found that 2ww failed to detect early stage head and neck cancer. There is no current study to examine the survival outcome of head and neck cancer patients diagnosed on 2ww and non-2ww pathways. The aim of this study is to compare the outcome of cancer patients diagnosed on these pathways. We performed a retrospective review of head and neck cancer patients diagnosed between 2009 and 2013 in the ENT Department at Mid-Yorkshire NHS Hospitals Trust. Gender, age, disease staging, treatment modalities, route of referrals along with survival data were documented. Survival analysis was performed for 2ww and non-2ww cancer patients. There were 4123 patients referred on 2ww during the study period. 147 patients were diagnosed with cancers on 2ww and 89 patients were diagnosed on non-2ww. There were no statistical differences in clinical staging (p = 0.416) and overall survival (p = 0.376) between 2ww and non-2ww patients. This study failed to demonstrate a better overall survival in head and neck cancer patients diagnosed on 2ww pathway within the ENT cohort. Current referral system needs to be refined to improve the survival outcome in head and neck cancer patients.

Management of paediatric otogenic cerebral venous sinus thrombosis: a systematic review.

BACKGROUND: Otogenic paediatric cerebral venous sinus thrombosis (CVST) is rare but has potential clinical sequelae. Its management has long been debated mainly concerning the role of surgery and the use of anticoagulant therapy. OBJECTIVE OF REVIEW: To review the current literature and examine the medical and surgical management of paediatric otogenic CVST and its clinical and radiological outcome. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: The electronic databases (MEDLINE, EMBASE, Cochrane) were searched from inception to November 2014 using text words 'cerebral venous sinus thrombosis OR cerebral venous thrombosis OR lateral sinus thrombosis OR sigmoid sinus thrombosis' AND 'otogenic OR mastoiditis OR otitis media' AND 'children OR paediatric OR pediatric'. EVALUATION METHOD: Inclusion criteria were applied by two reviewers and data extraction was carried out. The type of otological surgery (conservative versus extensive) and the use of anticoagulants with their clinical and radiological outcomes were tabulated. RESULTS: Thirty-six studies (15 case reports and 21 case series) were included with a total of 190 patients. A total of 92.1% of patients underwent otological surgery, and 69.5% had conservative surgery and 30.5% extensive otological surgery. Anticoagulants were used in 59%. A total of 79.2% of patients were reported to have had a good clinical outcome. Within this group, 56% had conservative surgery and anticoagulants. Follow-up scans were documented in 61.6% of patients and complete recanalisation was observed in 51%. Complete recanalisation was observed in 47% of those who had been anticoagulated and 55% of those who received no anticoagulation. CONCLUSIONS: Conservative otological surgery with the combination of anticoagulation was the most common treatment modality found in the group of patients with good clinical outcome. However, given the current low level of evidence, a multicentre collaborative study is needed to help establish the optimum surgical approach and the role of anticoagulation in managing paediatric otogenic CVST.

Clinical Outcomes of Conservative Treatment for Low-Risk Ductal Carcinoma in Situ: A Systematic Review and Pooled Analysis.

AIMS: The current gold standard of treatment for ductal carcinoma in situ (DCIS) is surgical resection with or without adjuvant radiotherapy. However, the increased detection and radical treatment of DCIS did not result in a declined incidence of invasive breast cancers, leading to the debate if DCIS has been overtreated. While ongoing randomised controlled trials on active surveillance of DCIS are still in progress, this systematic review aims to evaluate the best evidence on conservative treatment for DCIS from the literature. MATERIALS AND METHODS: This systematic review was conducted in line with the PRISMA statement. We included all relevant studies published up to June 2022 for analysis. The primary outcomes were overall survival and breast cancer-specific survival (BCSS) of conservative treatment for DCIS. RESULTS: Three studies, with a total of 34 007 women with low-risk DCIS, were included in the analysis. Active and conservative treatments both resulted in excellent 10-year BCSS, with no statistically insignificant difference (98.6% versus 96.0%, 31 478 women). One study comparing 5-year BCSS of active and conservative treatments only in subjects aged over 80 years also reported [AQ1]an insignificant difference (98.2% versus 96.0%, 2529 women). One study measuring 5- and 10-year overall survival between the treatment groups also reported [AQ1]an insignificant difference (5-year: 96.2% versus 92.4%; 10-year: 85.6% versus 86.7%, 31 106 women). CONCLUSION: BCSS between active and conservative treatment for women with low-risk DCIS is both excellent and comparable, suggesting that conservative treatment is a possible alternative without compromising survival.

Morphometric sex determination of Milky and Painted Storks in captivity.

Logistic regression was applied to develop a morphometric sexing method of two closely related stork species that were previously sexed through amplification of the CHD gene. Tarsus length (TL) and bill length (BL) measurements were recorded from captive populations of adult Milky Stork (Mycteria cinerea) (n = 60) and Painted Stork (Mycteria leucocephala) (n = 58) at Zoo Negara Malaysia. Despite having monomorphic plumages, both stork species exhibited normal sexual size dimorphism in which males were significantly larger than females in the tested variables. Based on logistic regression analysis, BL correctly classified the sex of sampled individuals from Painted and Milky stork with an overall predicted accuracy of 94.8 and 90.0%, respectively. However, TL measurements generated a lower predicted accuracy level of 86.2% and a same accuracy level of 90% on the sex classification of individuals from Painted and Milky stork, respectively. By comparing the measurements of both species, only the average BL measurements of the Milky storks were significantly lower than that of Painted storks (t-test, P80.001). The logistic regression equation in this study may serve as a simple and more practical option for sexing Milky and Painted storks for their breeding and conservation programmes.

Electrochemotherapy for the palliative management of non-skin-origin head and neck cancer: case series and UK national survey.

OBJECTIVES: Electrochemotherapy uses electric fields to facilitate the influx of chemotherapy into cancer cells, producing a targeted effect. For head and neck cancer, it is mainly used for palliation of non-skin-origin metastases. It is used infrequently in the UK. This paper presents our experience and a UK survey to identify its frequency of use. METHODS: Between 2016 and 2019, a prospective database was created and reviewed. Only patients with non-skin-origin metastatic head and neck cancer, with no other palliative options, were included. Survival length, complications and symptomatic benefit were assessed. The survey was conducted via e-mail. RESULTS: Five patients were included: three with squamous cell carcinoma, one with esthesioneuroblastoma and one with hepatocellular carcinoma. Survival ranged from 1 month to over 20 months. Minor complications were seen. Only 15 out of 69 UK head and neck multidisciplinary teams offer electrochemotherapy. CONCLUSION: Electrochemotherapy is a well-tolerated adjunct to standard palliation of metastatic head and neck cancer, and is offered by a limited number of UK multidisciplinary teams.

Prognostic value of the neutrophil-to-lymphocyte ratio in patients with laryngeal squamous cell carcinoma.

BACKGROUND: The neutrophil/lymphocyte ratio (NLR) has been found to be predictive of survival outcome in a range of tumors. The purpose of this study was to investigate the prognostic value of pretreatment (NLR) in patients with laryngeal squamous cell carcinoma (SCC). METHODS: A retrospective analysis of 140 patients with laryngeal SCC treated between 2005 and 2010 in the Hull and East Yorkshire Hospitals NHS Trust was carried out. Patient records were evaluated and both pretreatment neutrophil and lymphocyte counts were documented together with survival data, sex, smoking status, nodal classification, and disease staging. RESULTS: An elevated NLR was significantly associated with advanced disease stage (eg, node-positive and tumors stage III and IV). In addition, a high NLR was significantly associated with poor overall survival (OS) but not disease-free survival (DFS) on multivariate analysis, with the greatest significance seen in patients with the highest NLR. CONCLUSION: Pretreatment NLR may serve as a useful prognostic marker in laryngeal SCC; however, a large prospective study is required to determine an optimal NLR cutoff value. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1903-E1908, 2016.

A survey of how and why medical students and junior doctors choose a career in ENT surgery.

OBJECTIVE: To ascertain determinants of an interest in a career in ENT surgery through a survey of medical students and junior doctors. METHODS: A survey was administered, comprising Likert scales, forced response and single option questions, and free text responses, at five different courses or events for those interested in a career in ENT. RESULTS: The survey had an 87 per cent response rate; respondents consisted of 43 applicants for national selection, 15 foundation doctors and 23 medical students. The most important factors that encourage ENT as a career included: the variety of operative procedures, work-life balance, inherent interest in this clinical area and inspirational senior role models. Exposure to ENT in undergraduate or post-graduate training is critical in deciding to pursue this specialty. CONCLUSION: It is important to promote those aspects of ENT surgery that attract people to it, and to argue for greater exposure to ENT during undergraduate and post-graduate training.

Simple method for maintaining serum lidocaine levels in the therapeutic range.

Lidocaine hydrochloride is commonly infused intravenously to prevent ventricular arrhythmias. In some patients, elevations in serum lidocaine levels can cause serious toxic effects. In a group of 19 patients given a constant infusion of lidocaine, we confirmed the observation that serum lidocaine levels rose significantly between four and 24 hours after initiation of therapy. One of these patients manifested a toxic reaction to lidocaine. The lidocaine infusion rate was modified in a second group of 32 patients on the basis of the four-hour serum level. In these patients, after dosage adjustment, the mean lidocaine level did not rise, and all levels remained within the 2- to 4-mg/L therapeutic range at 24 hours. Without dosage adjustment, half of these levels would have fallen outside the desired range. A simple formula can be used to adjust prophylactic lidocaine infusion rates to attain levels that remain therapeutic, yet nontoxic.

Effect of regional myocardial ischaemia on left ventricular isovolumic contraction.

In anaesthetised, open-chest dogs, global isovolumic contractility indices were reduced by acute regional ischaemia involving 12 to 14% or more of left ventricular mass. These effects were not altered by controlled reduction of blood flow to the non-ischaemic region, but were exaggerated by isoprenaline during normal perfusion of the non-ischaemic region. The results were consistent with a contraction model characterised by simple reduction of the effective length of the contractile elements.

Transduction of rIL-2 expanded CD4+ and CD8+ ovarian TIL-derived T cell lines with the G1Na (neor) replication-deficient retroviral vector.

We have expanded ovarian tumor-infiltrating lymphocytes (TIL) in low concentrations of recombinant interleukin-2 (rIL-2) to conduct intraperitoneal adoptive immunotherapy trials in patients with ovarian cancer. We have previously demonstrated that certain T cell lines and clones derived from ovarian TIL exhibit in vitro autologous tumor-specific cytotoxicity and/or cytokine production (interferon-gamma, tumor necrosis factor-alpha) preferentially in response to autologous tumor cells. Studies that utilize a marker gene introduced into the DNA of TIL can provide useful information on specific uptake or localization of TIL at tumor sites and on the survival of TIL in vivo. We have conducted a series of preclinical experiments in which we have successfully transfected TIL with G1Na, which encodes the gene for neomycin phosphotransferase (neoR). NeoR was detected in at least 10% of CD8+ cells (mean = 10.4%) and between 2.5 and 20% of CD4+ TIL (mean = 8.5%). Transduction of ovarian TIL with G1Na caused no substantial changes to the T cell phenotypes or in vitro cytotoxicities against ovarian and hematogenous tumor cell targets, or on the rIL-2 requirements of TIL for growth and proliferation. In addition, the intact G1Na provirus in transduced TIL cells was rescuable by replication-competent retrovirus and was transferred into the genome of NIH-3T3 fibroblasts, which were rendered resistant to G418. An enhanced polymerase chain reaction (PCR) procedure utilizing detection by ethidium bromide staining was developed. The enhanced PCR detected 1 in 100,000 neoR-labeled cells. Furthermore, detection of the G1Na genome in transduced TIL by in situ hybridization with an RNA probe provided evidence for expression of the neoR gene in transduced TIL. Results obtained from these studies suggest that ovarian TIL-derived T cell lines transduced with the neoR gene post infection with the G1Na retroviral vector can be utilized to examine the in vivo trafficking pattern of ovarian TIL-derived T cell lines expanded in low concentrations of rIL-2 and their survival.

Transient unifascicular, bifasicular and trifascicular block: electrophysiologic correlations in a patient with rate-dependent left bundle branch block and transient right bundle branch block.

Correlations of the His to ventricular (H-V) conduction time were made with the surface electrocardiogram during normal intraventricular conduction, unifascicular block (right bundle branch block), bifascicular block (left bundle branch block) and trifascicular block (right and left bundle branch block) in a patient with rate-dependent left bundle branch block who had transient right bundle branch block during recording of the His bundle electrogram. The results provide a functional confirmation of the theory that a prolonged H-V time is a manifestation of trifascicular disease.

Clinical significance of the V wave in the main pulmonary artery.

Among 68 patients with mitral insufficiency who had right and left cardiac catheterization and left ventriculography, 6 had retrograde transmission of the left atrial V wave into the main pulmonary artery. All of these patients had mitral insufficiency of acute onset. The remaining 62 patients had chronic mitral insufficiency that was considered severe in 17. Pulmonary vascular resistance was lower in the group with acute insufficiency (mean 139 dynes sec cm-5) than in the group with chronic severe insufficiency (mean 631 dynes cm-5) (P less than 0.005). Nondistensibility of the left atrium and low pulmonary vascular resistance were the two factors favoring retrograde transmission of V waves. Because both factors are present in acute mitral regurgitation, this finding is helpful in differentiating patients with acute mitral insufficiency.

Modulation of cytochrome P-450IA1-mediated mutagenicity, DNA binding and metabolism of benzo[a]pyrene by Chinese medicinal herbs.

Oldenlandia diffusa (OD) and Scutellaria barbata (SB) have been used in traditional Chinese medicine for treating liver, lung and rectal tumors. We previously showed that they inhibited mutagenesis, DNA binding and metabolism of benzo[a]pyrene (BaP) and aflatoxin B1 (AFB1) bioactivated by Aroclor 1254-induced rat hepatic S9. The purpose of this study was to investigate the effects of OD and SB on the cytochrome P-450IA1-mediated mutagenicity of BaP in Salmonella typhimurium TA100 using beta-naphthoflavone (beta NF)-induced rat hepatic S9. We also determined the effects of OD and SB on cytochrome P-450IA1-linked ethoxyresorufin O-deethylase (EROD) activity in beta NF-induced hepatic microsomes. In addition, we studied the effects of these two herbs on BaP metabolite binding to calf thymus DNA and using high performance liquid chromatography (HPLC) we investigated the effects of OD and SB on the metabolism of BaP by beta NF-induced S9. Our experimental results showed that OD and SB inhibited the mutagenicity of BaP in the presence of either non-induced or beta NF-induced S9. SB significantly inhibited BaP binding to DNA. These effects correlated with the inhibition of cytochrome P-450IA1-linked EROD activity in beta NF-induced microsomes and with an inhibition of beta NF-induced S9 mediated metabolism of [3H]BaP as determined by HPLC. These results suggest that OD and SB may possess antimutagenic activity by inhibiting P-450IA-mediated metabolism of BaP.

Chinese medicinal herbs modulate mutagenesis, DNA binding and metabolism of benzo[a]pyrene 7,8-dihydrodiol and benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide.

Oldenlandia diffusa(OD) and Scutellaria barbata (SB) have been used in traditional Chinese medicine for treating liver, lung and rectal tumors. In this study, the effects of aqueous extracts of these two herbs on benzo[a]pyrene 7,8-dihydrodiol. (BaP 7,8-DHD) and benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE)-induced mutagenesis using Salmonella typhimurium TA100 as the bacterial tester strain and rat liver 9000 x g supernatant (S9) as the metabolic activation system were assessed. We also determined the effects of these two herbs on BaP 7,8-DHD and BPDE binding to calf thymus DNA. Organosoluble metabolites of BaP 7,8-DHD and water-soluble conjugates of BaP 7,8-DHD and BPDE were analyzed by high-performance liquid chromatography (HPLC) and alumina column liquid chromatography. Mutagenesis assays revealed that these two herbs produced a significant concentration-dependent inhibition of histidine-independent (His+) revertants induced by BaP 7,8-DHD and BPDE. OD and SB also inhibited BPDE-induced mutagenesis in a concentration-dependent manner in the absence of S9. SB had a greater inhibitory effect than OD. SB significantly inhibited BaP 7,8-DHD and BPDE binding to DNA while OD significantly enhanced DNA binding of both compounds. OD and SB inhibited the formation of organosoluble metabolites of BaP 7,8-DHD and decreased the formation of water-soluble conjugates of BaP 7,8-DHD and BPDE. However, the fraction of the total radioactivity in the water-soluble conjugates present as sulfate and glutathione was increased by OD and SB. Glucuronide fraction was decreased. The results of this study affirm our previous work suggesting that these two Chinese medicinal herbs possess antimutagenic properties and further suggest that they act as blocking agents through a scavenging mechanism.

Echocardiographic features of an aneurysm of the left sinus of Valsalva.

The echocardiographic features of an aneurysm of the left sinus of Valsalva are described and correlated with angiographic findings. The echocardiogram showed the presence of a thin line of echoes occurring proximal to the anterior leaflet of the mitral valve and moving in and out of apposition with the posterior aortic wall. During systole, this line of echoes moved away from the aorta into the left atrium, and during diastole, the line moved into the aorta. Recognition of these features provides a potential noninvasive way to diagnose aneurysms of the left sinus of Valsalva prior to rupture.

Diagnosis of pericardial effusion by computed tomography.

We assessed the diagnostic utility of computed tomography (CT) in the detection of pericardial effusion by using a dog model in which the amount and type of pericardial fluid were controlled and by obtaining CT scans on patients with suspected pericardial effusion prior to pericardiocentesis. The experimental studies showed that CT was capable of detecting pericardial effusion composed of serous fluid or saline in amounts as small as 50 ml. However, the hemopericardium was radiographically isodense with the heart and difficult to detect by CT unless the epicardial fat pad was identified or intravenous contrast enhancement of the heart was used. CT clearly demonstrated the presence of pericardial effusion in all six patients studied prior to successful pericardiocentesis or pericardiectomy. We conclude that CT is a sensitive noninvasive method which can be used for the diagnosis of pericardial effusion.

Progression of aortic stenosis.

We assessed progressive stenosis of the aortic valve in 11 adult patients (mean age of 48 years) with aortic stenosis who had undergone two cardiac catheterizations without intervening aortic valve surgery. The mean time between cardiac catheterization was 59 months (range 20 to 133). No patients had mitral valve disease. Two patients had coronary artery disease. The results showed that progressive stenosis of the aortic valve occurred in 10 of 11 patients with a significant decrease in the calculated mean aortic valve area from 1.2 +/- 0.2 sq cm to 0.7 +/- 0.1 sq cm (P less than 0.005); a significant increase in mean left ventricular peak systolic pressure from 149 +/- 8 mm Hg to 199 +/- 3 mm Hg (P less than 0.01), and a significant increase in mean left ventricular aortic pressure gradient from 31 +/- 4 mm Hg to 75 +/- 13 mm Hg (P less than 0.005). On an individual basis, the change in left ventricular pressure and the left ventricular-aortic gradient did not always reflect the decrease in aortic valve area because of variations in cardiac output. The shortest period of time in which progression of aortic stenosis occurred was 27 to 29 months. Thus, progressive stenosis of the aortic valve occurs in adults with isolated aortic valvular stenosis. Significant decrease in the aortic valve area can develop in as short a period as 27 to 29 months.