Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress.

OBJECTIVE: We have previously identified peroxiredoxin-3 (PRDX-3) as a cell-surface protein that is androgen regulated in the LNCaP prostate cancer (PCa) cell line. PRDX-3 is a member of the peroxiredoxin family that are responsible for neutralising reactive oxygen species. EXPERIMENTAL DESIGN: PRDX-3 expression was examined in tissue from 32 patients using immunohistochemistry. Subcellular distribution was determined using confocal microscopy. PRDX-3 expression was determined in antiandrogen-resistant cell lines by western blotting and quantitative RT-PCR. The pathways of PRDX-3 overexpression and knockdown on apoptosis and response to oxidative stress were investigated using protein arrays. RESULTS: PRDX-3 is upregulated in a number of endocrine-regulated tumours; in particular in PCa and prostatic intraepithelial neoplasia. Although the majority of PRDX-3 is localised to the mitochondria, we have confirmed that PRDX-3 at the cell membrane is androgen regulated. In antiandrogen-resistant LNCaP cell lines, PRDX-3 is upregulated at the protein but not RNA level. Resistant cells also possess an upregulation of the tricarboxylic acid (TCA) pathway and resistance to H2O2-induced apoptosis through a failure to activate pro-apoptotic pathways. Knockdown of PRDX-3 restored H2O2 sensitivity. CONCLUSION: Our results suggest that PRDX-3 has an essential role in regulating oxidation-induced apoptosis in antiandrogen-resistant cells. PRDX-3 may have potential as a therapeutic target in castrate-independent PCa.

Use of the self-controlled case-series method in vaccine safety studies: review and recommendations for best practice.

The self-controlled case-series method was originally developed to investigate potential associations between vaccines and adverse events, and is now commonly used for this purpose. This study reviews applications of the method to vaccine safety investigations in the period 1995-2010. In total, 40 studies were reviewed. The application of the self-controlled case-series method in these studies is critically examined, with particular reference to the definition of observation and risk periods, control of confounders, assumptions and potential biases, methodological and presentation issues, power and sample size, and software. Comparisons with other study designs undertaken in the papers reviewed are also highlighted. Some recommendations are presented, with the emphasis on promoting good practice.

Effectiveness of influenza vaccine in children in preventing influenza associated hospitalisation, 2018/19, England.

2013/14 saw the start of the introduction of a new live attenuated influenza vaccine (LAIV) programme for children in England. 2018/19 saw co-circulation of both A(H1N1)pdm09 and A(H3N2), when LAIV was offered to all healthy children 2-9 years of age. LAIV effectiveness against influenza hospitalisation is not well described. This paper presents the 2018/19 end-of-season adjusted vaccine effectiveness (aVE) against laboratory confirmed influenza related hospitalisation in children aged 2-17. The test negative case control approach was used to estimate aVE by influenza A subtype and vaccine type. Cases and controls were selected from a sentinel laboratory surveillance system which collates details of individuals tested for influenza with reverse-transcription polymerase chain reaction (RT-PCR) on respiratory samples. Vaccine and clinical history was obtained from general practitioners of study participants. There were 307 hospitalised cases and 679 hospitalised controls. End-of-season influenza aVE was 53.0% (95% CI: 33.3, 66.8) against influenza confirmed hospitalisation; 63.5% (95% CI: 34.4, 79.7) against influenza A(H1N1)pdm09 hospitalisation and 31.1% (95% CI: -53.9, 69.2) against influenza A(H3N2). LAIV aVE was 49.1% (95% CI: 25.9, 65.0) for any influenza and 70.7% (95% CI: 41.8, 85.3) for A(H1N1)pdm09, whereas for those receiving quadrivalent inactivated influenza vaccine (QIV), aVE was 64.4% (95% CI: 29.4, 82.0) and 44.4% (95% CI: -51.9, 79.6) respectively. We provide evidence of overall significant VE for both LAIV and QIV against influenza associated hospitalisation in children 2-17 years of age, most notably against influenza A(H1N1)pdm09, with non-significant protection against A(H3N2).

Language production: electroencephalographic localization in the normal human brain.

Slow negative potentials, which are at a maximum over Broca's area in the left hemisphere, were recorded when normnal subjects spontaneously produced polysyllabic words. Bilaterally symmetrical potentials were seen with analogous, nonspeech control gestures. These potentials began up to 1 second before word or gesture articulation. These results are the first demonstration of localization of language production in normal human brain.

Measures of disassortativeness and their application to directly transmitted infections.

We propose a measure of disassortativeness to summarize contact patterns relevant to the transmission of directly transmitted infections. We discuss the properties of this measure, describe standardization relative to homogeneous mixing, and generalize it to multivariate contact structures. We explore some of its properties and apply our methods to serological surveys of close contact infections and surveys of self-reported social contacts obtained in several European countries.

A novel mutation in the human androgen receptor suggests a regulatory role for the hinge region in amino-terminal and carboxy-terminal interactions.

CONTEXT: The androgen insensitivity syndrome (AIS) is caused by molecular defects in the androgen receptor (AR). Clinically, the partial AIS has a variable phenotype. Many mechanisms explain the phenotype in the AIS. A crucial step in AR action is the interaction of the N and C termini. OBJECTIVE: The role of the hinge region of the AR is not as well understood as other parts of the receptor. We aim to study the role of this region in the N/C-termini interaction. PATIENT AND METHOD: We report a patient with severe undermasculinization and poor response to exogenous androgens. Androgen binding was performed, and the AR gene was sequenced. The mutation was recreated and transfected in COS-1 cells. Transactivation was studied. N/C-termini interaction was studied using a mammalian two-hybrid assay. A nuclear localization study was performed. RESULTS: Androgen binding was normal, and a novel mutation (Arg629Trp) in the AR hinge region was identified. Mutant AR transactivation was 40% higher compared with wild type (WT). A 3-fold increase in transcription occurred when both WT N and C-terminal domains were cotransfected; no response occurred when the mutated region of the AR was included (P < 0.001). Cells with mutant AR showed a comparable nuclear localization to the WT AR. CONCLUSIONS: A mutation in the hinge region impaired N/C-domain interaction in the presence of normal AR binding and nuclear localization. It resulted in severe undermasculinization at birth and resistance to androgens. The findings confirm a unique regulatory role for the hinge region in AR function.

Discovery and evaluation of single nucleotide polymorphisms (SNPs) for Haliotis midae: a targeted EST approach.

In this study, we describe the first set of SNP markers for the South African abalone, Haliotis midae. A cDNA library was constructed from which ESTs were selected for the screening of SNPs. The observed frequency of SNPs in this species was estimated at one every 185 bp. When characterized in wild-caught abalone, the minor allele frequencies and F(ST) estimates for every SNP indicated that these markers may potentially be useful for population analysis, parentage assignment and linkage mapping in Haliotis midae. No linkage disequilibrium was observed between SNPs originating from different EST sequences. These SNPs, together with additional SNPs currently being developed, will provide a useful complementary set of markers to the currently available genetic markers in abalone.

Pathogenesis of prostate cancer and hormone refractory prostate cancer.

Prostate cancer is the second most common malignancy in males and the leading cause of cancer death. Prostate cancer is initially androgen dependent and relies upon the androgen receptor (AR) to mediate the effects of androgens. The AR is also the target for therapy using antiandrogens and LHRH analogues. However, all cancers eventually become androgen independent, often referred to as hormone refractory prostate cancer. The processes involved in this transformation are yet to be fully understood but research in this area has discovered numerous potential mechanisms including AR amplification, over-expression or mutation and alterations in the AR signaling pathway. This review of the recent literature examines the current knowledge and developments in the understanding of the molecular biology of prostate cancer and hormone refractory prostate cancer, summarizing the well characterized pathways involved as well as introducing new concepts that may offer future solutions to this difficult problem.

Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding?

BACKGROUND: A 15-fold increased risk of gastrointestinal bleeding has been reported with concurrent use of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Recent guidance cautions against concurrent prescription, particularly in older people. AIM: To quantify the risk of gastrointestinal bleeding associated with current exposure to non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and both drugs concurrently. METHODS: We conducted a case-control analysis of 11,261 cases with upper gastrointestinal bleeding and 53,156 controls matched by gender, age and general practice from computerized primary care data. We coupled this with self-controlled case series analysis. RESULTS: Both drugs were associated with a twofold increased risk of gastrointestinal bleeding (odds ratio =2.38, 95% confidence interval 2.08-2.72 for selective serotonin reuptake inhibitors and odds ratio = 2.15, 95% confidence interval 2.02-2.28 for non-steroidal anti-inflammatory drugs). This increased risk was marginally higher for concurrent prescription (odds ratio = 2.93, 95% confidence interval 2.25-3.82). The self-controlled analysis showed a greater incidence rate ratio for gastrointestinal bleeding with non-steroidal anti-inflammatory drugs (2.71, 95% confidence interval 2.51-2.91) and lower incidence rate ratio with selective serotonin reuptake inhibitors (1.71, 95% confidence interval 1.48-1.98). The incidence rate ratio when both drugs were combined was 3.25, 95% confidence interval 1.95-5.42. Estimates were similar after restricting to people over 80 years of age. Increased risk of gastrointestinal bleeding was not specifically related to class of non-steroidal anti-inflammatory drugs and was similar when we looked at tricyclic anti-depressants. CONCLUSIONS: Our study suggests that the risk of gastrointestinal bleeding is not substantially increased when non-steroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors are prescribed together, compared with their use alone.

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study.

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.

Jean-Baptiste Bouillaud, Claude-François Lallemand, and the role of the frontal lobe: location and mislocation of language in the early 19th century.

In 1825, Jean-Baptiste Bouillaud read a paper at the Royal Academy of Medicine in Paris supporting Franz Gall's theory of a relation between speech and the frontal lobes. Bouillaud argued that if the frontal lobes are crucial to speech, 2 conditions must be satisfied: when the frontal lobes are affected, speech must also be affected; conversely, when the frontal lobes are spared, speech is also spared. Following these principles, he tested and argued in support of Gall's theory by analyzing the data from 2 neuropathological casebooks (Lallemand, 1820-1823; Rostan, 1820 and 1823). We now know that Bouillaud was wrong, since the crucial dichotomy is between the left and right hemispheres and not between the anterior and posterior areas. What is interesting is that the actual data refute Bouillaud's conclusion. We replicated his experiment by reanalyzing the 147 clinical cases described by Lallemand. There were, of course, some cases with frontal lesions and speech disorders; other cases, however, had speech disorders with lesions outside the frontal lobes, and still others had frontal lesions without speech disorders. Although Bouillaud did not notice it, as we expected, almost all patients with speech disorders had a left hemisphere lesion.

The bilingual brain.

The localization of two languages in the lateral cortex of the dominant cerebral hemisphere was determined by the technique of mapping sites where electrical stimulation altered naming in two biligual patients. Sites in the center of the language area of each patient were involved in both languages. Peripheral to this, in both frontal and parietal cortex, were sites involved in only one of the languages. In each patient, each language in part used different areas of brain.

Acquired capsular/striatal aphasia in childhood.

We studied a case of language loss caused by an acquired vascular lesion in the putamen, anterior limb of the internal capsule, and lateral aspect of the head of the caudate nucleus in a 7-year-old right-handed girl. Acute right-sided hemiplegia, mutism, oral apraxia, and disturbance in language comprehension but no dysarthria were present. During recovery, a nonfluent aphasia with anomia was evident. After six months, only mild hemiparesis and minor spelling difficulties persisted. We compared this patient with an 11-year-old right-handed girl with right-sided hemiparesis and dysarthria but no language loss following a lesion in the globus pallidus, a portion of the posterior limb of the internal capsule, and the body of the caudate. The presence of a language disturbance in the first but not the second patient was attributed to the difference in lesion location. The symptoms and lesions were similar to those in recent reports of adult patients. To our knowledge, this is the first report of these findings in a child with a left-hemisphere lesion.

Agrammatism on inflectional bound morphemes: a case study of a Hindi-speaking aphasic patient.

In this report, we discuss a Hindi agrammatic patient who exhibited greater difficulty with the production of inflectional bound morphemes than with function words. The patient retained the metalinguistic judgement to differentiate function words with semantic content, such as postpositions which mark case functions in Hindi. His impaired ability to produce bound inflections also affected his retrieval of verbs; this failure to retrieve verbs was not due to anomia. Further neurolinguistic analyses of synthetic languages would seem likely to extend our understanding of syntactic processes.

Alliteration and assonance in neologistic jargon aphasia.

This paper discusses certain aspects of the speech patterns of neologistic jargon aphasic patients, whose syndrome is one form of a more general classification referred to as Wernicke's or cortical sensory aphasia. The classical lesion site is in the posterior superior temporal convolution of the dominant hemisphere. Patients with such lesions typically have difficulties in the comprehension of auditory linguistic stimuli and their speech is often marked with neologistic jargon. A neologism is a phonological form produced by the patient for which one cannot recover with any reasonable degree of certainty some single item in the patient's vocabulary as it presumably existed before the onset of the disease. Specific analysis is focused on those stretches of speech which exhibit perseveration to the point where there is an excessive amount of alliteration and assonance. The data is described in terms of segments, syllables and sequences of syllables and related to both a mechanism underlying the production of this sort of speech and to the more general problems of neologisms in jargon aphasia.

Cognitive disturbances in Parkinson's disease.

To test the hypothesis that the cognitive impairments that accompany Parkinson's disease (PD) arise from frontal lobe dysfunction, patients with idiopathic PD and controls were tested on a neuropsychological battery that included measures of anterograde memory, visuospatial perception, and naming, as well as several tests that are known to be sensitive to lesions of the frontal lobes. PD patients of normal mental status as measured by the Mini-Mental State Examination performed normally on the naming, line orientation, and verbal recognition memory tests but exhibited deficits on verbal recall. On tests of frontal lobe function, these patients showed mild deficits on a category fluency task and on the Wisconsin Card Sorting Test. However, their errors on the latter were not typical of patients with frontal lesions, and they performed normally on a letter fluency task and exhibited normal release from proactive interference. Patients of lower than normal mental status performed poorly on nearly all of the cognitive tasks including confrontational naming, line orientation, and recognition memory, suggesting that their cerebral dysfunction extended beyond subcortical-frontal circuits. The present study supports the usefulness of the Mini-Mental State Examination for cognitive screening of PD patients, but does not support the hypothesis that the cognitive impairments in PD arise principally from disruption of frontal lobe functioning.

Anterior cruciate ligament injury: evaluation of intraarticular reconstruction of acute tears without repair. Two to seven year followup of 155 athletes.

To evaluate the effectiveness of our treatment regimen, we retrospectively studied the surgically treated knees of 155 athletes, aged 15 to 42 years, who had sustained acute ACL tears. All were treated with ligament excision and intraarticular bone-patellar tendon-bone reconstruction followed by early motion with emphasis on full extension. The follow-up period ranged from 2 to 7 years. Of the 155 patients, 140 were available for final followup at a minimum of 2 years after reconstruction. The patients were evaluated by objective measures (KT-1000, Cybex, Lachman test, range of motion, and postoperative competition level) and subjective assessment scores (pain, swelling, stability, activity level, walking, stair climbing, running, jumping, or twisting). The subjective scores were tabulated for stability level, total score, and activity level. After the patients achieved full range of motion, the KT-1000 measurements at a 20 pound force revealed an average difference of 1.3 mm between the injured and noninjured knees. All but 3 of the 140 patients had a firm endpoint on the Lachman test, and the Cybex tests showed a mean hamstring strength of 98% and mean quadriceps strength of 90%. Sixty of the 69 varsity athletes who were eligible to play returned to preinjury competition level the following season. One had reconstruction failure and eight chose not to continue competition for academic reasons. The questionnaire score average was 92.7 (maximum, 100 points, normal athletic knee score 93.5). We concluded that the surgical procedure, with emphasis on early full extension postoperatively, achieved excellent results and provided a stable knee.

Theodor Meynert's contribution to classical 19th century aphasia studies.

Carl Wernicke (1848-1905) is traditionally considered the first to have described the features of, and the brain pathology underlying, impaired auditory comprehension and related symptoms. Although Wernicke (1874) clearly and repeatedly indicates his indebtedness to Theodor von Meynert (1833-1892), this is usually understood as an acknowledgment that Meynert taught Wernicke neuroanatomy (Eggert, 1977); Wernicke's own words in part support this interpretation. A more sophisticated historical analysis notes that, prior to Wernicke, both Johann Schmidt in 1871 and Charlton Bastian in 1869 had described the concept of receptive aphasia, but neither had supported their analyses with autopsy evidence as did Wernicke, thus not dislodging Wernicke's claim of priority. However, a virtually unknown work by Theodor von Meynert, published in 1866, has recently been rediscovered by us ["Ein Fall von Sprachstörung, anatomisch begründet." Medizinische Jahrbücher. XII Band der Zeitschrift der K. K. Gesellleschaft der Arzte in Wien, 22. Jahr. Pp. 152-189]. In this paper Meynert analyzes the anatomical basis for localizing the comprehension of language in the superior temporal gyrus, he argues that lesions in this area should (by analogy to Broca's earlier observations on language expression) cause impairments in language comprehension, and he presents a case of receptive aphasia with autopsy evidence of destruction of the superior temporal gyrus in the left hemisphere. The patient's aphasia was classic; impaired auditory comprehension, and fluent speech with paraphasias. It is clear that Meynert should be given historical credit for his work.

The ontogeny of hemispheric specialization: some old hypotheses revisited.

This paper re-examines two hypotheses on the ontogeny of hemispheric specialization that long ago fell into disfavor in neuropsychology. It is argued that these hypotheses, equipotentiality and progressive lateralization, may have suffered from misinterpretation that fostered premature acceptance of the developmental invariance view of hemispheric specialization. An alternative view is presented that incorporates both hypotheses within a neurodevelopmental context using anatomical (postmortem) and childhood aphasia data.