The reactivity of murine monoclonal antibodies (McAbs) directed against the monomorphic determinants of Class I and Class II antigens of the major histocompatibility complex (MHC), and against antigens expressed by discrete populations of leucocytes was studied using the indirect immunoperoxidase technique on serial tissue sections of 16 benign and 17 malignant primary human breast tumours. Class I antigens (detected by the McAb 2A1) were consistently associated with stromal leucocytes, fibroblasts and vascular endothelium, but expression on epithelial cells particularly of malignant provenance, was more variable. Class II antigens (detected by TDR 31.1) were present upon a variety of cell types which also included sporadic expression on malignant and benign epithelia. The distribution of leucocytes grossly monitored with 2D1 (reactive with a common leucocyte antigen) was largely interepithelial and periductal in benign lesions. Leucocytes were generally more numerous in malignant tumours, where they were largely confined to the stroma. The majority (approximately 75%) of leucocytes were T lymphocytes (reactive with UCHT1), some of which appeared to react with TDR 31.1 and were therefore activated. Ratios of helper/inducer (OKT4+) and suppressor/cytotoxic (OKT8+) subsets generally exceeded unity in malignant neoplasms. There was no correlation between the extent and distribution of T cells and the HLA status of the epithelial cells. Leucocytes detected by the monoclonal antibody OKM1 which reacts with monocytes/macrophages, granulocytes and large granular lymphocytes were numerically few and again mainly confined to the stroma. In a limited number of tests, leucocytes detected with HNKl, reactive with a differentiation antigen expressed on some cells which mediate natural and antibody-dependent cellular cytotoxicity in vitro although detectable interepithelially in benign tumours, were virtually absent from malignant tissue. HNK1 also cross-reacted with myoepithelial cells in the ducts of benign lesions.


Small cell bronchial carcinoma (SCC) xenografts with differing sensitivity to cyclophosphamide (CY) were investigated using a variety of techniques. Two xenografts (HX78 and HX88) were relatively sensitive to CY, one xenograft (HX72) was inherently resistant to CY and a fourth xenograft (HX78Cy) was a CY induced resistant subline of HX78 and was unstable when maintained without CY exposure. Conventional light microscopy, cytology and electron microscopy examination of the xenografts revealed appearances consistent with SCC. An antikeratin antibody demonstrated the presence of keratin in the inherent and the induced resistant xenografts (and in the unstable revertant) but not in the two sensitive xenografts; the presence of keratin suggested squamous differentiation. Monolayer culture morphology of the sensitive HX78 and the unstable revertant was anchorage independent with the cells forming floating aggregates; the induced resistant subline of this xenograft (HX78Cy) showed, by contrast, flattened, angular adherent cells. Beta HCG production was detected in the monolayer culture supernatant of sensitive HX78 cells; the level of production of beta HCG was increased in the induced resistant HX78Cy cells. Karyotype and flow cytometry studies were also performed. The morphological responses of small cell lung cancer to treatment are discussed.


We have examined the incidence of Harvey ras mutations in human squamous cell carcinomas (SCC) of the upper aerodigestive tract using the polymerase chain reaction (PCR) followed by direct sequencing. No mutations were detected at codons 12, 13, 59 or 61 of this gene in any of six papillomas, five erythroplakias, 56 squamous cell carcinomas, and 16 SCC cell lines. Some of the SCC were lymph node metastases (three) or tumours which had recurred following radiotherapy (seven). We conclude that Harvey ras mutations are not a common event in the pathogenesis or recurrence of SCCs from Caucasian subjects, in contrast to the situation with Indian populations .


We have examined two new oestrogen receptor (ER) assays--an enzyme immunoassay (EIA) and an immunocytochemical assay (ICA) in a large series of primary breast tumours to compare their potential as predictors of (1) response to endocrine therapy and (2) survival in patients developing advanced breast cancer. Response to endocrine therapy was categorised at 6 months (UICC criteria). ER-ICA appears the better predictor of response to endocrine therapy than ER-EIA. Combining ICA and EIA results did not improve the prediction of response. With both assays patients with ER positive tumours survived longer from the time of diagnosis of advanced disease than those with ER negative tumours. The predictive power of these assay for progression of disease appears slightly better for the ER-ICA.


To evaluate the association between mood and anxiety disorders in Hashimoto disease and Euthyroid Goitre in a case control study.Cases included 19 subjects with Hashimoto disease in euthyroid phase, 19 subjects with euthyroid goitre, 2 control groups each of 76 subjects matched (4/1) according to age and sex drawn from the data base of a community based sample. Psychiatric diagnoses were formulated using the International Composite Diagnostic Interview Simplified, according to DSM-IV criteria. All subjects underwent a complete thyroid evaluation including physical examination, thyroid echography and measure of serum free T4 (FT4), free T3 (FT3), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase autoantibodies (anti-TPO). Results: Subjects with Hashimoto disease showed higher frequencies of lifetime Depressive Episode , Generalized Anxiety Disorders  and Social Phobia  whilst no differences were found between subjects with goitre and controls.The study seems to confirm that risk for depressive disorders in subjects with thyroiditis is independent of the thyroid function detected by routine tests and indicates that not only mood but also anxiety disorders may be associated with Hashimoto disease. Clinical and epidemiological studies seem to indicate that an association between high levels of thyroid autoantibodies may be implicated in the increased frequencies of mood disorders observed in thyroid disease, independently of impairment of thyroid function -3. A stuThe aim of the present study was to compare 2 clinical samples of subjects, one with Hashimoto disease (in euthyroid phase) and the second with euthyroid goitre versus controls drown from a community sample, in order to clarify whether the association of mood and anxiety disorder in Hashimoto disease is evident prior to impairment of thyroid dysfunction.Cases: 19 subjects, 18 females, mean age 39.7+/-12.6, with Hashimoto disease in euthyroid phase and 19 subjects, 16 females, mean age 38.1+/-10.4, with euthyroid goitre, all of whom were attending the Endocrinological Unit of the Department of Internal Medicine, University of Cagliari, Italy.Two control groups, each of 76 subjects aged 18–64 years, were obtained by matching each "case" with four "controls" randomly selected on the basis of demographic characteristics (sex and age) from the data base of a larger population enrolled during a previous epidemiological study aimed at defining the prevalence of psychiatric  and thyrTwo standardized forms were used to acquire information concerning: demographic data, state of health and use of social and health services. Psychiatric diagnosis was made using the Italian Simplified version of the Composite International Diagnostic Interview (CIDIS) . The comAll subjects underwent a complete thyroid evaluation including physical examination, thyroid echography and measure of serum free T4 (FT4), free T3 (FT3), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase autoantibodies (anti-TPO). FT4 and FT3 were measured by means of a chromatographic method based on separation of free T4 on Lisophase columns ; TSH was measured by a chemiluminescent method  with normal values ranging from 0.3–3.0 μU/ml. Thyroid echography was performed using a "real time" echograph , Generalized Anxiety Disorders , Social Phobia  and Primary Sleep Disorders ; a tendency towards an increased frequency of Panic Disorder was observed, although statistical significance was not reached . No differences were found in the evaluation of lifetime prevalence of DSM-IV Psychiatric Disorders between patients with Euthyroid goitre and controls (Table 1).This study seems to indicate an association between the presence of a lifetime diagnosis of mood or anxiety disorder and Hashimoto disease without functional thyroid impairment. No difference was observed in mood and anxiety disorders between goitre cases and controls.These findings are congruent with the results of a previous study  that indThe above-cited community survey found that subjects with at least one lifetime diagnosis of anxiety disorders presented anti-TPO+ more frequently than subjects without mood or anxiety disorders. However, no specific anxiety diagnosis was found to be associated with anti-TPO+, although General Anxiety Disorder showed a strong trend toward association (P < 0.058). Anxiety Disorder Not Otherwise Specified was more frequently observed with anti-TPO+, but this is only a sub-threshold condition. A previous research carried out on celiac patients indicated thyroid autoimmunity as possible risk factor for panic disorder . In the Indeed, these 3 surveys seem to indicate a congruent trend of possible risk for anxiety disorders such Generalized Anxiety Disorder, Social Phobia and Panic Disorder in Hashimoto Disease.To our knowledge, the data concerning the association between sleep disorders and Hashimoto disease is the first such evidence published in literature, although it may be consistent with a dysregulation of sleep architecture in subjects with sub-clinical thyroid impairment .A sub-clinical dysfunction of axis thyrotropin releasing hormone (TRH) thyroid stimulating hormone (TSH) with consequent alteration of circadian rhythms of TSH has been hypothesized in several depressive disorders. Indeed, this hypothesis may explain why some forms of mood disorders were associated with anti-TPO+ without hypothyroidism, as defined by blood routine tests. A slight reduction in thyroid hormone secretion such as that found in sub-clinical hypothyroidism may affect cognition and mood . At variAlternatively, autoimmunity may be implicated in some form of extra-thyroid disease associated (even indirectly) with the depressive symptomatology.In Hashimoto disease the onset of vasculitis is frequently observed and would seem to be directly correlated to the duration of the illness .In this disease brain perfusion modifications would appear to be of an aspecific nature; recently however, Spect examination revealed a marked compromising of the left cingulum posterioris, thus related in the etiology of associated affective disorders .Recent evidence suggests that thyroid autoimmunity may be affected by the Hypothalamic-pituitary-adrenal axis (HPA) through the balance of proinflammatory and antiinflammatory cytokines ,16. In lThe potential of this study is limited by the small sample size, particularly regard to psychiatric diagnoses less frequently observed in the general population, such as Panic Disorder; the extension of the findings is therefore rather limited.This study seems to indicate an association between the presence of a lifetime diagnosis of mood or anxiety disorder and sleep disturbance and anti-TPO+. The findings obtained suggest the need for further longitudinal studies aimed at clarifying the association between anxiety and depressive disorders and anti-TPO+.


The prognostic role of drug-induced amenorrhea (DIA) was restrospectively evaluated in 221 out of 254 consecutive premenopausal patients treated with adjuvant CMF or a CMF-containing regimen; 33 patients were eliminated because of lack of menstrual data. All patients had metastatic axillary nodes; drug regimens were: CMF x 9 courses +/- Tamoxifen (TM) and CMF x 6 courses; median age was 43 (range 26-54). Premenopausal status was defined as last normal menses within the 6 weeks preceding initiation of chemotherapy: DIA as cessation of menses for at least 3 months not later than 3 months from the end of chemotherapy. DIA occurred in 166,221 (75.1%) patients and was strictly related to the age of the patients; also, the older the patients the shorter the time required to develop DIA. At median follow up of 69 months, Mantel-Byar analysis showed a longer disease free survival (DFS) for patients who developed DIA as compared with non amenorrheic women (P less than 0.001). DIA prognostic value was independent of age, number of involved nodes, tumour size and number of CMF cycles, as assessed by the Cox model , in which DIA was entered as a time dependent covariate.


Nuclear deoxyribonucleic acid (DNA) content of hepatocellular carcinoma (HCC) in 41 South African and 47 Japanese patients at autopsy was analysed by dual-wavelength microspectrophotometry. The DNA distribution patterns were classified as type I, II, III or IV and as low ploidy  or high ploidy , according to the degree of dispersion. We found a significantly higher incidence of high ploidy in South African HCC than in Japanese HCC. Moreover, type IV was significantly more frequent among South Africans than among the Japanese. These findings demonstrate that large differences in biological characteristics and clinical behaviour of HCC between South Africa and Japan may reflect differences in DNA distribution patterns which we observed between these two races.


The cell kinetics of 82 squamous cell carcinomas of the head and neck were studied by in vivo administration of the thymidine analogue, bromodeoxyuridine (BrdUrd). Ploidy, BrdUrd labelling index (LI), duration of S-phase (Ts), potential doubling time (Tpot) and S-phase fraction (SPF) were measured by flow cytometry on 50 microns paraffin embedded sections. The range of values obtained compared well with other in vivo cell kinetic studies of head and neck cancer. Aneuploid tumours had a significantly higher BrdUrd labelling index and SPF, and a short Tpot than diploid tumours. To validate the use of 50 microns sections for measuring cell kinetic parameters by flow cytometry a comparison of values obtained by 50 microns sections and small blocks of tissue was made. No significant difference was found between the two methods. Reproducibility of values between two consecutive thick sections was also good. We conclude that reproducible cell kinetic measurements can be made in tumour samples using 50 microns sections of BrdUrd labelled tissue.


This study was designed to compare two different modalities of TBI which are currently used in clinical practice. The same dose of 750 cGy was given to CBA mice either in a single dose at a low dose rate (4 cGy min-1) (STBI) or in a fractionated regimen (six fractions of 125 cGy three times a day) at a higher dose rate (25 cGy min-1) (FTBI). After TBI completion we simultaneously studied the in vivo radiation response of bone marrow cells, two murine bone marrow clonogenic cells (CFU-S and GM-CFC) and peripheral blood lymphocytes and granulocytes for a period of 1 month. The percentage of spleen erythrocytic and granulocytic colonies was also determined. No significant differences were observed between the two groups in the first 48 hours after irradiation except in bone marrow cell numbers, probably due to differences in the overall treatment time between the two TBI schedules. After the first 48 hours the repopulation patterns of the different cells were very similar in both groups. These findings suggest that the different dose rates and fractionation used in this study caused similar radiation damage to the murine haemopoietic system. Moreover, no significant repopulation occurred during the longer overall treatment time of the fractionated regimen. These preliminary results must be corroborated with a larger range of doses before any firm conclusion can be drawn.


Nine primary pulmonary carcinomas, one metastatic carcinoma, and two malignant pleural mesotheliomas have been analysed for the expression at the mRNA level of metalloproteinases (MPs) and tissue inhibitors of MPs (TIMPs). In situ hybridisation showed TIMP-1 and TIMP-2 transcripts predominantly over tumour stroma and gelatinases evenly distributed over both stromal and tumour cells. While both TIMP-1 and TIMP-2 were expressed in non-neoplastic lungs (NNL) as well as in carcinomas, stromelysin 3 (ST3), 92 kDa gelatinase and interstitial collagenase were expressed only by carcinomas. Expression of these MPs by carcinomas was independent of histologic type and such tumour features as fibrosis or necrosis. The consistent expression of ST3 by all of the carcinomas examined and absence of its expression in NNL indicates that ST3 production is likely associated with the malignant phenotype. However, since 92 kDa gelatinase and interstitial collagenase transcripts were found in some but not all tumour samples, their expression is not a uniform feature of pulmonary carcinomas. The possible prognostic significance of the expression of the latter two enzymes by carcinomas remains to be established.


Antigenic modulation of major histocompatibility and tumour associated antigens was observed in neoplastic cells obtained from patients with pleural and abdominal effusions of breast and ovary carcinomas following a single intracavitary dose of 18 x 10(6) U recombinant IFN-alpha. This regimen resulted in antigenic modulation in seven out of 11 tested cases, suggesting a potential, although limited, responsiveness of at least a fraction of breast and ovary carcinoma cells to in situ biomodification with IFN-alpha.


Drug resistance in haemopoietic cells may be partly related to the expression of the glutathione-s-transferase (GST) pi and mdr-1 genes. We have used RNA slot blotting techniques to investigate the expression of GST pi in peripheral blood and bone marrow of eleven normal subjects, nine patients with myelodysplastic syndrome (MDS), eighteen patients with acute myeloblastic leukaemia (AML), and thirty-two patients with chronic lymphocyte leukaemia (CLL). We found increased expression of GST pi in 8 of 9 MDS,  12 of 18 AML  and in the peripheral blood of 24 of 32 CLL  relative to normal controls. Increased expression of GST pi can occur at any stage of disease and shows no clear relation to mdr-1 expression except, possibly, in CLL. In 3 AML patients GST pi transcript levels were the same or lower on relapse compared to presentation. Upregulation of the GST pi gene could not be demonstrated in 2 CLL patients in response to treatment with intermittent chlorambucil.


The QR regressor tumour (QR-32), a fibrosarcoma which is unable to grow progressively in normal syngeneic C57BL/6 mice, was able to grow progressively in 13 out of 22 mice (59%) when it was subcutaneously coimplanted with gelatin sponge. We established four culture tumour lines from the resultant tumours (QRsP tumour lines). These QRsP tumour lines were able to grow progressively in mice even in the absence of gelatin sponge. The ability of QRsP tumour cells to colonise the lungs after intravenous injection and to produce high amounts of prostaglandin E2 (PGE2) during in vitro cell culture was much greater than that of parent QR-32 cells. These biological characteristics of QR-32 cells and QRsP tumour cells were found to be stable for at least 6 months when they were maintained in culture. We also observed that QR-32 cells were able to grow progressively in five out of 12 (42%) mice after coimplantation with plastic non-adherent peritoneal cells obtained from mice which had been intraperitoneally implanted with gelatin sponge. These host cells reactive to gelatin sponge increased the production of high amounts of PGE2 by QR-32 cells during 48 h coculture. Preliminary in vitro studies implicated the involvement of hydrogen peroxide and hydroxyl radical as some of the factors necessary to induce QR-32 cells to produce high amounts of PGE2 and to accelerate tumour progression.


We have found that elevation of preoperative serum sialyl-Tn antigen (STN) levels is associated with a poor prognosis for gastric cancer patients, and these high levels remain in the advanced stage of the disease. We have now examined findings with the combined assay of STN and carcinoembryonic antigen (CEA) levels with regard to prediction of the prognosis of gastric cancer patients. Serum CEA levels and STN levels were determined preoperatively in 349 Japanese patients with gastric cancer. The patients were divided into four groups: (A) the CEA (-) STN (-) group ; (B) the CEA (-) STN (+) group ; (C) the CEA (+) STN (-) group ; and (D) the CEA (+) STN (+) group . Clinicopathological features and the prognosis of these groups were examined. The distribution of two markers showed no significant correlation. The patients in the CEA (+) STN (+) group (group D) had more advanced disease than the patients in CEA (-) STN (-) group (group A); tumour size was larger, serosal invasion was prominent, lymphatic and vascular involvement was frequent and the tumour was more infiltrative. Lymph node metastasis and hepatic metastasis were more common. Total gastrectomy was usually performed, and the non-curative rate was higher. The 5-year survival of patients in the CEA (+) STN (+) (group D) was 14.5 +/- 9.5%, that is lower than that of patients in any other group . This combined assay of these markers will aid in estimating the prognosis and selecting appropriate drugs and care for gastric cancer patients.


Growth in soft-agar bilayer cultures of human tumour cells derived from 4 in vitro continuous cell lines, from 21 xenografts carried in athymic mice, and from 197 samples of fresh human solid tumours of various histologic types was analyzed by computer-assisted image analysis. Replicate cultures for each specimen were assessed on successive days of incubation for the number and volume of growth units within multiple size categories. Our results confirm the recent finding of others that there is an upper limit of approximately 10(9) microns 3 to the cumulative growth unit volume obtainable in a 2 ml bilayer soft agar culture system. Since this upper limit to the carrying capacity of the closed culture system exists, the extent of growth within the cultures is determined in a fundamental way by the cumulative volume of growth units initially inoculated into cultures. A growth index of greater than or equal to 16-fold was only seen when initial cumulative growth unit volume was less than 10(7) microns 3 per culture dish. Computer-assisted volume analysis (CAVA) appears to be a useful quantitative method to study the growth of human tumour cells in soft agar cultures.


As yet, there is no reported study of chromosome allele loss in fibrolamellar carcinoma (FLC), a distinct, rare variant of hepatocellular carcinoma (HCC). We searched for evidence of allele loss in FLC using 18 DNA probes for 10 chromosomes and compared the pattern of loss with our series of HCC. Two of the probes, lambda MS32 (1q42-43) and cMS621 (5p) showed allele losses in one tumour, while other probes showed no loss. The frequency of allele loss in FLC was much lower than in HCC, which may be associated with their different prognoses.


Two hundred and twenty-two women with advanced cancer of the breast were asked to complete two previously validated self-assessment questionnaires  and the Rotterdam Symptom Checklist (RSCL) in order to determine the prevalence and persistence of affective disorders in this group of patients. Fifty-six (27%) of 211 women who completed the HADS and 33 (22%) of 204 who completed the RSCL rated as probable cases of an anxiety state and/or depressive illness. One hundred and fifty-five patients completed the questionnaires again 1-3 months later. Twenty-one (13%) were persistently anxious or depressed as judged by the HADS compared with 14 (10%) on the RSCL. When both questionnaires were considered together, approximately one third of patients had scores suggestive of an affective disorder and in one third of these it was persistent. Only 30 patients (43% of cases) were detected as 'cases' by both questionnaires and this finding warrants further investigation.


Transcriptome data from quantitative PCR (Q-PCR) and DNA microarrays are typically obtained from a fixed amount of RNA collected per sample. Therefore, variations in tissue cellularity and RNA yield across samples in an experimental series compromise accurate determination of the absolute level of each mRNA species per cell in any sample. Since mRNAs are copied from genomic DNA, the simplest way to express mRNA level would be as copy number per template DNA, or more practically, as copy number per cell.Here we report a method (designated the "Percellome" method) for normalizing the expression of mRNA values in biological samples. It provides a "per cell" readout in mRNA copy number and is applicable to both quantitative PCR (Q-PCR) and DNA microarray studies. The genomic DNA content of each sample homogenate was measured from a small aliquot to derive the number of cells in the sample. A cocktail of five external spike RNAs admixed in a dose-graded manner  was prepared and added to each homogenate in proportion to its DNA content. In this way, the spike mRNAs represented absolute copy numbers per cell in the sample. The signals from the five spike mRNAs were used as a dose-response standard curve for each sample, enabling us to convert all the signals measured to copy numbers per cell in an expression profile-independent manner. A series of samples was measured by Q-PCR and Affymetrix GeneChip microarrays using this Percellome method, and the results showed up to 90 % concordance.Percellome data can be compared directly among samples and among different studies, and between different platforms, without further normalization. Therefore, "percellome" normalization can serve as a standard method for exchanging and comparing data across different platforms and among different laboratories. E. coli. Statistical approaches have been proposed for ratiometric data to improve inter-microarray variations, especially of non-linear relations : an Excel spreadsheet file containing 2 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 4 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 8 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 24 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 2 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 4 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 8 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 24 hr Percellome data (15 sample data) of the 60 samples of the TCDD study (cf. Figure Click here for fileExcel spreadsheet file containing 15 Affymetrix MG-U74v2 A GeneChip raw data of the uterotrophic response study (cf. Figure Click here for fileExcel spreadsheet file containing Percellome data of the same 15 samples of the uterotrophic response study (cf. Figure Click here for file


The morphological appearance, incidence and prognostic significance of human chorionic gonadotrophin (HCG)-containing cells in seminomas were examined in a retrospective series of 228 orchidectomy specimens, obtained between 1958 and 1972. Sections from each tumour were stained with haematoxylin and eosin (H & E) and immunocytochemically for HCG. In 33 (14.5%) of the tumours HCG-containing cells were observed, but in only 12 were these recognised in an initial study of the H & E stained sections. HCG staining was seen predominantly in syncytiotrophoblastic giant cells and rarely in "mulberry" cells and mononuclear seminoma cells. Of the patients whose tumours included HCG-containing cells 23% died of their disease within 2 years of orchidectomy, compared with only 8% of the patients whose tumours lacked this feature. It is concluded that immunocytochemical staining for HCG should form part of the routine histological assessment of seminomas, and that the presence of HCG-containing cells indicates a more aggressive disease.


An analysis of the primary tumour histopathology was performed on 103 patients managed by orchidectomy and surveillance for stage I seminoma. Patients have been followed for 14-141 months (median 62 months) after orchidectomy. Seventeen patients relapsed, the probability of remaining relapse free at 5 years being 82% . No patients died of progressive germ cell tumours. The only significant histological factor predicting relapse was the presence of lymphatic and vascular invasion. Four of 42 patients with neither lymphatic or vascular invasion recurred, nine of 53 patients with either lymphatic or vascular invasion recurred and three of eight cases with both lymphatic and vascular invasion recurred (P = 0.05-trend). Though initial recurrence was usually of moderate volume and confined to para-aortic nodes, eight patients were treated with chemotherapy either because of the extent of their initial relapse (four cases), or because of subsequent relapse (four cases). In view of the difficulties of identifying patients at risk and of detecting early relapse, surveillance for stage I seminoma should remain a research protocol.


The "Sir Charles Bell Society (SCBS)" is an inThe SCBS began as an informal group in 1992 during the VIIth International Facial Nerve Symposium in Cologne. At this initial meeting, 74 attendees confirmed the need for a multinational approach. The original 74 attendees were to be considered as "Founding Members" and they drafted a Statement of Purpose: "The SCBS is to be an international forum for clinicians of all medical specialties and researchers in basic or clinical science who have a special interest in the facial nerve and its disorders. This unique international multi-disciplinary organization is dedicated to the collection, dissemination and exchange of ideas relating to the facial nerve and its diseases." Their first charge was to aid Professor Naoki Yanagihara in organizing the "VIIIth International Facial Nerve Symposium" to be held in Japan in 1997.The SCBS was officially recognized June 23, 1993, incorporated in the state of California as a non-profit mutual benefit corporation organized under the non-profit mutual benefit corporation law meeting the criteria of: Internal Revenue Code Section 501 C (6) with FEDERAL Employee Identification Number: 94-320802 and California Corporate Number; 1917755 SCOBS.Membership includes otolaryngologists, plastic-reconstructive surgeons, neurologists, neurosurgeons, basic science researchers, physiotherapists, audiologists, anatomists, psychologists, psychiatrists, radiologists, and internists. At present there are over 229 members from 32 countries.The scientific impact is based on the interdisciplinary discussion of problems dealing with the facial nerve. An international meeting is held every four years in different countries. Main topics of discussion and international exchange are:▶ Facial nerve regeneration following different kind of lesions▶ Changes of the Central Nervous System following different kind of nerve lesions▶ Surgical and conservative methods for treatment of facial nerve diseases▶ Evaluation of grading systems.An important aspect of the SCBS is that these problems are discussed on an interdisciplinary platform.The last meeting of the SCBS was held in 2005 in Maastricht/Netherlands during the "Xth International Facial Nerve Symposium (Chairman: Hans Manni)" with election of Rainer Laskawi (Germany), President; Jacqueline Diels (USA), Secretary; Paul Mulkens (Netherlands), Treasurer, Mihael Podvinec (Switzerland) is Webmaster and Kedar Adour (USA) President-Emeritus. The next meeting will be held in Rome  in 2009.


Placental and placental-like alkaline phosphatase (PLAP) levels in the culture media of 87 cell lines of neoplastic and 'normal' origin were measured by a conventional immunosorbent enzymatic assay (IAEA) and by a new immunoradiometric assay (IRMA). The IRMA detected immunoreactive PLAP in 37 of 80 (46%) human epithelial and germ cell cultures, while the IAEA detected PLAP in only 25 (33%). Of the 52 non-germ cell tumour cultures, the IRMA detected expression in 24 (46%) and the IAEA in only 16 (31%). In 17 cases (21%) the IRMA recorded levels double that of the IAEA, while in five cultures (6%) the reverse was true. The IRMA was much more robust than the IAEA and had considerably lower inter- and intra-assay coefficients of variation (3.75-8.5% vs 5.2-46%). Detection of PLAP(-like) expression by IAEA is dependent on neoplastic expression of enzymatically functional molecules and quantification assumes constant enzyme kinetics. PLAP-like material has a higher catalytic rate constant than PLAP and thus will give higher values on a stoichiometric basis in an IAEA. The higher detection rate and levels of PLAP-like material in neoplastic cultures when measured by the IRMA clearly demonstrate ectopic expression of non-enzymatic PLAP and PLAP-like genes. The incidence of PLAP(-like) expression by non-germ cell and possible germ cell tumours has been underestimated and its utility as a tumour marker should be re-examined using assays which measure antigen mass rather than phosphatase activity.


Inconsistent findings on the efficacy of psychosocial interventions in cancer may be due to their lack of specificity. The aim of this study was to identify priorities of psychosocial need among cancer patients currently receiving treatment in Western Sydney (NSW) as a prelude to targeted intervention. A sample of 188 patients , with various solid tumours, completed a self-report ranking questionnaire listing eight major areas of psychosocial need based on a literature search of relevant studies. The resulting ranking of priorities was: family (1), dealing with emotional stress (2), getting information (3), money (4), work (5), social life (6), sex life (7), and dealing with hospital staff (8). These priorities were independent of demographic characteristics, including time since diagnosis, suggesting that support in the areas of major need may be just as important during follow-up as it is at diagnosis. Males reported less distress than females, and patients with cancer of the head/neck or breast reported most distress. To be maximally effective, psychosocial intervention for cancer patients should focus on the principal areas of family interaction, effective stress management, and access to information.


Helix pomatia agglutinin (HPA)- and Concanavalin A (Con A)-binding carbohydrate expression were studied on 32 tumour samples from primary adenocarcinoma of the breast and 12 samples from lymph node metastases. Live cells were spilled from each of the fresh samples and the extent of fluorescent-labelled HPA and Con A-binding was assessed by flow cytometry. The extent of brightness was expressed in a defined quantitative fashion and the percentage of positive cells was accurately determined from a sample of 10,000 cells per tumour. Correlation of binding with clinicopathological features showed that HPA but not Con A related to lymph node involvement (P = 0.001) in tumours of higher grade (II and III). Spilled tumour cells (non-lymphocytes) were selected from the lymph nodes and the presence of HPA binding cells in the involved lymph nodes was found to relate to positive HPA binding in autologous primary tumours (P = 0.002). Dual-label analysis of HPA and Con A binding showed characteristic features for each tumour. The study demonstrates the use of flow cytometry as a simple and effective technique in detecting differences in lectin binding in live spilled cells from fresh breast cancer tissues. This method may prove to be particularly useful if performed preoperatively on cells in fine-needle aspirates.


The present investigation shows the effect of vitamin A deficiency on the initiation and postinitiation phases of benzo(a)pyrene-induced lung carcinogenesis in male Wistar rats. Lung tumours were induced by giving three intratracheal instillations, one week apart, of 10 mg benzo(a)pyrene per instillation. Maximum tumour incidence (100%) and tumour burden per rat was found in rats which were kept on vitamin A deficient diet for 4 weeks prior to the first administration and 8 weeks after the last administration of benzo(a)pyrene. Rats in which vitamin A deficiency was terminated after the last administration of the carcinogen had 83% tumour incidence, whereas corresponding control pairfed animals had 39% incidence of tumours. These data represent the values obtained 32 weeks after the last administered dose of the carcinogen and indicate the role of vitamin A, both in the initiation as well as in the postinitiation phases of lung carcinogenesis.


The clinical significance of neuron-specific enolase (NSE) as a tumour marker was evaluated in 54 patients with seminoma. Before orchiectomy NSE was elevated in six out of 21 patients with stage I seminoma and 11 out of 16 patients with metastases. After orchiectomy NSE normalised in all evaluated stage I cases, but was still elevated in six out of 12 patients with metastatic disease. NSE monitored the effect of cisplatin-based chemotherapy in patients with metastases. In some patients, increased serum NSE was found together with raised levels of human choriogonadotropin (HCG) and lactate dehydrogenase (LDH), while in others only NSE was elevated. No false positive NSE values were observed. NSE seems to be a clinically worthwhile serum tumour marker for monitoring seminoma patients, with a sensitivity and specificity of the same order as HCG.


Pancreatic ductal adenocarcinomas are characterised by a dense connective tissue reaction. To test the hypothesis that stroma components are synthesised and produced by the tumour cells themselves, eight cell lines as well as six xenografted tumours from human ductal adenocarcinomas of the pancreas were examined for the expression of extracellular matrix proteins (ECM), using cDNA probes and antibodies to collagen types I, III and IV, vitronectin, fibronectin, undulin and laminin. All tumour cell lines  and xenografted human pancreatic tumours expressed at least one of the examined ECM at the RNA (collagen type IV > laminin = fibronectin = vitronectin > collagen type III > undulin > collagen type I) or protein level (collagen type IV = collagen type III > vitronectin > laminin > collagen type I = fibronectin > undulin). In nude mouse tumours expression of laminin and collagen I was most pronounced in well-differentiated carcinomas. In a few tumours, collagen type III, vitronectin and undulin were expressed on the luminal side of the neoplastic glands, suggesting loss of normal polar differentiation. Incubation with fetal calf serum modulated ECM RNA levels to a varying extent in all but one cell line (AsPC-1). The results suggest that human pancreatic ductal adenocarcinomas cells are capable of synthesising and producing extracellular matrix proteins in vitro and in vivo, but that the extent and pattern of ECM expression differs between the various tumours and conditions tested.


Serum levels of TAG 72 were measured in 726 serum samples from patients with benign and malignant gynaecological conditions in order to evaluate the clinical usefulness of TAG 72 alone or in combination with other tumour markers. Sixty-six per cent of patients with ovarian cancer showed abnormal concentrations of TAG 72 antigen. A good correlation was also found between serial TAG 72 values and the clinical course of disease during chemotherapy and follow-up. In cervical and endometrial cancer abnormal TAG 72 values occurred in 23% and 14% of cases, while none of the patients with breast cancer had abnormal TAG 72 levels. Among patients with benign disease only one out of 12 patients (8%) with benign ovarian tumours and one of 15 patients with uterine fibromyomatosis (7%) showed high TAG 72 serum levels. However, the determination of TAG 72 did not increase the sensitivity of CA 125 and squamous cell carcinoma antigen (SCC), in ovarian and cervical cancer, respectively. The systemic administration of recombinant interferon alpha-2b to 15 patients with ovarian cancer and different basal levels of TAG 72 did not increase serum levels of the antigen.


Serial image guided 31P magnetic resonance spectroscopy (MRS) studies were performed in eight patients with non-Hodgkin's lymphoma to determine the changes in phosphorus metabolites that occur in vivo in response to chemotherapy. Pre-treatment spectral characteristics were different in high and low grade lymphoma. A larger inorganic phosphate (Pi) peak was seen in high grade NHL relative to phosphomonoesters (PME) or beta adenosine triphosphate (beta ATP), producing significant differences in the PME/Pi and Pi/beta ATP metabolite ratios, and probably reflecting a larger hypoxic cell fraction within the high grade lymphomas. Consistent metabolite changes were seen with treatment, and before reductions in tumour bulk had occurred. Alterations in tumour energetics with changes in Pi and beta ATP, and increases in phospholipid turnover reflected as an increase in the phosphodiester (PDE) resonance were detected. Changes were seen between days 10 and 27 in low grade lymphoma treated with oral alkylating therapy and between days 1 and 5 in lymphoma treated with intensive combination chemotherapy. Increases in the PDE/beta ATP metabolite ratio may be an early indicator of response to chemotherapy in human tumours. These studies illustrate the feasibility and clinical potential of image guided 31P MRS as a means of assessing response to therapy.


Sequential methotrexate (Mtx) absorption studies were undertaken in 127 children undergoing treatment for childhood non-T acute lymphoblastic leukaemia (ALL) to determine whether serum drug concentration, clearance and dosage affect event free survival (EFS). Higher serum concentration and area under the plasma concentration curve (AUC) were not associated with an improved EFS. Methotrexate clearance was not found to be of prognostic significance. Patients who tolerated only low 6-mercaptopurine (6-MP) doses because of neutropaenia and those who randomly were prescribed higher doses of Mtx had a lower rate of leukaemia relapse after the completion of therapy. This suggests that the use of maintenance therapy in maximally tolerated doses may be associated with an increased survival in childhood ALL.


Prognostic information is essential for the evaluation, judgement and optimal treatment of patients with squamous cell cancers (SCCs) of the upper aerodigestive tract. Using immunohistochemical and flow cytometric techniques, we have studied the significance of cellular expression of the Ki-67 antigen, epidermal growth factor receptor (EGFR), the transferrin receptor (TFR) and DNA ploidy status in a prospective analysis of patients with SCCs of the head and neck region. All 42 fresh tumour samples  expressed both EGFR and TFR to varying degrees. Receptor expression was most marked on the peripheral invading margin of cancer cell islands although staining was also demonstrated in a random fashion within cellular islands and consistently along the basal cell layer of overlying stratified squamous epithelium. The percentage of cancer cells that reacted with the Ki-67 monoclonal antibody was assessed as low (less than 10%) in 15 samples (35.8%), intermediate (10-30%) in 19 samples (45.2%) and high (greater than 30%) in eight samples (19.0%). Eleven of 15 samples (73%) with a low percentage reactivity were DNA diploid, whereas seven of eight samples (87.5%) with a high percentage reactivity were DNA aneuploid. Poorly differentiated SCCs were significantly more often aneuploid than were either moderately or well differentiated tumours. Our results suggest that EGFR and TFR are widely distributed on SCCs, especially on proliferating cells at the invading tumour margin. In addition, there is a close spatial correlation between cells expressing EGFR, TFR and those expressing the Ki-67 antigen. Tumours in which the staining intensity for both EGFR and TFR was intense invariably expressed the Ki-67 antigen in a high proportion of cells. Further patient follow-up will be important in determining whether intense EGFR and TFR staining, combined with a high percentage reactivity with Ki-67 antibody and DNA aneuploidy, will ultimately define a subset of head and neck cancer patients with a poor clinical outcome.


ABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs.Generalized progressive retinal atrophy (gPRA) is a hereditary ocular disorder with progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina  analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA4 (for 9 breeds), CX36 (for 12 breeds), MERTK  and RDH12 (for 9 breeds).Based on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes  Single strand conformation polymorphism (SSCP) analysis is a simple and cost-effective method with high reliability for the identification of base substitutions or other sequence variations like small deletions or insertions in large cohorts of individuals . We usedABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) for mutations leading to ar gPRA in 29 breeds of dogs. The ABCA4 gene encodes the ABCR or RIM protein (RmP), thought to act as a flippase for N-retinylidene phosphatidylethanolamine (N-retinylidene-PE), thereby facilitating the transport of all-trans-retinal from the disk lumen to the photoreceptor cytoplasm  dCTP (10 mCi/ml) was included. PCR products were digested depending on the lengths of the fragments with different restriction enzymes [see All PCRs were performed under standard PCR conditions -12 in a 2 see . For SSCymes see  in orderTL conceived the experimental outline, collected blood samples, conducted the experiments, analyzed the data and drafted the manuscript. SMP, BK and SED carried out parts of the experiments and were involved in analyzing the data. JTE and GD participated in design and coordination of the study and helped to draft the manuscript. All authors read and approved the final manuscript.ABCA4, CX36, MERTK and RDH12 genes in different dog breeds and indirect exclusion of the genes as causing gPRA, respectively. The data provided represent the results of the mutation screening of the candidate genes ABCA4, CX36, MERTK and RDH12.Sequence variations in the Click here for filePrimers, conditions for PCR amplification and restriction enzymes used before SSCP analyses. The data provided represent the information for PCR amplification and restriction of PCR products which were used in SSCP analyses.Click here for file


The testis is the third common site of relapse after primary treatment of childhood acute lymphoblastic leukaemia, but in adults relatively few testicular relapses of acute lymphoblastic leukaemia have been reported. In the present investigation the differences in the behaviour of leukaemia in immature and mature rat testis and the interactions of testicular and leukaemic cells were studied. Intraperitoneal injection of rat T-leukaemic cells to sexually immature animals induced testicular infiltrations in 100% of animals in 17 days. The infiltrations were small and located perivascularly in the interstitial tissue. Intraperitoneal injection of T-leukaemic cells to sexually mature animals induced testicular infiltrates in 42% of the animals. Leukaemic cells injected directly to the lymph sinusoids of sexually immature and mature testis proliferated rapidly causing testicular enlargement. The M(r) > 5 K fraction of extracts of 50 days old normal rat testes inhibited 3H-TdR incorporation of both normal and leukaemic ConA-stimulated rat lymphoblasts significantly. The same fraction of extracts of testes of 25 days old rats did not have any effect on 3H-TdR incorporation. The normally occurring pubertal increase in the lymphocyte inhibitory effect of the M(r) > 5 K fraction of testis extracts on 3H-TdR incorporation of PBL was prevented following either intraperitoneal or intratesticular injection of rat leukaemic lymphoblasts administered at the age of 25 days. The present observations suggest that physiological pubertal changes in the permeability of vascular endothelium and immunosuppressive effect of the testis may be important explanatory factors for the smaller number of testicular relapses in men compared to boys seen after treatment of ALL.


In the Edinburgh Randomised Breast Screening Project (EBSP) to December 1988 there were 500 cancers in the study population invited to screening and 340 cancers identified in the control population. The size and negative lymph node status characteristics of invasive cancers from the two populations were significantly different (P less than 0.05). The cancers detected by screening were predominantly 'early stage', with 16% noninvasive (PTIS) and 42% invasive stage I (pT1 node negative), whereas cancers were frequently 'late stage' (more than pT2) and inoperable in nonattenders (44%) and controls (36%). Grouped according to customary size ranges of invasive cancers, the proportion of cases lymph node positive differed in those screen detected compared with controls, but the benefit in favour of screen detection was not constant. In comparisons of cancers detected at prevalence and incidence screens, as a test of conformity with screening theory, no significant differences were apparent according to size and lymph node status, yet the characteristics of histological type of cancer discriminated significantly (P less than 0.05). When these same histological characteristics were used to compare survival, the capacity to separate invasive cancers into two groups having good and poor survival probabilities was evident, with a significant improvement for the screen detected poor survival group compared with controls (P less than 0.05).


Immunoreactive inhibin-like material (ILM) was measured by radioimmunoassay (RIA) in serum and gastric juice samples of 23 fasting normal men, 27 men with chronic superficial gastritis (CSG), and 21 men with carcinoma of stomach . Serum ILM levels in carcinoma of stomach patients (367 +/- 55.5 ng ml-1) were significantly higher than in normal men  and in patients with CSG . Sixty two per cent and 86% of patients with carcinoma of stomach showed elevated ILM levels which were higher than the highest noted in patients with CSG and normal men respectively.


Thyroid dysfunction is a well-recognised side-effect of treatment with interleukin-2 (IL2). We assessed the correlation between the development of abnormal thyroid function and tumour response in 13 patients receiving IL2 and interferon-2 alpha  for advanced malignancy. Seven patients had normal thyroid function during treatment, and all of these patients have since died of progressive disease. Of six patients who did develop thyroid dysfunction during treatment, one patient has died of progressive disease. However, statistically we were unable to confirm a definite correlation between the development of thyroid dysfunction and survival in this small group of patients.


Widely disseminated neuroblastoma in children older than infancy remains a very poor prognosis disease. Even the introduction of marrow ablative chemotherapy with autologous rescue has not significantly improved the outlook for these children, presumably because of a failure to eradicate minimal residual disease. One additional approach which may hold promise is the use of immunomodulation with cytokines such as IL2 in the setting of minimal residual disease (MDR), for example after intensive chemotherapy and ABMT. However, considerable variability in the susceptibility of neuroblastoma cells to natural killer (NK) and lymphokine-activated (LAK) killing has been observed, and it is presently unclear how NK and LAK cells recognise neuroblastoma cells. In this paper we examine expression of cell adhesion molecules on neuroblastoma to determine which of these modify interaction with NK and LAK cells. We find that LFA-3 (CD58), the ligand for CD2 is of predominant importance in predicting susceptibility of neuroblastoma to the cytotoxic actions of NK and LAK cells, while expression of ICAM-1 (CD54) may also modify susceptibility. These findings were confirmed by blocking experiments in which co-culture of target cells with ICAM-1 and LFA-3 reduced LAK and NK cytotoxicity. Study of the immunophenotypic features of each patient's neuroblastoma cells before induction of MRD may be valuable in determining the likely effect of IL2 in predicting disease reactivation.


Antipsychotic medications are widely prescribed for the treatment of psychotic disorders but carry a variable propensity to increase weight. Thus metabolic dysfunction is the primary cause of premature death in psychosis patients. A system-based approach to understanding the molecular mechanisms behind metabolic dysfunction can potentially provide scope for tailored interventions and alternative treatment pathways that avert such risks on an individual basis. The aim of this study is to identify transcriptomic predictors of high Body Mass Index (BMI) and blood glucose in first episode and chronic psychosis patients.100 first-episode and 100 chronic cases of psychosis meeting ICD-10 criteria (F20-29 and F30-33) were recruited as part of 2 independent studies from 3 NHS Trusts: South London and Maudsley (SLAM), Oxleas and Sussex. Cases were ethnically mixed and aged between 18–65. All participants gave informed consent for biological sampling and a range of physical health assessments. Blood glucose was measure using HbA1c while height and weight data were also taken and used to calculate BMI. For FEP subjects biological measures were taken at baseline, 3 months and 12 months post recruitment. RNA samples were collected at the baseline timepoint via PAXgene blood tubes and interrogates, using the Illumina HumanHT-12.v4 beadchip array. Samples were run at the National Institute for Health Research’s (NIHR) Biomedical Research Centre for Mental Health (BRC-MH) at the Institute of Psychiatry, Psychology and Neuroscience. A total of 4756 probes passed a stringent quality control across the 200 samples.Quantitative data on BMI and hba1c levels were used to assess the predictive efficacy of variables grouped by source  in first episode psychosis patients. All the predictor categories were included in the initial model, although individual categories were then dropped one at a time. This leave-one-out strategy allowed the direction, impact and relative contribution of the different feature classes to be assessed. Gene-expression and clinical features were consistently associated with the lowest Mean Squared Error after 100 iterations of K-fold cross-validation and after 11 different values of the alpha parameter across 500 imputed datasets. Hba1c or BMI was used as the clinical predictor, depending on whether Hba1c or BMI was used as the target variable. Unattributed surrogate variables derived from surrogate variable analysis (n=6) were analysed within the technical feature set. Having established that gene expression has inherent value as a predictor of metabolic status the same analytical steps were repeated for the discretised versions of these traits (ie. diabetes and obesity). Top-ranking gene transcripts were compared between the quantitative and discretised models. Rank lists of transcripts were subsetted to allow the power distribution across ordered transcripts to be profiled.The top performing transcripts identified are undergoing validation analysis in the chronic sample. Results will be conveyed in terms of sensitivity and false positive rates (ie. the area under the Receiver Operating Characteristic curve). We will undertake further validation through trajectory analysis of gene-expression profiles in followed-up patients.


PRJEB18926), and paired antibody heavy and light chain variable region-encoding transcripts of memory B cells of three subjects . The nucleotide compositions of the corresponding 5′-ends of sequences encoding the CDR3 are presented for transcripts with an origin in 47 different IGHV alleles. These data have been used  The highly variable complementary determining region 3 (CDR3) of antibodies is generated through recombination of immunoglobulin heavy chain variable (IGHV), diversity, and joining genes. The codons encoding the first residues of CDR3 may be derived directly from the IGHV germline gene but they may also be generated as part of the rearrangement process. Data of the nucleotide composition of these codons of rearranged genes, an indicator of the degree of contribution of the IGHV gene to CDR3 diversity, are presented in this article. Analyzed data are presented for two unrelated sets of raw sequence data. The raw data sets consisted of sequences of antibody heavy chain-encoding transcripts of six allergic subjects (European Nucleotide Archive accession number  Specifications TableValue of the data•These data are useful for further development of processes used to infer the immunoglobulin gene repertoire of an individual, and for interpretation of the results of such analyses.•These data are useful for further development of processes used to infer new germline gene sequences.•These data are useful to investigators of antibody repertoire as they suggest avenues to identify the existence of, to this date, unrecognized alleles of immunoglobulin germline genes.•These data are useful for interpretation of sequence diversity in the ascending strand of CDR3 of naïve and antigen-specific immune repertoires.1This article present data of nucleotide composition in antibody heavy transcripts originating in 47 different immunoglobulin heavy chain variable (IGHV) germline genes/alleles  [1]. The22.1Peripheral blood and bone marrow samples of six allergic subjects were collected , and used to construct libraries of antibody H chain V domains, as previously described 2.2PRJEB18926) generated in our laboratory, constituted the main data set. They were processed as previously described FASTQ raw data files  Another, unrelated set of raw sequence data was downloaded from the European Nucleotide Archive  may however also encode the first base of codon 108. Thereby, the nucleotide composition was analysed also at this position for transcripts originating in any of these four germline genes/alleles.Most of the studied IGHV genes may contribute to nucleotides of the first three codons that encode the CDR3 . The structures were visualized using MacPyMol 1.8.0.6 .Example structures of antibodies encoded by genes with a particular germline gene origin were identified using IMGT/3Dstructure-DB


Literature has confirmed the pathogenic role of cadmium (Cd) and its exposure in the induction of dyslipidemia implicated in the development and increasing incidence of cardiovascular diseases. The current study explored whether polyphenolics isolated from virgin coconut oil (VCO) prevent Cd-induced dyslipidemia and investigate the underlying mechanism of action, in rats.Rats were pretreated with VCO polyphenols  2 weeks prior to concurrent Cd administration (5 mg/kg) for 5 weeks. Subsequently, serum concentrations of lipid and lipoprotein cholesterol and cardiovascular risk ratios were determined. Hepatic activities of superoxide dismutase (SOD) and catalase (CAT) as well as reduced glutathione (GSH) and malondialdehyde (MDA) contents were analyzed.Sub-chronic Cd administration significantly increased the serum levels of total cholesterol, triglycerides, low density lipoprotein cholesterol and very low density lipoprotein cholesterol while markedly reduced high density lipoprotein cholesterol. Hepatic activities of SOD and CAT as well as GSH content were suppressed by Cd, whereas MDA level was obviously increased. The co-administration of VCO polyphenol with Cd remarkably restored lipid profile and cardiovascular risk ratios and stabilized antioxidant defense systems comparable to control group.This is the first study presenting that polyphenols isolated from VCO prevent Cd-induced lipid abnormalities and cardiovascular risk ratios by improving antioxidant defense systems.  Cadmium (Cd) is a widespread environmental and occupational pollutant that has emerged as a major cause of pathobiochemical events and damage in a number of organs. Cadmium concentration has increased in the biosphere through mining, smelting, agricultural and industrial activities , gallic acid, and 1, 1-diphenyl-2-picrylhydrazyl (DPPH) were obtained from Sigma-Aldrich Chemical Co. . Folin-Ciocalteu reagent was purchased from Merck Co. . Solvents such as n-hexane and methanol were purchased from Loba Chemie Pvt. Ltd. Mumbai, India. Reagents used for the assays were commercial test kits and products purchased from Randox, UK. All other chemicals used were obtained from local commercial suppliers.Cadmium . They were kept in cages with wood-chip bedding and allowed free access to standard pellet diet  and clean water, ad libitum. The rats were acclimatized one week prior to initiation of the treatment and were handled in a humane manner according to the approved animal experimental procedures of NIH Guidelines for the Care and Use of Laboratory Animals  were used as experimental animals in the present investigation. The rats were housed in animal facility of the Department of Biochemistry, Ebonyi State University, Nigeria, under standard conditions  according to the method of Nevin and Rajamohan (2004)oC) to remove moisture. The floating oil was gently scooped out and filtered into an air-tight container. This oil which was prepared without refining, bleaching and deodorizing, was used for the isolation of polyphenols administered to rats in the current study.The coconuts were purchased from the Central market, Abakaliki, Ebonyi State Nigeria, in November, 2016. The VCO was extracted from coconuts (Extraction of polyphenols from VCOin vitro antioxidant activity of the polyphenol fraction was determined.Polyphenols in VCO were extracted according to the method described by Nevin and Rajamohan (2004)In vitro antioxidant assay of polyphenol fractionDetermination of total phenolic contentTotal phenolic content of the VCO polyphenol fraction was estimated by Folin–Ciocalteu colorimetric method  radical according to the method described by Blois (1958)Ferric reducing antioxidant power (FRAP) assay3+) to ferrous ion (Fe2+) complex. The reducing power was calculated using the following formula: The total antioxidant activity of the VCO polyphenol fraction was evaluated using the ferric reducing antioxidant power (FRAP) assay described by Oyaizu  = 100 × (absorbance of the control - absorbance of the sample)/absorbance of the control.Experimental designAfter 1 week of acclimatization, rats were randomly divided into 6 groups (n=8) as follow:Group 1 : received clean water  for 7 weeks.Group 2 (polyphenols=PF control): received PF  for 7 weeks.Group 3 (Cd control): received Cd  for the last 5 weeks of experimental period : received PF  for 7 weeks + Cd  for the last 5 weeks.Group 5 (PF + Cd II): received PF  for 7 weeks + Cd  for the last 5 weeks.Group 6 (PF + Cd III): received PF  for 7 weeks + Cd  for the last 5 weeks.The rats were pretreated daily with polyphenols  2 weeks prior to concurrent administration of Cd (5 mg/kg) daily for 5 weeks. At the end of the treatment period (7 weeks), all animals (fasted) were slightly anaesthetized using diethyl ether and blood samples were collected from retro-orbital venous plexus by capillary tubes into plain sample bottles and allowed to clot. The clotted blood samples were centrifuged (3000g for 15 min) for separation of serum used for analysis of lipid profile, total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C) and high density lipoprotein cholesterol (HDL-C). The liver was dissected out after sacrifice by decapitation, washed in cold saline solution, dried using tissue paper, homogenized in 0.1M phosphate buffer  and centrifuged (4000 g for 20 min). The obtained supernatant was used for analyses of hepatic antioxidant enzyme activity (SOD and CAT), and GSH and MDA content.Biochemical analysesoC using RANDOX kits. The hepatic activity of SOD was assayed by the method of Arthur and Boyne (1985). The activity of catalase was assayed by the method of Sinha (1972)Determination of biochemical parameters was carried out using standard commercially available kits purchased from RANDOX, UK. Lipid profile parameters were analyzed in serum stored at 4Cardiovascular risk indicesThe coronary risk index (CRI), cardiovascular risk index (CVRI) and atherogenic index (AI) were calculated using the following formulae  = LDL cholesterol/HDL cholesterolCoronary Risk Index (CRI) = Total cholesterol/HDL cholesterolCardiovascular risk index (CVRI) = Triglyceride/HDL cholesterolStatistical analysispost-hoc test . A p<0.05 was considered significant. Results are expressed as mean ± SEM. Statistical evaluation was conducted by one-way ANOVA followed by Tukey’s Effects of administration of VCO polyphenols and Cd on lipid profile parameters in treated ratsEffects of administration of VCO polyphenols and Cd on coronary and cardiovascular risk indices in treated ratsAntioxidant activity of polyphenol fractionEffect of administration of VCO polyphenols, and Cd as well as their co-administration on hepatic markers of oxidative stress in treated ratsThe hepatic markers of oxidative stress are depicted in Cadmium is a non-essential heavy metal known to induce a broad spectrum of toxicological effects and biochemical disruptions posing serious hazards to health. Published papers indicate that Cd toxicity triggers lipid and lipoprotein abnormalities which play undeniable roles in the pathogenesis of CVD and diabetes complications , while CAT decomposes H2O2 to water and molecular oxygen 0122 and Moreover, evidence shows that lipid ratios are important in predicting cardiovascular risk (Gasevic et al., 2014Conclusively, this is the first study to assess beneficial health effect of polyphenols extracted from VCO in Cd-induced dyslipidemia. This study confirmed previous findings that Cd can adversely affect lipid and lipoprotein profile. It has provided evidence that dyslipidemia induced by Cd exposure may be attenuated by antioxidant property of VCO polyphenols in rats. The authors declare no conflict of interest


This article presents the psychosocial risk factors identified in the cases of 20 children less than four years of age who were victims of fatal or near-fatal physical abuse during a 12 month period in the Commonwealth of Kentucky. These data are related to the article “History, injury, and psychosocial risk factor commonalities among cases of fatal and near-fatal physical child abuse”   Specifications TableValue of the data•These data reveal commonalities among cases of fatal and near-fatal child abuse and highlight the high prevalence of psychosocial risk factors among caregivers.•prior to each child׳s fatal or near-fatal event, these data may assist medical providers, psychologists, social workers, and legal representatives in collaboratively assessing risk for maltreatment and intervening to prevent future injury.By identifying indicators of maltreatment that were present •These data open doors for further exploration of risk factors for maltreatment, and may guide future research efforts to better inform strategies for child abuse prevention.1Psychosocial risk factors identified in 20 cases  of physical child abuse are presented in 2n=10) or near-fatal (n=10) child abuse in the Commonwealth of Kentucky The Institutional Review Boards at the University of Louisville and the Kentucky Cabinet for Health and Family Services (KY CHFS) approved this research. Our retrospective record review included 20 children younger than four years of age who had been victims of fatal (


Turdus merula) populations as 15.7% inside USUV-suitable areas but found no significant effect for the other 14 common bird species investigated. Our results show that the emergence of USUV is a further threat for birds in Europe and that the large-scale impact on population levels, at least for common blackbirds, must be considered.Usutu virus (USUV) is an emerging mosquitoborne flavivirus with an increasing number of reports from several countries in Europe, where USUV infection has caused high avian mortality rates. However, 20 years after the first observed outbreak of USUV in Europe, there is still no reliable assessment of the large-scale impact of USUV outbreaks on bird populations. In this study, we identified the areas suitable for USUV circulation in Germany and analyzed the effects of USUV on breeding bird populations. We calculated the USUV-associated additional decline of common blackbird ( In addition, we selected a new set of 10,000 random background points for each model. We weighted background points and occurrence points equally in each of the 300 BRT models, which we averaged for the final USUV distribution map. We converted the continuous distribution map for USUV to a binary map with areas that are suitable or unsuitable for USUV. Following Pigott et al. (We applied an ensemble boosted regression tree (BRT) approach using R software  and 10 subsets for test datasets (comprising 90% of the presence and background observations) each. We used the training datasets to assess the ability of the models to predict the test dataset with the area under the curve (AUC) statistic. We averaged the AUC values of the models across the 10 models of each split sampling dataset and finally across the 300 average AUC values. Furthermore, we applied a pairwise distance sampling procedure to avoid AUC inflation due to spatial sorting bias, which is considered to give a more realistic quantification of the model performance especially regarding its transferability (Cyanistes caeruleus), common chaffinch (Fringilla coelebs), Eurasian magpie (Pica pica), European greenfinch (Chloris chloris), black redstart (Phoenicurus ochruros), great tit (Parus major), common blackbird, house sparrow (Passer domesticus), Eurasian tree sparrow (Passer montanus), common swift (Apus apus), common house martin (Delichon urbicum), carrion crow (Corvus corone), common wood pigeon , European robin (Erithacus rubecula), and common starling (Sturnus vulgaris). The dataset consisted of 317,533 unique observation datasets with anonymized sampling locations at the level of postal code regions in Germany, each giving information on the number of specimens per bird species and sampling site. Bird abundance data were collected within the citizen science program Stunde der Gartenvögel (Hour of the Garden Birds) in Germany. This program is organized by the German BirdLife partner Naturschutzbund Deutschland (Nature and Biodiversity Conservation Union) and its counterpart Landesbund für Vogelschutz in Bayern (Bavarian Society for the Protection of Birds). During the second weekend of May each year, German citizens were requested to count the maximum number of specimens per bird species observed in their gardens in a time frame of 1 hour. We used the data for the 15 most commonly detected bird species, with at least 247,000 observed specimens each during 2006–2016, for further analyses: Eurasian blue tit ; this year was the last time bird abundance data were collected before the first epizootic outbreak of USUV in Germany (2 of the country (2.7%). The EuroLST bioclimatic variable with the strongest influence on USUV risk was the annual mean temperature, contributing 71.4% to the variation in the ensemble of models. The next most influential variables were mean temperature of the coldest quarter of the year (8.9%), temperature seasonality (7.2%), and minimum temperature of the coldest month (5.2%). The other 5 variables had <5.0% effect each on USUV risk: mean temperature of the warmest quarter (2.8%), mean diurnal range (1.6%), temperature annual range (1.3%), maximum temperature of the warmest month (1.2%), and isothermality (0.4%)   Figure 2Eleven of 15 bird species analyzed did not show a statistically significant difference in the population development between the areas suitable and unsuitable for USUV since 2011. We determined overlapping 95% bootstrap CIs between USUV-suitable and USUV-unsuitable areas for 2016 Figure 3,During the past 2 decades, an ongoing spread of USUV and a continuous circulation of the virus after initial establishment have been observed in different countries in Europe  (2 (8 million breeding pairs each having approximately 3 fledglings per year [2), >167,119 birds died due to USUV since 2011; this estimate does not include other population effects like immigration compensating a part of the USUV-related population decline. The estimate is substantially higher than the one determined in the study by Bosch et al.  and a statistically significant lower population index in the USUV-suitable area compared with the USUV-unsuitable area (nonoverlapping CIs between both areas). We observed no significant effect for the other 14 bird species included in the study. Five years after the first detection of USUV in southwest Germany, the circulation of the virus resulted in an additional decline of ≈15.7% in the common blackbird populations compared with the development of populations not affected by USUV. Avian populations are under different threats, including changes of land use and climate change (Additional information regarding the analysis of Usutu virus in Germany.


Combined effects of climate change and deforestation have altered precipitation patterns in the Amazon. This has led to changes in the frequency of extreme events of flood and drought in recent decades and in the magnitude of the annual flood pulse, a phenomenon that influences virtually all aspects of river-floodplain ecosystem dynamics. Analysis of long-term data revealed abrupt and synchronous changes in hydrology and fish assemblage structure of a floodplain lake near the confluence of Amazon and Negro rivers. After an intense drought in 2005, the assemblage assumed a different and fairly persistent taxonomic composition and functional structure. Declines in abundance after 2005 were more pronounced for species of all sizes having equilibrium life history strategy, large species with periodic life history strategy, and for all trophic levels except primary consumers. Our results suggest that the extreme drought triggered changes in the fish assemblage and subsequent anomalous hydrological conditions have hampered assemblage recovery. These findings stress the need to account for climatic-driven hydrological changes in conservation efforts addressing aquatic biodiversity and fishery resources in the central Amazon. Climate change is impacting biodiversity and ecosystem services on a global scale46789111213Hydrology in the middle reaches of the Amazon is regulated by precipitation in catchments that span a vast portion of the basin6616Consequences of hydrological changes on the Amazonian fish fauna are poorly understood. Only a few studies have examined impacts of recent climatic change on aquatic ecology in the Amazon, and these have analyzed responses to drought over relatively short time intervals18Here we investigate temporal changes in fish assemblage structure during the period of 1999–2014, when the central Amazon experienced abnormally large inter-annual hydrological variation. To evaluate trends in inter-annual and intra-annual hydrologic variation, we analyzed river discharge data from 1950 to 2014 using principal components analysis (PCA). Multivariate ordination methods also were used to assess taxonomic and functional assemblage structures, the latter according to two ecological aspects: life-history strategies and trophic positions. Fish abundance data were obtained from standardized fish surveys conducted in a floodplain lake  near the confluence of Negro and Amazon rivers . We applMultivariate ordination of hydrological data produced a dominant gradient in the first axis (PCA1) that contrasted annual flood pulses with lower amplitudes, dry seasons with higher water levels, and longer periods of rising water level with the opposite set of conditions . In the Taxonomic and functional composition of the fish assemblage differed markedly before and after 2005 ; the rel5,7 = 13.54, P = 0.001; trophic levels: RM-ANOVA F 4,8 = 14.527, P < 0.001; The 2005 drought significantly affected abundance (capture per unity effort CPUE) of most groups  and 2 (secondary consumers), all of which shifted to lower values after 2005 and then remained relatively stable . HoweverThe year of 2005 corresponded to the first extreme drought that occurred within our field study time frame and after which a set of changes occurred in the river hydrological regime26273031Significant changes in Amazon floodplain fish assemblages after the 2005 drought have now been reported by two different studies, this supports the hypothesis that recent extreme climatic events have altered key environmental factors affecting fish ecology. The Amazon has undergone unprecedented shifts in rainfall and hydrology over the last 10–12 years101186sensu ref. 35Hemiodus sp., Curimatella alburna, Triportheus angulatus), and would be especially affected by reduced habitat connectivity during longer dry seasonsBrycon spp., Colossoma macropomum, Prochilodus nigricans, Semaprochilodus spp.), and therefore should be particularly sensitive to changes in flood-pulse timing as well as lateral connectivity.The similarity of response functions obtained for hydrological and biological time series, together with concordance of their change points and the fundamental importance of seasonal flood pulsing for fish ecology, strongly implies that hydrology  was the main driver  and Brazil’s National Agency for Water (http://hidroweb.ana.gov.br). Temporal components of the annual flood pulse were defined based on analysis of water level recorded over 100 yearsstats library and prcomp function4949Daily records of the water level in the Negro River in Manaus were obtained from the website of Porto de Manaus Company  as defined for the hydrological analysis (see previous paragraph).vegdist function in vegan library. PCoA analysis was performed using stats and BiodiversityR.Taxonomic structure - In total, 97 common species out of 196 total species were included in the data matrix for analysis ; Equilibrium-large ; Intermediate-small ; Periodic-large ; Periodic-small . Fishes with an opportunistic life history strategy  essentially were missing from our samples, because they were too small (<60 mm SL) to be caught by the standardized sampling method (gillnets). Further details on criteria used to categorize species according to life-history traits can be found in Life history - For all 97 species, we obtained information on five life history traits that were considered likely to influence how populations respond to patterns of environmental variation and allow assignment of species into life history strategies3052Consumer trophic level 1- herbivorous and detritivorous species (n = 26); Consumer trophic level 1.5- omnivorous species (n = 21); Consumer trophic level 2- invertivorous and planktivorous species (n = 26); Consumer trophic level 3- piscivorous species (n = 24) (Trophic level - Each species was assigned one of the four trophic levels: (n = 24) . Furtherdecostand function in the vegan library to reduce influence of more abundant groups but keeping proportionality before performing PCATemporal variation in life history and trophic assemblage structures was assessed using PCA25The effect of 2005 and 2010 droughts on abundance (CPUE) of each functional group was tested by Repeated-measures analysis of variance (RM-ANOVA) using two analytical designs: i) years before 2005 compared to years after 2005; ii) years after 2005 drought  compared to after 2010 drought . Assumptions regarding data normality and homoscedasticity were met for this analysis.To evaluate temporal changes of fish assemblage (PCA and PCoA object scores) and temporal trends of abundance (CPUE) of each functional group, we applied a statistical procedure recently proposed to identify regime shifts in time series data254949nlme package and gnls functionAICcmodavg library and AICc function25Response functions and significance of shifts were tested using generalized nonlinear least-squares regression, a method that allows dealing with nonlinear relationships and non-normal errors25The possible driving factors of assemblage dynamics  were inferred by comparing the type of response function between environmental and assemblage structure changesHow to cite this article: Röpke, C. P. et al. Simultaneous abrupt shifts in hydrology and fish assemblage structure in a floodplain lake in the central Amazon. Sci. Rep.7, 40170; doi: 10.1038/srep40170 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


There is an error in the third sentence of the Abstract. The correct sentence is: This study aimed to describe features of Australian commercial chicken farms, with particular interest in free range farms, by conducting on-farm interviews of 25 free range layer farms, nine cage layer farms, nine barn layer farms, 15 free range meat chicken farms and 15 barn meat chicken farms in the Sydney basin bioregion and South East Queensland.


Individuals with schizophrenia typically suffer a range of cognitive deficits, including in executive functioning (EF) and working memory (WM) . Such difficulties are strongly predictive of functional outcomes, but there is a lack of effective therapeutic interventions [3].Transcranial direct current stimulation (tDCS) is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive applications; however there has been a dearth of understanding of mechanistic effects of this intervention [4].The aim of this study was to evaluate the neurophysiological effects of tDCS during WM and EF assessment in individuals with schizophrenia.We utilized functional magnetic resonance imaging (fMRI) to evaluate the impact of tDCS on WM and EF in individuals with schizophrenia, randomized to receive either ‘real’ or ‘sham’ (placebo tDCS). Participants completed a WM (blocked 0–3 back) and an EF (color-word Stroop) during 30 min of 2mA tDCS applied to Broadman area 10/46 (anode 35cm2); with cathode placed on right supraorbita. Sham stimulation was applied for 30 sec. tDCS was applied during fMRI (online) [5].In addition to whole brain, we also conducted task relevant region of interest analysis (ROI) to compare mean frontal and prefrontal (Broadman are 10/46 mask) and anterior cingulate cortex (ACC) activity between the two groups during tDCS. All analyses were restricted a p-value of 0.05, following family wise-error correction (FWE).There were no between-group differences in socio-demographic or clinical characteristics (Tab 1.) Participants did not differ on WM task performance during online tDCS (Tab 2). However, there were significant between-group differences in manipulation of information with the real tDCS performing significantly better than sham, controlled for baseline  after consolidation [6].During WM the ROI analysis demonstrated increased activation underneath the site of the anode in the medial frontal gyrus in the real tDCS group, as compared to sham. There was a positive correlation between with consolidated performance and the activity in the medial frontal gyrus.Further, tDCS demonstrated significantly reduced activation in the left cerebellum.During EF task, increased performance was associated with decreased activity in the ACC [5].This is the first tDCS study to examine the brain activity during WM and EF assessment in individuals with schizophrenia using fMRIThis data suggests that biasing the membrane potential of neuronal populations in the frontal cortex seems to improve their response to other inputs i.e. decreased BOLD activation in the WM and EF network. Although the mechanism of action of tDCS is not clear yet [6], one may speculate that if the BOLD response represents synaptic activity [7], including input from other areas, then tDCS might increase the probability that a synaptic input will generate a response in an output neuron, without the need of any additional energy expended by the cell. tDCS offers a potential new therapeutic approach to the treatment of cognitive deficits.


Progranulin deficiency in humans is associated with neurodegeneration. Its mechanisms are not yet fully understood. We performed a Yeast-2-Hybrid screen using human full-length progranulin as bait to assess the interactions of progranulin. Progranulin was screened against human fetal brain and human bone marrow libraries using the standard Matchmaker technology (Clontech). This article contains the full Y2H data table, including blast results and sequences, a sorted table according to selection criteria for likely positive, putatively positive, likely false and false preys, and tables showing the gene ontology terms associated with the likely and putative preys of the brain and bone marrow libraries. The interactions with autophagy proteins were confirmed and functionally analyzed in "Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy"   Specifications TableValue of the data•Progranulin Y2H interactors are useful for comparison of interactors obtained with different methods or with different libraries.•Progranulin interactors give insight into its putative functions.•Progranulin Y2H results can be used to build protein networks and signaling paths.1The full Y2H table contains all of the information and data from the screen and the blast analysis, as well as the sequence of the inserts. If the blast analysis gave two identically scoring hits for a prey sequence, both hits can be found in the full table. A description of the columns is given in comments of the column headers (full table) and explained in the "Info" and in the "The short table shows a summary of the results sorted according to the libraries (brain and bone marrow) and marked with different colors to indicate likely positive hits (green), putative hits (white), possibly wrong hits (yellow) and false hits (red), based on the selection criteria explained in the "The tables "GO terms" and "GO slim" contain the results of the Gene Ontology over-representation analysis of likely positive and putative preys.22.1The Y2H screen was done for human fetal brain and bone marrow libraries with the Matchmaker GAL4 system (Clontech) by ImaGenes GmbH  using Gateway Invitrogen plasmids for human full length progranulin as bait as described in 2.2http://genetrail.bioinf.uni-sb.de/) https://david.ncifcrf.gov/home.jsp) and subsequently IDs were submitted to ORA using all genes in the database as background. ORA parameters were set to p-value threshold tp=0.05 and Bonferroni α correction (Results in http://www.pantherdb.org/). The results are in The gene ontology terms associated with the Y2H progranulin-preys were obtained by means of over-representation analysis (ORA) using the web-based GeneTrail tool (


Upon publication of the original article  it was hAdditional file 1:Location of epigenetic clock CpGs in relation to the nearest glucocorticoid response element (as shown by within GR ChIP-Seq peaks in a lymphoblastoid cell line) and their methylation changes in response to the glucocorticoid receptor agonist dexamethasone. (XLSX 69 kb)


Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP).MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general.


To the editor: We read with concern the reports of two human cases infected with swine influenza virus (SIV) that both occurred in October 2016 in Europe [Eurasian avian-like SIV A(H1N1)v were identified in both patients. In Europe, these viruses circulate widely in the pig population . The virThese two cases are the first severe human cases of SIV A(H1N1)v reported to the European Centre for Disease Prevention and Control (ECDC) or the World Health Organization Regional Office for Europe (WHO/Europe) since the 2009 influenza A(H1N1) pandemic, apart from a few sporadic detections in mild or asymptomatic persons during research projects . The detThe 2009 pandemic was the latest of several pandemics caused by a swine-origin influenza virus . The twoPeople who develop influenza-like symptoms after exposure to pigs should be promptly assessed for influenza infection. Specimens should be characterised virologically and isolates should be shared with the WHO Collaborating Centres. Early treatment with neuraminidase inhibitors should be considered and patients isolated to reduce risk of further transmission, in line with relevant national recommendations. Follow-up of other exposed individuals and contacts of the index cases should be considered to identify further cases and to detect any human-to-human transmission of the virus. A rapid sharing of such information nationally as well as internationally through the European Union’s Early Warning and Response System (EWRS), the International Health Regulations  or direc


There is an error in the first sentence of the fifth paragraph in the "Methods" section. The correct sentence is: We compared baseline characteristics (at the time of first-line ART failure), rates of key adverse events, treatment discontinuation and virologic suppression among patients receiving second-line ART and concomitant tuberculosis therapy who received super-boosted lopinavir (with ritonavir 400 mg twice daily) and patients who received standard boosted lopinavir (with ritonavir 100 mg twice daily).


The objective of this study was to compare trajectories of antipsychotic response before and after relapse following response from a first episode of schizophrenia or schizoaffective disorder.The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse  in association with non-adherence; and (4) reintroduction of antipsychotic treatment. The following outcomes were used as an index of antipsychotic treatment response: change in the Brief Psychiatric Rating Scale (BPRS) total score and number of patients who achieved positive symptom remission, including 20% and 50% response improvement.A total of 130 patients were included in the analyses. All patients took the same antipsychotic in both episodes. Antipsychotic doses in the second episode were significantly higher than those in the first episode (P=0.03). There were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year  in favor of the first episode compared to the second episode. Results remained unchanged after adjusting for antipsychotic dose.The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.


Timing of pulmonic valve replacement (PVR) following repaired Tetralogy of Fallot (rTOF) is determined by the severity of right ventricular (RV) dilation. While it is known that cardiovascular magnetic resonance (CMR) can more accurately quantify RV size than 2D-echocardiography (2DE), many centers have not fully integrated serial CMR assessment into the management of these patients, despite guideline recommendations. The aim of this study is to determine the extent to which visual assessment of RV size using 2DE would wrongly classify individuals that should be considered for PVR.CMR and 2DE results were obtained from 61 patients with a history of rTOF. Patients were first classified into events and non-events , based on three cutoffs of RV volume determined by CMR . For each event and non-event group, patients were then reclassified based on presence of greater-than-moderate RV dilation determined qualitatively by 2DE. The net reclassification index (NRI), a measure of prediction improvement, was calculated for each of the three CMR cutoff values. Negative NRI values suggest poorer prediction with 2DE, while positive values suggest improved prediction. Hypothesis testing was conducted with McNemar's method.A cutoff of greater-than-moderate RV dilatation determined by 2DE yielded negative NRI for all three CMR event cutoffs . All three NRI were also negative for non-events (Table Regardless of the RV cutoff value used to trigger referral for PVR, visual assessment of RV size using 2DE results in significant misclassification of both individuals with rTOF who should be referred for PVR and those who should not be referred for PVR. Visual determination of RV size based on 2DE cannot substitute current guidelines recommendations for using CMR to determine timing of PVR. Solutions to increase CMR availability or the identification of appropriate surrogates are needed for the management of these patients.