Aha! The return of Alan Partridge

Throughout a long and occasionally distinguished career first as a television sports correspondent, then chat show host (dramatically ended by the accidental homicide of a guest live on air), then rebirth as a radio presenter at North Norfolk Digital, Alan Partridge has navigated the stormy waters of the British media landscape, now achieving mainstream success on the big screen with a starring role in Steve Coogan’s Alpha Papa (Declan Lowney, 2013). A man who in his desperation for a television series of his own once sank so low as to pitch a show called Monkey Tennis to the BBC finally finds his inner hero in a film which, while presenting mainly as comedy, also contains a biting critique of trends in the British media with which all journalists and media practitioners in general will be familiar. Alpha Papa is a nostalgic, elegiac riff on the pleasures and values of local radio the way it used to be, exemplified by North Norfolk Digital’s stable of flawed, but endearing jocks – Wally Banter, Bruno Brooks, Dave Clifton (who in one scene recounts the depths to which he sank as an alcoholic, drug addicted wreck—“I woke up in a skip with someone else’s underpants in my mouth. I can laugh about it now …”), and Pat Farrell. 50- something Pat is sacked by the new owners of North Norfolk Digital, who in their efforts to transform the station into a “multiplatform content provider” going by the more Gen Yfriendly name of Shape (“the way you want it to be”), wish to replace him with a younger, brattish model lacking in taste and manners. Out go records by the likes of Glen Campbell and Neil Diamond (“You can keep Jesus Christ”, observes Partridge after playing Diamond’s Sweet Caroline in a demonstration of the crackling radio repartee for which he is by now renowned, “that was the king of the Jews”), in comes Roachford. Pat, grieving his dead wife Molly, finally snaps and turns the glitzy media launch of Shape into a hostage siege. Only Alan Partridge, it seems, can step in and talk Pat out of a looming catastrophe.

Physical and functional implications of aquatic exercise for nursing home residents with dementia

Exercise has reported benefits for those with dementia. In the current study we investigated the feasibility of delivery and the physical and functional benefits of an innovative aquatic exercise program for adults with moderate to severe dementia living in a nursing home aged care facility. Ten adults (88.4 years, inter quartile range 12.3) participated twice weekly for 12 weeks. Anthropometric and grip strength data, and measures of physical function and balance were collected at baseline and post-intervention. Feasibility was assessed by attendance, participation, enjoyment and recruitment. Following exercise, participant's left hand grip strength had improved significantly (p = .017). Small to moderate effect sizes were observed for other measures. A number of delivery challenges emerged, but participant enjoyment, benefits and attendance suggest feasibility. Aquatic exercise shows promise as an intervention among those with dementia who live in a nursing home aged care facility. Greater program investigation is warranted.

Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas

Background Genetic testing is recommended when the probability of a disease-associated germline mutation exceeds 10%. Germline mutations are found in approximately 25% of individuals with phaeochromcytoma (PCC) or paraganglioma (PGL); however, genetic heterogeneity for PCC/PGL means many genes may require sequencing. A phenotype-directed iterative approach may limit costs but may also delay diagnosis, and will not detect mutations in genes not previously associated with PCC/PGL. Objective To assess whether whole exome sequencing (WES) was efficient and sensitive for mutation detection in PCC/PGL. Methods Whole exome sequencing was performed on blinded samples from eleven individuals with PCC/PGL and known mutations. Illumina TruSeq™ (Illumina Inc, San Diego, CA, USA) was used for exome capture of seven samples, and NimbleGen SeqCap EZ v3.0 (Roche NimbleGen Inc, Basel, Switzerland) for five samples (one sample was repeated). Massive parallel sequencing was performed on multiplexed samples. Sequencing data were called using Genome Analysis Toolkit and annotated using annovar. Data were assessed for coding variants in RET, NF1, VHL, SDHD, SDHB, SDHC, SDHA, SDHAF2, KIF1B, TMEM127, EGLN1 and MAX. Target capture of five exome capture platforms was compared. Results Six of seven mutations were detected using Illumina TruSeq™ exome capture. All five mutations were detected using NimbleGen SeqCap EZ v3.0 platform, including the mutation missed using Illumina TruSeq™ capture. Target capture for exons in known PCC/PGL genes differs substantially between platforms. Exome sequencing was inexpensive (<$A800 per sample for reagents) and rapid (results <5 weeks from sample reception). Conclusion Whole exome sequencing is sensitive, rapid and efficient for detection of PCC/PGL germline mutations. However, capture platform selection is critical to maximize sensitivity.

Altered formalin-induced pain and Fos induction in the periaqueductal grey of preadolescent rats following neonatal LPS exposure

Animal and human studies have demonstrated that early pain experiences can produce alterations in the nociceptive systems later in life including increased sensitivity to mechanical, thermal, and chemical stimuli. However, less is known about the impact of neonatal immune challenge on future responses to noxious stimuli and the reactivity of neural substrates involved in analgesia. Here we demonstrate that rats exposed to Lipopolysaccharide (LPS; 0.05 mg/kg IP, Salmonella enteritidis) during postnatal day (PND) 3 and 5 displayed enhanced formalin-induced flinching but not licking following formalin injection at PND 22. This LPS-induced hyperalgesia was accompanied by distinct recruitment of supra-spinal regions involved in analgesia as indicated by significantly attenuated Fos-protein induction in the rostral dorsal periaqueductal grey (DPAG) as well as rostral and caudal axes of the ventrolateral PAG (VLPAG). Formalin injections were associated with increased Fos-protein labelling in lateral habenula (LHb) as compared to medial habenula (MHb), however the intensity of this labelling did not differ as a result of neonatal immune challenge. These data highlight the importance of neonatal immune priming in programming inflammatory pain sensitivity later in development and highlight the PAG as a possible mediator of this process

Altered nociceptive, endocrine, and dorsal horn neuron responses in rats following a neonatal immune challenge

Summary The neonatal period is characterized by significant plasticity where the immune, endocrine, and nociceptive systems undergo fine-tuning and maturation. Painful experiences during this period can result in long-term alterations in the neurocircuitry underlying nociception, including increased sensitivity to mechanical or thermal stimuli. Less is known about the impact of neonatal exposure to mild inflammatory stimuli, such as lipopolysaccharide (LPS), on subsequent inflammatory pain responses. Here we examine the impact of neonatal LPS exposure on inflammatory pain sensitivity and HPA axis activity during the first three postnatal weeks. Wistar rats were injected with LPS (0.05 mg/kg IP, Salmonella enteritidis) or saline on postnatal days (PNDs) 3 and 5 and later subjected to the formalin test at PNDs 7, 13, and 22. One hour after formalin injection, blood was collected to assess corticosterone responses. Transverse spinal cord slices were also prepared for whole-cell patch clamp recording from lumbar superficial dorsal horn neurons (SDH). Brains were obtained at PND 22 and the hypothalamus was isolated to measure glucocorticoid (GR) and mineralocorticoid receptor (MR) transcript expression using qRT-PCR. Behavioural analyses indicate that at PND 7, no significant differences were observed between saline- or LPS-challenged rats. At PND 13, LPS-challenged rats exhibited enhanced licking (p < .01), and at PND 22, increased flinching in response to formalin injection (p < .05). LPS-challenged rats also displayed increased plasma corticosterone at PND 7 and PND 22 (p < .001) but not at PND 13 following formalin administration. Furthermore, at PND 22 neonatal LPS exposure induced decreased levels of GR mRNA and increased levels of MR mRNA in the hypothalamus. The intrinsic properties of SDH neurons were similar at PND 7 and PND 13. However, at PND 22, ipsilateral SDH neurons in LPS-challenged rats had a lower input resistance compared to their saline-challenged counterparts (p < .05). These data suggest neonatal LPS exposure produces developmentally regulated changes in formalin-induced behavioural responses, corticosterone levels, and dorsal horn neuron properties following noxious stimulation later in life. These findings highlight the importance of immune activation during the neonatal period in shaping pain sensitivity later in life. This programming involves both spinal cord neurons and the HPA axis.

Workmen's Circle collection, undated, 1903-1993.

Collection consists of material from the administration, services, individual branches, and schools of the Workmen's Circle. The majority of the collection are publications of the Workmen's Circle relating to conventions and education. The collection also includes annual reports, newsletters, bulletins, and pamphlets.

Lipperode; Jewish Community Collection 1830-1939

Community record book 1846-1939; documents; business contracts; papers of individuals.

Queensland Agricultural Journal Volume 13 Parts 1-6 July to December 1903

General Index Vol 13 Parts 1-6, pages 1-81

Eugen Fuchs Collection 1903-1960

Articles by Fuchs; letters to his son; obituaries.

Mothers, your's is a sacred work! Naiskysymys adventistijulistaja Ellen Whiten profeetallisessa terveysopetuksessa vuosina 1866 1878

Tarkastelen pro gradu -tutkielmassani naiskysymystä Seitsem��nnen päivän adventtikirkon oppiäiti Ellen Whiten (1827 1915) terveysopetuksessa. White tunnetaan ennen kaikkea näyistään, joiden välityksellä hän koki saavansa Jumalalta hyvinvointiin liittyviä ohjeita. White kirjoitti näkyjensä innoittama terveysoppaita ja julisti pääasiassa Yhdysvalloissa yli 70 vuotta. Päälähteenäni ovat kaksi Whiten omaeläm��kertaa vuosilta 1880 ja 1915 sekä 83 artikkelia, jotka hän julkaisi adventistien johtavassa terveyslehdessä, Health Reformerissa, vuosina 1866 1878. Tutkimuskysymykseni ovat, miksi White osoitti lähes kaiken terveyteen liittyvän opetuksensa naisille ja miten hän ymmärsi terveyden osana naisen roolia ja tehtäviä. Tulkintani mukaan White julisti naisille, sillä hän uskoi, että naisen asema oli selkeytettävä. Yhdysvallat teollistui ja kaupungistui nopeasti 1800-luvulla, mikä aiheutti naisille taloudellisia, sosiaalisia ja terveyteen liittyviä ongelmia. Lisäksi toinen suuri herätys (1800 1830) synnytti keskustelua naisen roolista. Monet kirkot antoivat naisille luvan esimerkiksi saarnaamiseen, mutta Yhdysvalloissa vahvistui samaan aikaan myös käsitys naisesta kodin uskonnollisena johtajana. Ymmärrän, että Whiten mukaan ratkaisu naisen sekavaan asemaan oli terveys. Uskon, että Whiten mukaan nainen pystyi ottamaan oman paikkansa yhteiskunnassa, mikäli hän pysyi terveenä ja oppi tuntemaan terveyden periaatteet. Toisaalta White sai vaikutteita naisten yhteiskunnallisten oikeuksien puolustajilta. He ajattelivat, että vain koulutettu ja terve nainen kykeni vapautumaan avioliitosta. Toisaalta White oli naisasianaisia maltillisempi. Hän ymmärsi, että vain terve ja terveyskoulutuksen saanut nainen saattoi olla hyvä äiti. Ellen White osallistui terveysopetuksellaan keskusteluun myös naisen uskonnollisesta roolista. White oli itse kiertelevä terveyssaarnaaja. Silti hän ymmärsi, että muiden naisten kutsumus oli olla terve ja koulutettu äiti. White korosti äitien pyhyyttä luultavasti siksi, että hän pyrki turvaamaan oman auktoriteettiasemansa Adventtikirkossa. White myös luultavasti ymmärsi roolinsa ja tehtävänsä poikkeuksellisiksi ja arvosti vilpittöm��sti äitiyttä. Whiten mukaan äidin tehtävä oli kasvattaa terveitä ja moraalisia kansalaisia. Tehtävän arvon hän perusteli aikansa tieteellisillä teorioilla. White korosti luonnontieteilijä Charles Darwinin (1809 1882) evoluutioteorian mukaisesti, että äidin velvollisuus oli siirtää lapsilleen hyvä terveys. Käsityksensä terveyden ja moraalin suhteesta hän selitti frenologialla, jonka mukaan ihmisen eläm��ntavat vaikuttivat hänen luonteenpiirteisiinsä. White oli myös todennäköisesti kiinnostunut sosiaalitieteilijä Herbert Spencerin (1820 1903) ajatuksista, joiden mukaan kansalaisten kehittyessä myös yhteiskunta jalostui yhä paremmaksi. Vaikka White perusteli opetustaan modernilla tieteellä, hän oli ennen kaikkea uskonnollinen julistaja. Hän kuului 1840-luvulla herätyssaarnaaja William Millerin (1782 1849) liikkeeseen, jonka jäsenet uskoivat, että Jumala tuhoaa Yhdysvallat viimeisellä tuomiolla, mikäli kansan moraalin tila ei nopeasti kohene. Millerin liikkeen painotukset säilyivät Adventtikirkossa, joka perustettiin vuonna 1863. Siten White ymmärsi, ettei äiti ollut vastuussa vain perheensä ja kansansa maallisesta hyvinvoinnista vaan myös heidän pelastuksestaan. Whiten käsitys äidistä on mielestäni ristiriitainen. White antoi äideille paljon valtaa, mutta myös suuren vastuun. Hän korosti äitien arvokkuutta, mutta toisaalta he eivät olleet hänen mukaansa korvaamattomia. White ei myöskään huomioinut naisia, jotka eivät olleet äitejä.

Association of FOXE1 Polyalanine Repeat Region with Papillary Thyroid Cancer

CONTEXT: Polyalanine tract variations in transcription factors have been identified for a wide spectrum of developmental disorders. The thyroid transcription factor forkhead factor E1 (FOXE1) contains a polymorphic polyalanine tract with 12-22 alanines. Single-nucleotide polymorphisms (SNP) close to this locus are associated with papillary thyroid cancer (PTC), and a strong linkage disequilibrium block extends across this region. OBJECTIVE: The objective of the study was to assess whether the FOXE1 polyalanine repeat region was associated with PTC and to assess the effect of polyalanine repeat region variants on protein expression, DNA binding, and transcriptional function on FOXE1-responsive promoters. DESIGN: This was a case-control study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS AND METHODS: The FOXE1 polyalanine repeat region and tag SNP were genotyped in 70 PTC, with a replication in a further 92 PTC, and compared with genotypes in 5767 healthy controls (including 5667 samples from the Wellcome Trust Case Control Consortium). In vitro studies were performed to examine the protein expression, DNA binding, and transcriptional function for FOXE1 variants of different polyalanine tract lengths. RESULTS: All the genotyped SNP were in tight linkage disequilibrium, including the FOXE1 polyalanine repeat region. We confirmed the strong association of rs1867277 with PTC (overall P = 1 × 10(-7), odds ratio 1.84, confidence interval 1.31-2.57). rs1867277 was in tight linkage disequilibrium with the FOXE1 polyalanine repeat region (r(2) = 0.95). FOXE1(16Ala) was associated with PTC with an odds ratio of 2.23 (confidence interval 1.42-3.50; P = 0.0005). Functional studies in vitro showed that FOXE1(16Ala) was transcriptionally impaired compared with FOXE1(14Ala), which was not due to differences in protein expression or DNA binding. CONCLUSIONS: We have confirmed the previous association of FOXE1 with PTC. Our data suggest that the coding polyalanine expansion in FOXE1 may be responsible for the observed association between FOXE1 and PTC.

Improving diagnosis of tumor-induced osteomalacia with gallium-68 DOTATATE PET/CT

Context: Tumor-induced osteomalacia (TIO) is a rarely diagnosed disorder presenting with bone pain, fractures, muscle weakness, and moderate-to-severe hypophosphatemia resulting from fibroblast growth factor 23-mediated renal phosphate wasting. Tumors secreting fibroblast growth factor 23 are often small and difficult to find with conventional imaging. Objective: We studied the utility of 68Ga-DOTA-octreotate (DOTATATE) somatostatin receptor positron emission tomography (PET)/computed tomography (CT) imaging in the diagnosis of TIO. Design and Setting: A multicenter case series was conducted at tertiary referral hospitals. Patients and Methods: Six patients with TIO diagnosed between 2003 and 2012 in Australia were referred for DOTATATE PET imaging. We reviewed the clinical history, biochemistry, imaging characteristics, histopathology, and clinical outcome of each patient. Results: Each case demonstrated delayed diagnosis despite severe symptoms. DOTATATE PET/CT imaging demonstrated high uptake and localized the tumor with confidence in each case. After surgical excision, there was resolution of clinical symptoms and serum phosphate, except in one patient who demonstrated residual disease on PET/CT. All tumors demonstrated high somatostatin receptor subtype 2 cell surface receptor expression using immunohistochemistry. Conclusions: In patients with TIO, DOTATATE PET/CT can successfully localize phosphaturic mesenchymal tumors and may be a practical first step in functional imaging for this disorder. Serum phosphate should be measured routinely in patients with unexplained muscle weakness, bone pain, or stress fractures to allow earlier diagnosis of TIO. - See more at: http://press.endocrine.org/doi/abs/10.1210/jc.2012-3642#sthash.eXD0CopL.dpuf

Pheo-type: A diagnostic gene-expression assay for the classification of pheochromocytoma and paraganglioma

Context: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers. Objective: This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology. Design: A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential. Results: A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes; RTK1–3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application. Conclusions: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.

Illuminating the glass box: The lighting designs of Richard Kelly

A promotional brochure celebrating the completion of the Seagram Building in spring 1957 features on its cover intense portraits of seven men bisected by a single line of bold text that asks, “Who are these Men?” The answer appears on the next page: “They Dreamed of a Tower of Light” (Figures 1, 2). Each photograph is reproduced with the respective man’s name and project credit: architects, Mies van der Rohe and Philip Johnson; associate architect, Eli Jacques Kahn; electrical contractor, Harry F. Fischbach; lighting consultant, Richard Kelly; and electrical engineer, Clifton E. Smith. To the right, a rendering of the new Seagram Tower anchors the composition, standing luminous against a star-speckled night sky; its glass walls and bronze mullions are transformed into a gossamer skin that reveals the tower’s structural skeleton. Lightolier, the contract lighting manufacturer, produced the brochure to promote its role in the lighting of the Seagram Building, but Lightolier’s promotional copy was not far from the truth.

Cluster based core vector machine

Core Vector Machine(CVM) is suitable for efficient large-scale pattern classification. In this paper, a method for improving the performance of CVM with Gaussian kernel function irrespective of the orderings of patterns belonging to different classes within the data set is proposed. This method employs a selective sampling based training of CVM using a novel kernel based scalable hierarchical clustering algorithm. Empirical studies made on synthetic and real world data sets show that the proposed strategy performs well on large data sets.