Letter to Timothy Coggins regarding the Southeastern Law Librarian, May 25, 1988

A letter from Barbara Huff-Duff to Timothy Coggins regarding the Southeastern Law Librarian

Cognition in t(1;11) translocation carriers and patients with psychotic disorders

Deficits in a number of cognitive domains have been associated with core symptoms of schizophrenia, including working memory, attention, motor skills, reaction time, episodic memory and executive function. Bipolar Disorder is also associated with cognitive impairment; however the level of impairment appears to be less severe than that seen in schizophrenia. A translocation (t(1;11)) containing the Disrupted-in-Schizophrenia 1 (DISC1) gene has been found to be highly associated with schizophrenia, bipolar disorder and major depressive disorder. As such, this gene has been the focus of much research and to date DISC1 has been found to be associated with brain development, brain structure and the glutamate system - all key factors in current models of schizophrenia and affective disorders. The aim of this PhD is to identify cognitive domains that are differentially impaired or unimpaired in a large Scottish family, some of whom carry this rare DISC1 variant, a balanced translocation (t (1;11) (q 42; q14.3)), that segregates with schizophrenia and affective disorders, as well as psychiatric patients with schizophrenia and bipolar disorder and healthy control subjects. All participants have undergone standardised cognitive assessments to measure premorbid I.Q. (NART), current I.Q. (WASI) verbal memory, working memory, verbal fluency, processing speed, motor skills, executive function (BACS) and selected CANTAB tasks to assess simple and five-choice reaction time. Polygenic risk profile scores and self-report questionnaire data have also been investigated. Results indicate an impact of the DISC1 t(1;11) translocation on general intelligence and attention and processing speed. Significant differences were also identified between DISC1 t(1;11) carriers and non-carriers on self-report questionnaire data. Mean scores for polygenic risk for bipolar disorder were significantly different between DISC1 t(1;11) carriers and non-carriers and polygenic risk for schizophrenia was significantly associated with symptom severity, as measured by the Positive and Negative Symptom Scale (PANSS). Within the patient groups, a measure of processing speed (the token motor task) was found to be significantly different between those with schizophrenia and bipolar disorder and there was also a trend for attention and processing speed. As expected, I.Q. was significantly different between patients and control participants. Clinical ratings were significantly associated with neuropsychological and self-report measures. Polygenic risk for major depressive disorder was found to be significantly associated with impaired general intelligence (current IQ) and slowed reaction time in patients who were not currently depressed, suggesting there may be genetic risk markers in this population which impact on cognition. This is a novel finding and further suggests the possibility of a biological component related to the genetics of depression. In conclusion, and in line with the literature, psychosis has a negative impact on cognition with reduced performance across several neuropsychological tasks between patient groups, with schizophrenia patients performing worse than patients with bipolar disorder and both patient groups performing worse than healthy control participants. Cognition is markedly more impaired in DISC1 t(1;11) translocation carriers and especially in those with psychosis. The DISC1 t(1;11) translocation and psychosis may therefore confer a “double hit” on cognition - in addition to psychosis itself - which is known to impair cognitive function, significantly increasing the level of cognitive impairment and increasing the risk for psychosis in general

White matter connectivity, cognition, symptoms and genetic risk factors in Schizophrenia

Schizophrenia is a highly heritable complex neuropsychiatric disorder with a lifetime prevalence of around 1%. It is often characterised by impaired white matter structural dysconnectivity. In vivo and post-mortem alterations in white matter microstructure have been reported, along with differences in the topology of the structural connectome; overall these suggest a reduced communication between distal brain regions. Schizophrenia is characterised by persistent cognitive impairments that predate the occurrence of symptoms and have been shown to have a neural foundation reflecting aberrant brain connectivity. So far, 179 independent genome-wide significant single nucleotide polymorphisms (SNPs) have been associated with a diagnosis of schizophrenia. The high heritability and polygenicity of schizophrenia, white matter parameters and cognitive functions provides a great opportunity to investigate the potential relationships between them due to the genetic overlap shared among these factors. This work investigates the psychopathology of schizophrenia from a neurobiological, psychological and genetic perspective. The datasets used here include data from the Scottish Family Mental Health (SFMH) study, the Lothian Birth Cohort 1936 (LBC1936) and UK Biobank. The main goal of this thesis was to study white matter microstructure in schizophrenia using diffusion MRI (dMRI) data. Our first aim was to examine whether processing speed mediated the association between white matter structure and general intelligence in patients diagnosed with schizophrenia in the SFMH study. Secondly, we investigated specific networks from the structural connectome and their topological properties in both healthy controls and patients diagnosed with schizophrenia in the SFMH study. These networks were studied alongside cognition, clinical symptoms and polygenic risk factor for schizophrenia (szPGRS). The third aim of this thesis was to study the effects of szPGRS on the longitudinal trajectories of white matter connectivity (measured using tractography and graph theory metrics) in the LBC1936 over a period of three-years. Finally, we derived the salience network which has been previously associated with schizophrenia and examined the effect of szPGRS on the grey matter nodes associated with this network and their connecting white matter tracts in UK Biobank. With regards to the first aim, we found that processing speed significantly mediates the association between a general factor of white matter structure and general intelligence in schizophrenia. These results suggest that, as in healthy controls, processing speed acts as a key cognitive resource facilitating higher order cognition by allowing multiple cognitive processes to be simultaneously available. Secondly, we found that several graph theory metrics were significantly impaired in patients diagnosed with schizophrenia compared with healthy controls. Moreover, these metrics were significantly associated with intelligence. There was a strong tendency towards significance for a correlation between intelligence and szPGRS that was significantly mediated by graph theory metrics in both healthy controls and schizophrenia patients of the SFMH study. These results are consistent with the hypothesis that intelligence deficits are associated with a genetic risk for schizophrenia, which is mediated via the disruption of distributed brain networks. In the LBC1936 we found that higher szPGRS showed significant associations with longitudinal increases in MD in several white matter tracts. Significant declines over time were observed in graph theory metrics. Overall these findings suggest that szPGRS confer risk for ageing-related degradation of some aspects of structural connectivity. Moreover, we found significant associations between higher szPGRS and decreases in cortical thickness, in particular, in a latent factor for cortical thickness of the salience network. Taken together, our findings suggest that white matter connectivity plays a significant role in the disorder and its psychopathology. The computation of the structural connectome has improved our understanding of the topological characteristics of the brain’s networks in schizophrenia and how it relates to the microstructural level. In particular, the data suggests that white matter structure provides a neuroanatomical substrate for cognition and that structural connectivity mediates the relationship between szPGRS and intelligence. Additionally, these results suggest that szPGRS may have a role in age-related changes in brain structural connectivity, even among individuals who are not diagnosed with schizophrenia. Further work will be required to validate these results and will hopefully examine additional risk factors and biomarkers, with the ultimate aims of improving scientific knowledge about schizophrenia and conceivably of improving clinical practice

Artificially extended photoperiod administered to pre-partum mares via blue light to a single eye : observations on gestation length, foal birth weight and foal hair coat at birth

In seasonally breeding animals, photoperiod perception is crucial for timing of important physiological events. In the horse, long day photoperiod influences the onset of ovulation and cyclicity, shedding of the heavier winter coat and the timing of parturition. In this compilation of studies, conducted across three breeding seasons and two countries, the impact of artificially extended day length was investigated on gestation length, foal birth weight and foal hair coat at birth. The light therapy was administered to pre-partum mares via mobile head worn masks which provided short wavelength blue light to a single eye. In Study 1, reductions in gestation lengths were observed following administration of artificially extended day length (124.8 ± 15.11 days) in the final months of pregnancy to a group of Thoroughbred mares compared to controls (P < 0.05; 339.7 ± 9.56 days vs 350.6 ± 9.13). Study 2 revealed that pre-partum exposure to artificially extended day length (104.6 ± 9.89 days) increased foal birth weight compared to controls (47.13 ± 2.93 kg vs 43.51 ± 6.14 kg; P < 0.05) in mares bred early in the year. In Study 3, artificially extended day length (87.53 ± 19.6 days) administered to pre-partum mares affected the coat condition of foals at birth with respect to hair weight (P < 0.0001) and hair length (P < 0.0001) compared to controls (0.34 ± 0.20 μg vs 0.59 ± 0.12 μg and 1.93 ± 0.56 cm vs 2.56 ± 0.32 cm, respectively). Collectively, these studies serve to highlight the influential role of the circa-annual changes in photoperiod length on the pre-partum mare for normal foetal development during the natural breeding season. It also emphasizes the potential that exists to improve breeding efficiency parameters by artificially simulating this important environmental cue in the latter stages of gestation against the backdrop of an economically driven early breeding season.Study 2 was supported by an Enterprise Ireland Commercialisation Fund grant to B. A. Murphy.http://www.theriojournal.com2018-09-15hj2017Production Animal Studie

The Lantern Vol. 43, No. 1, Fall 1976

• Frustration • Think Again • My Sweet • Secret Society of One • November Ghosts • A Lonely Girl\u27s Prayer • Visions of You • The Innocence Baby • Society • Silence • Don\u27t Turn Around • Waves • Loneliness • Time Writer • Brood • It\u27s Not Funny • Four Haiku, Entwined • We\u27ll Have to Stop Meeting Like This • Castles In the Sand • The Seahttps://digitalcommons.ursinus.edu/lantern/1109/thumbnail.jp

Retrospective analysis of eff ectiveness and toleration of treatment with platinum derivative and pemetrexed in patients with advanced (stage IIIB and IV) non-small non-squamous cell lung cancer in a few oncology centers

Wstęp. Badanie Scagliottiego i wsp. zapoczątkowało stosowanie w leczeniu raka płuca schematów chemioterapiistosownie do konkretnego rozpoznania histologicznego: w raku o utkaniu innym niż płaskonabłonkowe — w połączeniuz cisplatyną pojawił się pemetreksed.Cel pracy. Retrospektywna ocena skuteczności i tolerancji paliatywnej chemioterapii z użyciem dwulekowegoschematu zawierającego pochodną platyny i pemetreksed w rutynowej praktyce klinicznej w okresie przed wprowadzeniemprogramu lekowego.Materiał i metody. Do badania włączono 50 chorych na zaawansowanego (stopień kliniczny IIIB lub IV) raka niedrobnokomórkowegoo utkaniu innym niż płaskonabłonkowe. W całej grupie przeprowadzono analizę odpowiedzii tolerancji leczenia. Czas wolny od progresji określono u 45 chorych, u których nie stosowano innego leczenia przedprogresją oraz u których czas do progresji lub zgonu (ewentualnie utraty z obserwacji) był znany.Wyniki. Chorzy otrzymali od 1 do 5 cykli leczenia, a 34 chorych (68%) — zalecane 3–4 cykle. U żadnego chorego nieuzyskano całkowitej remisji pod wpływem leczenia. U 8 chorych (16%) odnotowano częściową remisję, a u 29 chorych(58%) — stabilizację choroby. Progresja w trakcie leczenia wystąpiła u 13 chorych (26%). Korzyść kliniczną odniosło17 chorych (34%). Mediana czasu wolnego od progresji wyniosła w ocenianej grupie 19 tygodni (3–92 tyg.). Wśródchorych leczonych cisplatyną mediana czasu do progresji wyniosła 19,8 tygodnia (3–92 tyg.). Tolerancja leczenia byładobra, nie odnotowano powikłań zagrażających życiu. Wystąpiło 10 przypadków neutropenii, 1 małopłytkowość,niedokrwistość pojawiła się u 7 chorych, odnotowano też 6 przypadków powikłań niehematologicznych.Wnioski. Korzyść kliniczną odniosła około jedna trzecia chorych, a mediana czasu wolnego od progresji była krótszaod uzyskanego we wspomnianym badaniu rejestracyjnym dla pemetreksedu. Leczenie było dobrze tolerowane.Celowe byłoby przeprowadzenie prospektywnego badania obserwacyjnego w celu rzetelnej oceny efektywnościi tolerancji rutynowego leczenia schematem zawierającym pemetrekset.Background. The Scagliotti trial initiated the use of chemotherapy in non-small cell, non-squamous lung cancerchemotherapy with pemetrexed.Purpose. Retrospective analysis of eff ectiveness and toleration of palliative chemotherapy with platinum derivativeand pemetrexed.Materials and methods. The study population was 50 patients with stage IIIB/IV non-small cell non-squamous lungcancer who had been treated with platinum derivate and pemetrexed. Response and toxicity were analyzed in allgroups. Progression-free survival was assessed for 45 patients who had not received any other treatment beforedisease progression and whose date of progression or death was known.Results. Patients received 1 to 5 cycles of chemotherapy, but 34 (68%) had recommended 3 to 4 cycles. No patientachieved complete remission. 8 (16%) had a partial response and stabilization was reached in 29 (58%). Progression ofthe disease occurred in 13 patients (26%). Clinical benefi t was achieved in 17 patients (34%). Median progression-freesurvival was 19 weeks (range 3–92 weeks), and for patients treated with cisplatin 19.8 weeks (3–92 weeks). Treatmenttoleration was good. No life threatening side eff ects were reported. Toxicity was as follows: 10 cases of neutropenia,1 of thrombocytopenia, 7 of anemia, and 6 of non-hematological toxicities were also reported.Conclusions. Clinical benefi t was achieved in one-third of patients. Progression-free survival was shorter than fornon-squamous cell cancer patients treated with cisplatin and pemetrexed in the Scagliotti trial. Treatment was welltolerated. For better assessment of treatment eff ectiveness and toxicity a observational study would be useful

DNA sequence level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes

"The Book of Negroes’ illustrated edition: circulating African-Canadian history through the Middlebrow"

This article examines the 2009 deluxe illustrated edition of Lawrence Hill’s Commonwealth Writers’ Prize– and Canada Reads–winning novel The Book of Negroes, originally published in 2007. It relates the story of Aminata, a West African girl kidnapped and sold into slavery, and her experiences on an indigo plantation in the American south, followed by further displacements to Charleston, Nova Scotia, Sierra Leone, and London. In New York, as the Revolutionary War comes to a close, Aminata becomes the scribe for the Book of Negroes, documenting the Black Loyalists, as well as the slaves and indentured servants of white Loyalists, granted passage by the British to Canada. Hill has commented that the Book of Negroes is an important document about which Canadians are largely ignorant. This desire to circulate knowledge about African-Canadian history through the novel is particularly manifest in the illustrated edition of 2009, where a photograph of the Book of Negroes features prominently, along with countless other images and captions which supplement and interrupt Hill’s narrative. This article considers the significance and implications of this “keepsake” or “souvenir” edition, particularly its circulation of knowledge about African-Canadian history through visual pleasure

To whom does the law speak? Canvassing a neglected picture of law’s interpretive field

Among the most common strategies underlying the so-called indeterminacy thesis is the following two-step argument: (1) that law is an interpretive practice, and that evidently legal actors more generally hold different (and competing) theories of meaning, which lead to disagreements as to what the law says (that is, as to what the law is); (2) and that, as there is no way to establish the prevalence of one particular theory of meaning over the other, indeterminacy is pervasive in law. In this paper I offer some reflections to resist this trend. In particular I claim that a proper understanding of law as an authoritative communicative enterprise sheds new light on the relation between the functioning of the law and our theories of interpretation, leading to what can be considered a neglected conclusion: the centrality of the linguistic criterion of meaning in our juridical interpretive practices. In the first part of the chapter I discuss speech-act theory in the study of law, assessing its relevance between alternative options. Then I tackle the ‘to whom does the law speak?’ question, highlighting the centrality of lay-people for our juridical practices. Lastly, I examine the consequences of this neglected fact for our interpretive theories

Particular distribution and expression pattern of endoglin (CD105) in the liver of patients with hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Endoglin (CD105) has been considered a prognostic marker for hepatocellular carcinoma (HCC), and widely used as an appropriate targeting for antiangenesis therapy in some cancers. Our aim was to evaluate the distribution and expression of CD105 in the liver of patients with HCC, and to discuss whether CD105 may be used as an appropriate targeting for antiangenesis therapy in HCC.</p> <p>Methods</p> <p>Three parts of liver tissues from each of 64 patients with HCC were collected: tumor tissues (TT), adjacent non-tumor (AT) liver tissues within 2 cm, and tumor free tissues (TF) 5 cm far from the tumor edge. Liver samples from 8 patients without liver diseases served as healthy controls (HC). The distribution and expression of CD105 in tissues were evaluated by immunohistochemistry, Western blotting analysis, and real-time PCR. HIF-1alpha and VEGF₁₆₅protein levels in tissues were analyzed by Immunohistochemistry and Western blotting analysis or ELISA.</p> <p>Results</p> <p>CD105 was positively stained mostly in a subset of microvessels 'endothelial sprouts' in TT of all patients while CD105 showed diffuse positive staining, predominantly on hepatic sinus endothelial cells in the surrounding of draining veins in TF and AT. The mean score of MVD-CD105 (mean ± SD/0.74 mm²) was 19.00 ± 9.08 in HC, 153.12 ± 53.26 in TF, 191.12 ± 59.17 in AT, and 85.43 ± 44.71 in TT, respectively. Using a paired <it>t </it>test, the expression of CD105 in AT and TF was higher than in TT at protein (MVD, <it>p </it>= 0.012 and <it>p </it>= 0.007, respectively) and mRNA levels (<it>p </it>< 0.001 and <it>p </it>= 0.009, respectively). Moreover, distribution and expression of CD105 protein were consistent with those of HIF-1alpha and VEGF₁₆₅protein in liver of patients with HCC. The level of <it>CD105 </it>mRNA correlated with VEGF₁₆₅level in TF (r = 0.790, <it>p </it>= 0.002), AT (r = 0.723, <it>p </it>< 0.001), and TT (r = 0.473, <it>p </it>= 0.048), respectively.</p> <p>Conclusion</p> <p>It is demonstrated that CD105 was not only present in neovessels in tumor tissues, but also more abundant in hepatic sinus endothelium in non-tumor tissues with cirrhosis. Therefore, CD105 may not be an appropriate targeting for antiangenesis therapy in HCC, especially with cirrhosis.</p