Environmental pressures as they affect the acceptance of treatment by fifteen alcoholic patients in the Washingtonian Hospital 1942 to 1950

Thesis (M.S.)--Boston Universit

Phase I trial of the murine monoclonal anti-GD2 antibody 14G2a in metastatic melanoma

In a phase I trial, 12 patients with GD2 antigen-positive metastatic melanoma received the murine anti-GD2 monoclonal antibody 14G2a. The monoclonal antibody was administered in four doses over an 8-day period with total dose ranging from 10 to 120 mg. All patients receiving \u3e10 mg of 14G2a experienced transient abdominal/pelvic pain during the antibody infusion. Five patients had a delayed extremity pain syndrome following the third and fourth antibody infusion. Four of the five patients developed neurological toxicity, including two patients with significant although reversible motor neuropathy. Two of the patients developed hyponatremia secondary to a syndrome of inappropriate antidiuretic hormone. All 12 patients developed high levels of human anti-14G2a antibody. The plasma half-life of 14G2a was 42 ± 6 (SD) h. One patient each had a partial response, mixed response, and stable disease, respectively. The very modest antitumor activity accompanied by dose-limiting neurological toxicity at total doses \u3e80 mg may restrict the clinical utility of murine 14G2a

Genetic dissection of a Leishmania flagellar proteome demonstrates requirement for directional motility in sand fly infections

The protozoan parasite Leishmania possesses a single flagellum, which is remodelled during the parasite’s life cycle from a long motile flagellum in promastigote forms in the sand fly to a short immotile flagellum in amastigotes residing in mammalian phagocytes. This study examined the protein composition and in vivo function of the promastigote flagellum. Protein mass spectrometry and label free protein enrichment testing of isolated flagella and deflagellated cell bodies defined a flagellar proteome for L. mexicana promastigote forms (available via ProteomeXchange with identifier PXD011057). This information was used to generate a CRISPR-Cas9 knockout library of 100 mutants to screen for flagellar defects. This first large-scale knockout screen in a Leishmania sp. identified 56 mutants with altered swimming speed (52 reduced and 4 increased) and defined distinct mutant categories (faster swimmers, slower swimmers, slow uncoordinated swimmers and paralysed cells, including aflagellate promastigotes and cells with curled flagella and disruptions of the paraflagellar rod). Each mutant was tagged with a unique 17-nt barcode, providing a simple barcode sequencing (bar-seq) method for measuring the relative fitness of L. mexicana mutants in vivo. In mixed infections of the permissive sand fly vector Lutzomyia longipalpis, paralysed promastigotes and uncoordinated swimmers were severely diminished in the fly after defecation of the bloodmeal. Subsequent examination of flies infected with a single paralysed mutant lacking the central pair protein PF16 or an uncoordinated swimmer lacking the axonemal protein MBO2 showed that these promastigotes did not reach anterior regions of the fly alimentary tract. These data show that L. mexicana need directional motility for successful colonisation of sand flies

February 1967 Conference Issue

Massachusetts Turf and Lawn Grass CouncilBetter Turf Through Research and Educatio

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

Clinician Knowledge and Beliefs after Statewide Program to Promote Appropriate Antimicrobial Drug Use

In 1999, Wisconsin initiated an educational campaign for primary care clinicians and the public to promote judicious antimicrobial drug use. We evaluated its impact on clinician knowledge and beliefs; Minnesota served as a control state. Results of pre- (1999) and post- (2002) campaign questionnaires indicated that Wisconsin clinicians perceived a significant decline in the proportion of patients requesting antimicrobial drugs (50% in 1999 to 30% in 2002; p<0.001) and in antimicrobial drug requests from parents for children (25% in 1999 to 20% in 2002; p = 0.004). Wisconsin clinicians were less influenced by nonpredictive clinical findings (purulent nasal discharge [p = 0.044], productive cough [p = 0.010]) in terms of antimicrobial drug prescribing. In 2002, clinicians from both states were less likely to recommend antimicrobial agent treatment for the adult case scenarios of viral respiratory illness. For the comparable pediatric case scenarios, only Wisconsin clinicians improved significantly from 1999 to 2002. Although clinicians in both states improved on several survey responses, greater overall improvement occurred in Wisconsin

Testate amoebae in pollen slides

Among the non-pollen micro-fossils commonly encountered in Quaternary sediment samples prepared for pollen analysis are many shells of testate amoebae. Testate amoebae are eukaryotic micro-organisms which are increasingly used in ecological and palaeoecological studies, particularly as indicators of hydrological change in Sphagnum-dominated peatlands. In this study we address the extent to which testate amoebae are used in palynological research, the key challenges to more widespread use, and the extent to which ecological information is retained in the testate amoeba assemblages of standard palynological slides. To achieve this we review the literature on the use of testate amoebae in palynology, compare testate amoeba records produced by palynological and water-based preparation methods and carry out simulations using previously-derived datasets. Our results show that testate amoebae are widely encountered in Quaternary palynological studies, primarily in peatlands, but the information which they can provide is undermined by limited taxonomic knowledge. Many taxa are destroyed in pollen preparations, but for taxa that are retained patterns of abundance parallel those determined using water-based preparation methods. Although the loss of sensitive taxa limits the ecological information contained in testate amoeba assemblages the information preserved is likely to be useful in a multiproxy approach to palaeoenvironmental reconstruction. To help improve taxonomic awareness and encourage the use of testate amoebae in palynology we present a basic introduction to testate amoeba taxonomy and a guide to the taxonomic literature

Negation and the functional sequence

There exists a general restriction on admissible functional sequences which prevents adjacent identical heads. We investigate a particular instantiation of this restriction in the domain of negation. Empirically, it manifests itself as a restriction the stacking of multiple negative morphemes. We propose a principled account of this restriction in terms of the general ban on immediately consecutive identical heads in the functional sequence on the one hand, and the presence of a Neg feature inside negative morphemes on the other hand. The account predicts that the stacking of multiple negative morphemes should be possible provided they are separated by intervening levels of structure. We show that this prediction is borne out

Correlations of behavioral deficits with brain pathology assessed through longitudinal MRI and histopathology in the R6/1 mouse model of huntington's disease

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6 mouse models of HD express a mutant version of exon 1 HTT and typically develop motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Unlike the more commonly used R6/2 mouse line, R6/1 mice have fewer CAG repeats and, subsequently, a less rapid pathological decline. Compared to the R6/2 line, fewer descriptions of the progressive pathologies exhibited by R6/1 mice exist. The association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood in many models of HD. In attempt to link these factors in the R6/1 mouse line, we have performed detailed assessments of behavior and of regional brain abnormalities determined through longitudinal, in vivo magnetic resonance imaging (MRI), as well as an end-stage, ex vivo MRI study and histological assessment. We found progressive decline in both motor and non-motor related behavioral tasks in R6/1 mice, first evident at 11 weeks of age. Regional brain volumes were generally unaffected at 9 weeks, but by 17 weeks there was significant grey matter atrophy. This age-related brain volume loss was validated using a more precise, semi-automated Tensor Based morphometry assessment. As well as these clear progressive phenotypes, mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the R6/1 brain and was accompanied by neuronal loss. Despite these seemingly concomitant, robust pathological phenotypes, there appeared to be little correlation between the three main outcome measures: behavioral performance, MRI-detected brain atrophy and histopathology. In conclusion, R6/1 mice exhibit many features of HD, but the underlying mechanisms driving these clear behavioral disturbances and the brain volume loss, still remain unclear. © 2013 Rattray et al