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Objectives The neurobiological basis and nosological status of schizoaffective disorder remains elusive and controversial. This study provides a systematic review of neurocognitive and neuroimaging findings in the disorder. Methods A comprehensive literature search was conducted via PubMed, ScienceDirect, Scopus and Web of Knowledge (from 1949 to 31st March 2015) using the keyword 'schizoaffective disorder' and any of the following terms: 'neuropsychology', 'cognition', 'structural neuroimaging', 'functional neuroimaging', 'multimodal', ' DTI' and ' VBM'. Only studies that explicitly examined a well defined sample, or subsample, of patients with schizoaffective disorder were included. Results Twenty-two of 43 neuropsychological and 19 of 51 neuroimaging articles fulfilled inclusion criteria. We found a general trend towards schizophrenia and schizoaffective disorder being related to worse cognitive performance than bipolar disorder. Grey matter volume loss in schizoaffective disorder is also more comparable to schizophrenia than to bipolar disorder which seems consistent across further neuroimaging techniques. Conclusions Neurocognitive and neuroimaging abnormalities in schizoaffective disorder resemble more schizophrenia than bipolar disorder. This is suggestive for schizoaffective disorder being a subtype of schizophrenia or being part of the continuum spectrum model of psychosis, with schizoaffective disorder being more skewed towards schizophrenia than bipolar disorder. [ABSTRACT FROM AUTHOR]

Employers of animal science students value good writing skills. However, trying to develop those skills in our academic programs is challenging, given the amount of material, skills, and opportunities we want students to explore during their undergraduate career. Furthermore, many of us do not feel qualified to teach our students how to write. This article provides ideas for how faculty in the animal sciences can incorporate writing in the classroom that improves students' writing skills and their mastery of concepts. First, design assignments that meet course goals. Identify the most important concepts students need to learn and develop writing assignments in those areas. Provide targeted audiences to facilitate personal comprehension of the subject. Second, put the assignment in writing and discuss it in class. Clarifying the purpose and expectations can reduce anxiety and improve engagement. Third, provide opportunities for students to approach writing as a process. Opportunities for constructive feedback can promote learning important for thorough reflection on the topic. Writing assignments do not have to be long to achieve these goals. Anticipated outcomes include helping students better understand course material by putting ideas into their own words. Students also get a clearer understanding of scientific genres, leading to deeper development of critical thinking skills. If faculty devote time to teaching scientific writing, students will recognize the value of writing. Good writing takes practice. Increasing the number of courses in animal science that incorporate even one or two assignments that include feedback ultimately should improve their written expression. [ABSTRACT FROM AUTHOR]

Herbs are an increasingly popular treatment option for horses with cartilage inflammation, despite a relative paucity of research demonstrating efficacy. The research objective was to evaluate the differential anti-inflammatory and chondroprotective efficacy of a simulated digest of indomethacin and a commercially available herbal product in a cartilage model of osteoarthritis. Cartilage explant was integrated with simulated digestion of indomethacin and the herbal product in order to account, at least in part, for the actions of major digestive enzymes and pH. The resulting digests were ultrafiltrated (50 kDa), to account for absorption from the GI tract and movement into the cartilage matrix. We hypothesized that (i) a simulated digest of indomethacin would block interleukin 1 β-(IL-1) dependent formation of prostaglandin E2 (PGE2) and nitric oxide (NO) without protecting cartilage against IL-1-induced glycosaminoglycan (GAG) release, and (ii) the herbal product would reduce PGE2 and NO in IL-1-stimulated explants, and inhibit release of GAG, in IL-1-stimulated explants. Results showed that indomethacin is an effective anti-inflammatory, evidenced by strong inhibition of IL-1-induced PGE2 and NO from cartilage explants. However, indomethacin provided no protection against IL-1-induced GAG release. Simulated digest of the herbal extract significantly inhibited IL-1-induced NO production and GAG release, while having a slight increase in PGE2. These data provide evidence for the anti-inflammatory effect of indomethacin on IL-1-stimulated cartilage explants, and the herbal product MobilityTM may be a useful adjunct in arthritis because of its chondroprotective properties in IL-1-stimulated cartilage. [ABSTRACT FROM AUTHOR]

Objective: For a long time it was thought that Nietzsche suffered from general paralysis of the insane (GPI). However, this diagnosis has been questioned recently, and alternative diagnoses have been proposed. Method: We have charted Friedrich Nietzsche's final fatal illness, and viewed the differential diagnosis in the light of recent neurological understandings of dementia syndromes. Results: It is unclear that Nietzsche ever had syphilis. He lacked progressive motor and other neurological features of a progressive syphilitic central nervous system (CNS) infection and lived at least 12 years following the onset of his CNS signs, which would be extremely rare for patients with untreated GPI. Finally, his flourish of productivity in 1888 would be quite uncharacteristic of GPI, but in keeping with reports of burgeoning creativity at some point in the progression of frontotemporal dementia (FTD). Conclusion: We suggest that Nietzsche did not have GPI, but died from a chronic dementia, namely FTD. [ABSTRACT FROM AUTHOR]

In a nerve crush model of denervation, we examined muscle matrix metalloproteinase (MMP) expression, localization and activity. In normal muscle, MMP mRNA levels were low, and immunohistochemically MMPs were distributed around the muscle fibre with MMPs-3, -7 and -9 also staining at the neuromuscular junction. Seven days after nerve crush, muscle MMP immunoreactivity, especially MMP-12 and MMP-14, became irregularly distributed. At 20 days reinnervation of the muscle was observed, and some restitution of the normal pattern of immunoreactivity was noted concomitant with a higher level of MMP mRNA expression. In situ zymography showed that MMP activity was very weak in normal muscle whereas it was increased up to 40 days following denervation. Our results suggest that MMPs in muscle are involved in the tissue changes following denervation. Further experiments are required to test the hypothesis that MMP inhibition may be beneficial in protecting muscle from excessive remodelling following denervation and therefore improve reinnervation. [ABSTRACT FROM AUTHOR]

There is evidence that in sporadic amyotrophic lateral sclerosis (ALS) immunological mechanisms may be involved in the pathophysiology of the disease. We tested whether purified IgG from ALS patients induce cell death in rat mixed primary spinal cord cultures and compared this with the effect of IgG purified from patients with Guillain–Barré syndrome (GBS) or from healthy donors. Treatment with ALS-IgG increases caspase-3 apoptosis when compared with control IgG or with GBS-IgG, but does not induce death by necrosis. Because ALS is characterized by the selective loss of motor neurones, we next assessed the differential effect of ALS-IgG on motor neurones or astrocytes. We showed, semiquantitatively, that motor neurones are more susceptible to apoptosis when cultures were treated with ALS-IgG compared with control-IgG. In conclusion, we have demonstrated in primary spinal cord cultures that IgG from patients with ALS induces apoptosis selectively in motor neurones, and that the caspase-3 pathway is involved. This suggests that immunological mechanisms may contribute to the selective loss of motor neurones in ALS. [ABSTRACT FROM AUTHOR]

The pathophysiology of the myelodysplastic syndromes (MDS) involves disturbed regulation of angiogenesis, apoptosis, proliferation and differentiation as well as immune surveillance. Increasing data suggest that sirolimus might affect these pathways positively, thus being of possible therapeutic benefit in patients with this disease. Nineteen patients (n = 19) with a median age of 72 years (range 54–80 years) diagnosed with MDS received sirolimus orally with a target blood concentration of 3–12 ng/ml. Sirolimus was administered for a median of 3·7 months (range 0·3–11 months). Three patients [1 × refractory anaemia with excess blasts (RAEB)-2, 1 × RAEB-1, 1 × refractory cytopenia with multilineage dysplasia] showed either a major (1 × platelet, 1 × neutrophil) or a minor (1 × erythroid, 2 × platelet) haematological response according to International Working Group criteria. Major side-effects were hyperlipidaemia (n = 4), stomatitis (n = 3), thrombocytopenia (n = 2) and urinary tract infection (n = 1). These data suggest that sirolimus has activity in a subset of patients with more advanced MDS. [ABSTRACT FROM AUTHOR]

Abstract Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion in the number of glutamine repeats in the N-terminal region of the huntingtin protein. Nuclear and cytoplasmic aggregates of the N-terminal portion of huntingtin have been found in the brains of HD patients and the brains and non-neuronal tissues of the R6/2 HD transgenic mouse. We have cultured myoblasts and myotubes from transgenic R6/2 mice and littermate controls to investigate the formation of these inclusions in post mitotic cells. Huntingtin immunoreactivity was intense in differentiating, desmin positive myoblasts and myotubes from both control and R6/2 mice suggesting that it may play a role in myotube differentiation. Following differentiation huntingtin and ubiquitin positive aggregates were observed in R6/2 but not control cultures. After 3 weeks in differentiation medium cytoplasmic huntingtin and ubiquitin immunoreactive aggregates were observed in non-myotube cells, while nuclear huntingtin aggregates were seen in a proportion of myotubes after 6 weeks. Growth in the absence of serum resulted in a marked increase in the number of R6/2 myotubes containing nuclear inclusions after 6 weeks demonstrating that environmental factors influenced huntingtin aggregate formation in these cells. Consequently, cultured myotubes from R6/2 mice may be a useful post mitotic cell culture model to study both the biochemical consequences of huntingtin aggregates and the factors that may influence aggregate formation. [ABSTRACT FROM AUTHOR]

Studying individuals with extreme phenotypes could facilitate the understanding of disease modification by genetic or environmental factors. Our aim was to identify Huntington's disease (HD) patients with extreme symbol digit modality test (SDMT) scores. We first examined in HD the contribution of cognitive measures of the Unified Huntington's Disease Rating Scale (UHDRS) in predicting clinical endpoints. The language-independent SDMT was used to identify patients performing very well or very poorly relative to their CAG and age cohort. We used data from REGISTRY and COHORT observational study participants (5,603 HD participants with CAG repeats above 39 with 13,868 visits) and of 1,006 healthy volunteers (with 2,241 visits), included to identify natural aging and education effects on cognitive measures. Separate Cox proportional hazards models with CAG, age at study entry, education, sex, UHDRS total motor score and cognitive (SDMT, verbal fluency, Stroop tests) scores as covariates were used to predict clinical endpoints. Quantile regression for longitudinal language-independent SDMT data was used for boundary (2.5% and 97.5% quantiles) estimation and extreme score analyses stratified by age, education, and CAG repeat length. Ten percent of HD participants had an extreme SDMT phenotype for at least one visit. In contrast, only about 3% of participants were consistent SDMT extremes at two or more visits. The thresholds for the one-visit and two-visit extremes can be used to classify existing and new individuals. The identification of these phenotype extremes can be useful in the search for disease modifiers., (© 2019 Wiley Periodicals, Inc.)

The manifestation of motor signs in Huntington's disease (HD) has a well-known inverse relationship with HTT CAG repeat length, but the prediction is far from perfect. The probability of finding disease modifiers is enhanced in individuals with extreme HD phenotypes. We aimed to identify extreme HD motor phenotypes conditional on CAG and age, such as patients with very early or very late onset of motor manifestation. Retrospective data were available from 1,218 healthy controls and 9,743 HD participants with CAG repeats ≥40, and a total of about 30,000 visits. Boundaries (2.5% and 97.5% quantiles) for extreme motor phenotypes (UHDRS total motor score (TMS) and motor age-at-onset) were estimated using quantile regression for longitudinal data. More than 15% of HD participants had an extreme TMS phenotype for at least one visit. In contrast, only about 4% of participants were consistent TMS extremes at two or more visits. Data from healthy controls revealed an upper cut-off of 13 for the TMS representing the extreme of motor ratings for a normal aging population. In HD, boundaries of motor age-at-onset based on diagnostic confidence or derived from the TMS data cut-off in controls were similar. In summary, a UHDRS TMS of more than 13 in an individual carrying the HD mutation indicates a high likelihood of motor manifestations of HD irrespective of CAG repeat length or age. The identification of motor phenotype extremes can be useful in the search for disease modifiers, for example, genetic or environmental such as medication. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aims: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers., Methods: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers., Results: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen., Conclusions: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range., (© 2014 The British Pharmacological Society.)

Posterior cortical volume changes and abnormal visuomotor performance are present in patients with Huntington's disease (HD). However, it is unclear whether posterior cortical volume loss contributes to abnormal neural activity, and whether activity changes predict cognitive dysfunction. Using magnetic resonance imaging (MRI), we investigated brain structure and visual network activity at rest in patients with early HD (n = 20) and healthy controls (n = 20). The symbol digit modalities test (SDMT) and subtests of the Visual Object and Space Perception Battery were completed offline. For functional MRI data, a group independent component analysis was used. Voxel-based morphometry was employed to assess regional brain atrophy, and 'biological parametric mapping' analyses were included to investigate the impact of atrophy on neural activity. Patients showed significantly worse visuomotor and visual object performance than controls. Structural analyses confirmed occipitotemporal atrophy. In patients and controls, two spatiotemporally distinct visual systems were identified. Patients showed decreased activity in the left fusiform cortex, and increased left cerebellar activity. These findings remained stable after correction for brain atrophy. Lower fusiform cortex activity was associated with lower SDMT performance and with higher disease burden scores. These associations were absent when cerebellar function was related to task performance and disease burden. The results of this study suggest that regionally specific functional abnormalities of the visual system can account for the worse visuomotor cognition in HD patients. However, occipital volume changes cannot sufficiently explain abnormal neural function in these patients., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: The effects of doxycycline were tested in an in vitro system in which the cartilages of embryonic avian tibias are completely degraded., Methods: Tibias were cultured with 5, 20, or 40 microgram/ml doxycycline. Control tibias were cultured without doxycycline. Conditioned media and tissue sections were examined for enzyme activity and matrix loss., Results: Cartilages were not resorbed in the presence of doxycycline, whereas control cartilages were completely degraded. Collagen degradation was reduced in association with treatment with doxycycline at all doses studied. Higher concentrations of doxycycline reduced collagenase and gelatinase activity and prevented proteoglycan loss, cell death, and deposition of type X collagen in the cartilage matrix; in addition, treatment with doxycycline at higher concentrations caused increases in the length of the hypertrophic region., Conclusion: The effects of doxycycline extend beyond inhibition of the proteolytic enzymes by stimulating cartilage growth and disrupting the terminal differentiation of chondrocytes.