Tumor cell surface β1–6 branched oligosaccharides and lung metastasis

NIH3T3 cells transfected with an activated Ha-ras oncogene were treated with L-PHA, the leukoagglutinin from red kidney beans. Cell lines resistant to L-PHA-mediated cytotoxicity were isolated and found to contain reduced levels of L-PHA-binding oligosaccharides. The levels of N-acetylglucosaminyltransferase V, the enzyme responsible for the initiation of the1–6 branch, were reduced in L-PHA-resistant cells. Tumorigenicity in nude mice was unchanged by the change in oligosaccharide expression, but the ability to form lung tumors after intravenous injection was significantly reduced. These results demonstrate that the ability of NIH3T3 cells transfected with an activated Ha-ras oncogene to form lung tumors after intravenous injection into nude mice is reduced in all six L-PHA selected cell lines containing a reduction in1–6 branched Asn-linked oligosaccharides.     

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next‐generation sequencing

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.     

Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque

Dystonia is a movement disorder defined by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. To understand the abnormalities in pallidal discharge in dystonia, we have analyzed the spontaneous activity of 453 neurons sampled from the internal or external pallidum (GPi or GPe) of 22 patients with dystonia, 140 neurons from 11 patients with Parkinson's disease (PD), and 157 neurons from two normal non-human primates (NHPs; Macacca mulatta). All recordings were performed without systemic sedation. Mean GPi discharge rate in dystonia was 55.3 +/- 1.3 (SE) Hz. This was significantly lower than in the normal NHPs (82.5 +/-2.5 Hz) and lower than in PD patients (95.2 +/- 2.3 Hz). Mean GPe discharge rate in dystonia (54.0 +/- 1.9 Hz) was lower than in the normal NHPs (69.7 +/- 3.3 Hz) and was indistinguishable from that in PD patients (56.6 +/- 3.5 Hz). Mean GPi discharge rate was inversely correlated with dystonia severity. GPi showed increased oscillatory activity in the 2- to 10-Hz range and increased bursting activity in both dystonia and PD as compared with the normal NHPs. Because the abnormalities in discharge patterns were similar in dystonia compared with PD, we suggest that bursting and oscillatory activity superimposed on a high background discharge rate are associated with parkinsonism, whereas similar bursting and oscillations superimposed on a lower discharge rate are associated with dystonia. Our findings are most consistent with a model of dystonia pathophysiology in which the two striatal cell populations contributing to the direct and indirect intrinsic pathways of the basal ganglia both have increased spontaneous activity.     

Control and controllability: beliefs and behaviour in high and low expressed emotion relatives

BACKGROUND: Expressed emotion (EE) is a measure of the family environment that is a well replicated psychosocial predictor of psychiatric relapse. Theoretical models of EE place heavy emphasis on the notion of control. We explored the extent to which high and low EE relatives made both attributions of control about patients and engaged in controlling behaviours. METHODS: Trained raters who were blind to information about EE coded interviews with 35 relatives of patients with schizophrenia and 42 relatives of patients with unipolar depression. Relatives were rated on two reliable scales that assessed relatives' tendencies to make illness controllability attributions and relatives' efforts to exert direct behavioural control over patients. RESULTS: In both the schizophrenia and depressed groups, high-EE relatives attributed more control to their ill family members than did low EE relatives. They also behaved in a more controlling manner. Examination of patients' clinical outcomes during a 9-month follow-up period revealed that high levels of behavioural control on the part of relatives significantly predicted relapse in patients with schizophrenia but not in patients with depression. CONCLUSIONS: These findings support the attribution-based model of EE. They further suggest that controlling behaviours on the part of relatives may mediate the EE-relapse link in schizophrenia. Such behaviours may be important targets for modification in family-based interventions for schizophrenia.     

Cervicovaginal (Papanicolaou) smear findings in patients with malignant mixed Müllerian tumors

Malignant mixed Müllerian tumor is a rare neoplasm that occurs most frequently in elderly patients. It is characterized by a mixture of malignant epithelial and sarcomatous components. Little has been published about Papanicolaou smear findings pertaining to malignant mixed Müllerian tumors. We present our experience, with an emphasis on cytologic detail. Nine patients (median age, 65 yr) met our study criteria. All available smears and surgical specimens were reviewed. Four smears were positive for malignancy, with a sensitivity of 44% (3 adenocarcinoma, and 1 squamous-cell carcinoma, small-cell type). The results of our study showed that Papanicolaou smear findings pertaining to malignant mixed Müllerian tumors are seen in patients with advanced-stage disease with involvement of the lower uterine segment or cervix. The usual finding is large numbers of high-grade epithelial malignant cells in a necrotic background. The mesenchymal component rarely sheds cells visible on Papanicolaou smear.     

Identification of mutations in TCOF1: use of molecular analysis in the pre- and postnatal diagnosis of Treacher Collins syndrome

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of facial development, which results from mutations in TCOF1. TCS comprises conductive hearing loss, hypoplasia of the mandible and maxilla, downward sloping palpebral fissures and cleft palate. Although, there is usually a reasonable degree of bilateral symmetry, a high degree of both inter- and intrafamilial variability is characteristic of TCS. The wide variation in the clinical presentation of different patients, together with the fact that more than 60% of cases arise de novo, can complicate the diagnosis of mild cases and genetic counselling. In the current study, we describe how molecular techniques have been used to facilitate pre- and postnatal disease diagnoses in 13 TCS families.     

Ethics education in U.S. medical schools: a study of syllabi.

PURPOSE: Despite attempts to describe the "ideal" medical ethics curriculum, few data exist describing current practices in medical ethics education to guide curriculum directors. This study aimed to determine the scope and content of required, formal ethics components in the curricula of U.S. medical schools. METHOD: A questionnaire sent to all curriculum directors of four-year medical schools in the U.S. (n = 121) requested course syllabi for all required, formal ethics components in the four-year curriculum. Syllabi were coded and analyzed to produce a profile of course objectives, teaching methods, course contents, and methods for assessing students. RESULTS: Questionnaires were returned by 87 representatives of the schools (72%). A total of 69 (79%) required a formal ethics course, and 58 (84%) provided their ethics course syllabi. Analysis and codification of all syllabi identified ten course objectives, eight teaching methods, 39 content areas, and six methods of assessing students. The means for individual schools were three objectives, four teaching methods, 13 content areas, and two methods of assessment. The 58 syllabi either required or recommended 1,191 distinct readings, only eight of which were used by more than six schools. CONCLUSIONS: Ethics education is far from homogeneous among U.S. medical schools, in both content and extensiveness. While the study of syllabi demonstrates significant areas of overlap with recent efforts to identify an "ideal" ethics curriculum for medical students, several areas of weakness emerged that require attention from medical educators.     

P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis

Background  

The purinergic receptor P2x7 is expressed on myeloid cells as well as on CNS glial cells, and P2x7 activation has been shown to increase both glial and T-cell activation. These properties suggest a role in the development of autoimmune disease including multiple sclerosis.