Optic nerve head plasmacytoma as a manifestation of multiple myeloma.

Extramedullary disease in multiple myeloma is uncommon and associated with a poorer prognosis. Extramedullary disease involving the orbit is even more unusual, with optic nerve involvement being rare. We describe an optic nerve head plasmacytoma in a 45-year-old female in the setting of systemic relapsed, refractory IgA kappa multiple myeloma. The case highlights the importance of keeping extramedullary disease spread in the differential for vision loss in a patient with a history of multiple myeloma. In addition, it describes an unusual location for presentation of extramedullary disease, the optic nerve head, which has rarely been described.

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.

An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.

Some consequences of normal aging for generating conceptual explanations: A case study of vitalist biology.

Accumulating evidence suggests that not only diseases of old age, but also normal aging, affect elderly adults' ability to draw on the framework theories that structure our abstract causal-explanatory knowledge, knowledge that we use to make sense of the world. One such framework theory, the cross-culturally universal vitalist biology, gives meaning to the abstract concepts life and death. Previous work shows that many elderly adults are animists, claiming that active, moving entities such as the sun and the wind are alive (Zaitchik & Solomon, 2008). Such responses are characteristic of young children, who, lacking an intuitive theory of biology, distinguish animals from non-animals on the basis of a theory of causal and intentional agency. What explains such childlike responses? Do the elderly undergo semantic degradation of their intuitive biological theory? Or do they merely have difficulty deploying their theory of biology in the face of interference from the developmentally prior agency theory? Here we develop an analytic strategy to answer this question. Using a battery of vitalist biology tasks, this study demonstrates-for the first time-that animism in the elderly is due to difficulty in deployment of the vitalist theory, not its degradation. We additionally establish some powerful downstream consequences of theory deployment difficulties, demonstrating that the elderly's use of the agency theory is not restricted to animist judgments-rather, it pervades their explicit reasoning about animates and inanimates. Extending the investigation, we identify specific cognitive mechanisms implicated in adult animism, finding that differences between young and elderly adults are mediated and moderated by differences in inhibition and shifting mechanisms. The analytic strategy developed here could help adjudicate between degradation and deployment in other conceptual domains and other populations.