Type 1 fucosidosis. Anatomical study

The first Canadian child with complete absence of alpha L-fucosidase is described. The neurological course was characterised by rapid deterioration and he died at the earliest age recorded so far. There are only two published reports of autopsies in this condition to which we add another, together with the ultrastructural findings of a liver biopsy.     

Aging and cognition: facilitation of recent memory in aged nonhuman primates by nimodipine

Impairments of recent memory are a common complaint associated with aging and especially with respect to certain neural pathological conditions that may accompany aging. While this is well recognized, there is little clear evidence for a viable therapeutic treatment. Recently, however, certain investigations have suggested that blocking neuronal calcium channels may be an effective treatment for the memory impairments that are associated with brain injury as well as the memory failures that may occur during aging. The present research supports this suggestion by demonstrating that the dihydropyridine calcium channel blocker, nimodipine, will significantly improve the stabilized performance of 28-29-year-old rhesus monkeys when they are tested on a delayed-response task which depends upon trial-specific, or recent, memory.     

Accumulation of prion protein in the vagus nerve in creutzfeldt–jakob disease

Disease‐associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease‐associated prion protein (PrP^Sc) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt–Jakob disease (CJD), we applied 3 different anti‐PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. Four of 31 VV‐2 type sporadic CJD and 7 of 30 genetic CJD cases showed vagal PrP^Sc immunodeposits with distinct morphology. Thus, PrP^Sc in CJD affects the vagus nerve analogously to α‐synuclein in Parkinson disease. The morphologically diverse deposition of PrP^Sc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrP^Sc. Ann Neurol 2019;85:782–787     

Antidepressant Compounds Can Be Both Pro- and Anti-Inflammatory in Human Hippocampal Cells

Background:

The increasingly recognized role of inflammation in the pathogenesis and prognosis of depression has led to a renewed focus on the immunomodulatory properties of compounds with antidepressant action. Studies have, so far, explored such properties in human blood samples and in animal models.

Methods:

Here we used the more relevant model of human hippocampal progenitor cells exposed to an inflammatory milieu, induced by treatment with IL-1β. This increased the levels of a series of cytokines and chemokines produced by the cells, including a dose- and time-dependent increase of IL-6. We investigated the immunomodulatory properties of four monoaminergic antidepressants (venlafaxine, sertraline, moclobemide, and agomelatine) and two omega-3 polyunsaturated fatty acids (n-3 PUFAs; eicosapentanoic acid [EPA] and docosahexanoic acid [DHA]).

Results:

We found that venlafaxine and EPA were anti-inflammatory: venlafaxine decreased IL-6, with a trend for decreases of IL-8 and IP-10, while EPA decreased the levels of IL-6, IL-15, IL-1RA, and IP-10. These effects were associated with a corresponding decrease in NF-kB activity. Unexpectedly, sertraline and DHA had pro-inflammatory effects, with sertraline increasing IFN-α and IL-6 and DHA increasing IL-15, IL-1RA, IFN-α, and IL-6, though these changes were also associated with a decrease in NF-kB activity, suggesting distinct modes of action. Agomelatine and moclobemide had no effect on IL-6 secretion.

Conclusions:

These observations indicate that monoaminergic antidepressants and n-3 PUFAs have distinctive effects on immune processes in human neural cells. Further characterization of these actions may enable more effective personalization of treatment based on the inflammatory status of patients.     

Overcoming compound interference in fluorescence polarization-based kinase assays using far-red tracers

Kinase-mediated phosphorylation of proteins is critical to the regulation of many biological processes, including cell growth, apoptosis, and differentiation. Because of the central role that kinases play in processes that can lead to disease states, the targeting of kinases with small-molecule inhibitors is a validated strategy for therapeutic intervention. Classic methods for assaying kinases include nonhomogenous enzyme-linked immunosorbent assays or scintillation-based formats using [gamma-(32)P]ATP. However, homogenous fluorescence-based assays have gained in popularity in recent years due to decreased costs in reagent usage through miniaturization, increased throughput, and avoidance of regulatory costs associated with the use of radiation. Whereas the readout signal from a nonhomogenous or radioactive assay is largely impervious to interferences from matrix components (such as library compounds), all homogenous fluorescent assay formats are subject to such interferences. Interference from intrinsically fluorescent compounds or from scattered light due to precipitated compounds can interfere with assays that depend on a fluorescence intensity (or fluorescence quenching), fluorescence resonance energy transfer, or fluorescence polarization-based readout. Because these interfering factors show a greater effect at lower wavelengths, one strategy to overcome such interferences is to develop fluorescent assays using longer wavelength (red-shifted) fluorescent probes. In this article, we describe the PanVera PolarScreen far-red fluorescence polarization assay format, which mitigates assay interference from autofluorescent compounds or scattered light through the use of a far-red tracer. The tracer shows substantially less interference from light scatter or autofluorescent library compounds than do fluorescein-based tracers, and gives rise to a larger assay window than the popular far-red fluorophore Cy5.     

The development of adopted children after institutional care: a follow-up study

BACKGROUND: Research suggests that institutional care has long-lasting effects on children. However, no study has longitudinally studied infants in an institution and their subsequent development at age four. METHODS: Sixty-one adopted children aged four years who had spent their first two years of life in an institution were compared to 39 children reared in their own two-parent families. Cognitive development, security of attachment, shyness, children's emotional understanding and behavioural problems were examined in both groups. Parental health and stress were also assessed. RESULTS: At four years adopted children still had lower scores on cognitive development, were less secure, and less able to understand emotions than family-reared children. Children with a secure attachment type in infancy were found to be less secure at age four, compared with those who were classified in infancy as having an insecure attachment type. Their physical development had recovered, they were less shy, had no behavioural problems and no problems in the relationship with their teacher. CONCLUSIONS: Early residential group care has long-lasting effects on important socio-emotional and cognitive aspects of preschool children's development.     

Alpha-fetoprotein in congenital hypothyroidism.

alpha-Fetoprotein (alpha-FP) was measured in dried blood spots from normal, congenital hypothyroid (CH) and transient hyperthyrotropinemic (TH) newborns as well as in serum from CH and TH babies together with thyroxine, triiodothyronine and thyrotropin. The half-life of alpha-FP had a median value of 12 days in the CH cases and 4.9 days in the TH cases. alpha-FP was significantly higher in the CH group before treatment and showed a significant rise after discontinuation of thyroxine therapy. It would appear that thyroid hormones influence alpha-FP metabolism and that a hypothyroid environment results in increased alpha-FP levels.