Infantile type of Niemann-Pick disease with developmental defects of the central nervous system

Clinical and morphologic manifestations of a rare disease developing, as a rule, in early life--an infantile variant of Niemann-Pick disease--are illustrated with a fatal case of a 6.5-month-old child. The diagnosis was established histochemically using, in particular, Smith-Dietrich method which provided differential diagnosis with cerebroside lipidosis (Gaucher's disease). In addition to typical enlargement of the liver, spleen and lymph nodes, cerebral and adrenal affection there appeared true porencephalia.     

Phenotype delineation of ZNF462 related syndrome

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.     

Potassium model for slow (2-3 Hz) in vivo neocortical paroxysmal oscillations

In slow neocortical paroxysmal oscillations, the de- and hyperpolarizing envelopes in neocortical neurons are large compared with slow sleep oscillations. Increased local synchrony of membrane potential oscillations during seizure is reflected in larger electroencephalographic oscillations and the appearance of spike- or polyspike-wave complex recruitment at 2- to 3-Hz frequencies. The oscillatory mechanisms underlying this paroxysmal activity were investigated in computational models of cortical networks. The extracellular K(+) concentration ([K(+)](o)) was continuously computed based on neuronal K(+) currents and K(+) pumps as well as glial buffering. An increase of [K(+)](o) triggered a transition from normal awake-like oscillations to 2- to 3-Hz seizure-like activity. In this mode, the cells fired periodic bursts and nearby neurons oscillated highly synchronously; in some cells depolarization led to spike inactivation lasting 50-100 ms. A [K(+)](o) increase, sufficient to produce oscillations could result from excessive firing (e.g., induced by external stimulation) or inability of K(+) regulatory system (e.g., when glial buffering was blocked). A combination of currents including high-threshold Ca(2+), persistent Na(+) and hyperpolarization-activated depolarizing (I(h)) currents was sufficient to maintain 2- to 3-Hz activity. In a network model that included lateral K(+) diffusion between cells, increase of [K(+)](o) in a small region was generally sufficient to maintain paroxysmal oscillations in the whole network. Slow changes of [K(+)](o) modulated the frequency of bursting and, in some case, led to fast oscillations in the 10- to 15-Hz frequency range, similar to the fast runs observed during seizures in vivo. These results suggest that modifications of the intrinsic currents mediated by increase of [K(+)](o) can explain the range of neocortical paroxysmal oscillations in vivo.     

Behavioral effects of stimulating positive reward sites in the central tegmentum of rhesus monkeys.

Rhesus monkeys with electrodes chronically implanted in reward sites in central tegmentum were given telemetered brain stimulation while they were free ranging alone or with cagemates. Stimulation seemed to induce a relaxed positive affect as measured by increased huddling, increased lipsmacking, reduced muscle tone, increased solicitation of grooming and increased grooming of other monkeys. Stimulation did not increase dominant/submissive interactions and seemed to have no effect on aggression or fear. These results are very different from those obtained from an anterolateral hypothalamic self-stimulation site and indicate that fibers which provide input from this area to anterolateral hypothalamus are not solely responsible for effects obtained in the anterolateral hypothalamic area.     

Single-tube mixed agglutination test for the detection of staphylococcal protein A.

A simple, rapid mixed agglutination test using sheep erythrocytes (SRBC) sensitized with rabbit hemolysin and intact viable staphylococci is described for the detection of bound staphylococcal protein A. Soluble protein A was heat extracted from 50 clinical isolates as well as the Cowan I and Wood 46 strains of Staphylococcus aureus and titered by a hemagglutination test using sensitized SRBC and dilutions of soluble protein A. Protein A could be detected in all of these supernatants including that of S. aureus Wood 46, a strain generally considered to be protein A negative. These organisms were later retested by the mixed agglutination test and even those staphylococcal isolates expressing very low heat-extractable soluble protein A concentrations (1:2 titers) were positive, confirming the sensitivity of the test. In a screen of clinical isolates, only 4 of 235 (1.8%) coagulase-positive isolates were negative in the mixed agglutination test. Of 25 coagulase-negative isolates, none yielded a positive reaction.     

Self-sustained rhythmic activity in the thalamic reticular nucleus mediated by depolarizing GABAA receptor potentials

Intracellular recordings from reticular thalamic (RE) neurons in vivo revealed inhibitory postsynaptic potentials (IPSPs) between RE cells that reversed and became depolarizing at the hyperpolarized membrane potentials that occur during sleep. These excitatory IPSPs can directly trigger low-threshold spikes (LTSs). The oscillatory mechanisms underlying IPSP-triggered LTSs crowned by spike bursts were investigated in models of isolated RE networks. In a one-dimensional network model, external stimulation evoked waves of excitation propagating at a constant velocity of 25-150 cells per second. In a large-scale, two-dimensional model of the reticular nucleus, the network showed transient or self-sustained oscillations controlled by the maximum conductance of the low-threshold calcium current and the membrane potential. This model predicts that the isolated reticular nucleus could initiate sequences of spindle oscillations in thalamocortical networks in vivo.