Short and middle latency vestibular evoked responses to acceleration in man.

We have succeeded in recording short and middle latency vestibular evoked responses in human subjects. The head was held rigidly in a special, patented head holder, constructed individually for each subject, which gripped the teeth of the upper jaw. The stimulus consisted of 2/sec steps of angular acceleration impulses produced by a special motor with intensities of about 10,000 degrees/sec 2 and with a rise time of 1-2 msec. The electrical activity was recorded as the potential difference between special forehead and mastoid electrodes having a large, secure contact area with the skin. The activity was digitally filtered and averaged in 2 separate channels by means of a Microshev 2000 evoked response system. The short latency responses, with peaks at about 3.5 msec (forehead positive), 6.0 msec (forehead negative) and 8.4 msec (forehead positive; bandpass: 200-2000 Hz; average of 1024 trials), had amplitudes of about 0.5 microV. The middle latency responses had peaks at about 8.8 msec (forehead positive), 18.8 msec (forehead negative) and 26.8 msec (forehead positive; 30-300 Hz; N = 128 trials), with larger amplitudes (about 15 microV). These responses were consistently recorded in the same subject at different times and were similar in different normal subjects. Strenuous control experiments were conducted in order to ensure that these responses are not artefacts due to the movement of conducting media (head, electrodes and leads) in the electromagnetic field of the motor and are elicited by activation of normal labyrinths.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of locomotor activity of polymorphonuclear cells by cationic substances and cationic lysosomal fractions from human neutrophils

Seven cationic substances — human and egg-white lysozyme, RNase, protamine, histone, poly-l-lysine and poly-l-arginine; five cationic lysosomal fractions from human polymorphonuclears (PMNs); RNA; poly-l-glutamic acid; DNA; heparin; endotoxin; mastocytotropic agent compound 48/80; and cytochalasin B were tested for the influence on chemotaxis and random migration of human PMNs using under-agarose migration and Boyden chambers with two filters and [⁵¹Cr]PMNs. The above substances were either preincubated with PMNs, added to chemoattractants, or used instead of chemoattractants. In under-agarose migration method chemotaxis was inhibited by 11–35% when egg-white lysozyme, protamine, heparin, endotoxin, or compound 48/80 was added to the cells. High concentration of cytochalasin B inhibited chemotaxis by 73 %. Cationic fractions I and V and low concentration of cytochalasin B enhanced chemotaxis by 11%, 41%, and 30%, respectively. When human and egg-white lysozyme, DNA, or cytochalasin B was added to the chemoattractants, motility of PMNs was inhibited. Cationic fractions II and V from human PMNs, when used as chemoattractants, enhanced cellular motility by 143–167%. Random migration was enhanced by heparin and inhibited by cytochalasin B and by cationic fractions from human PMNs. These findings suggest that various cationic and anionic substances and cationic fractions from human PMNs have heterogeneous influence on random migration and chemotactic activity of human PMN. Analysis relating chemotaxis to phagocytosis and to intracellular bactericidal activity (ICBA) has shown several patterns. Protamine, poly-l-lysine, poly-l-arginine, and agent compound 40/80 all inhibit chemotaxis and enhance phagocytosis and ICBA; cationic fractions II and V enhanced all three functions, whereas cytochalasin B suppressed phagocytosis and ICBA and had concentration-dependent modulatory influence on chemotaxis. It implies diverse mechanisms of action and possible impact on inflammatory reactions.Supported by agrant-in-aid from the Medical Research Council of Canada.     

Right-left correlation of the sympathetically induced fluctuations of photoplethysmographic signal in diabetic and non-diabetic subjects

Photoplethysmography (PPG) records the cardiac-induced changes in tissue blood volume by light-transmission measurements. The baseline and amplitude of the PPG signal show very low-frequency (VLF) spontaneous fluctuations, which are mediated by the sympathetic nervous system, and high correlation between right and left extremities of healthy subjects. As sympathetic neuropathy is one of the diabetic complications, the right-left correlation of the PPG fluctuations was examined in diabetic patients. The PPG signal was simultaneously measured in the two index fingers and the two second toes of 35 diabetic patients and 33 non-diabetic subjects. For each PPG pulse, the baseline and amplitude were determined, and the right-left correlation coefficients of the VLF fluctuations in the baseline and amplitude were derived. The VLF fluctuations in the baseline showed high right-left correlation, both for fingers (0.93±0.05) and toes (0.93±0.06), for the non-diabetic subjects, and significantly lower correlation (0.78±0.22 and 0.84±0.17, respectively) for the diabetic patients. Similar results were obtained for the amplitude VLF fluctuations. The right-left correlation coefficients for diabetic patients decreased with the disease duration for the toe baseline and toe amplitude fluctuations and correlated with heart rate response to deep breathing for the finger baseline and toe amplitude fluctuations. The right-left correlation coefficients of the PPG fluctuations provide a simple and convenient means for assessing the adequacy of the sympathetic nervous system function.     

A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

The genetic basis of congenital heart malformations associated with disruption of left–right (L–R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left–right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab‐Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left–right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.     

2-Butoxyethanol model of haemolysis and disseminated thrombosis in female rats: a preliminary study of the vascular mechanism of osteoarthritis in the temporomandibular joint

Female rats develop haemolytic anaemia and disseminated thrombosis and infarction in multiple organs, including bone, when exposed to 2-butoxyethanol (BE). There is growing evidence that vascular occlusion of the subchondral bone may play a part in some cases of osteoarthritis. The subchondral bone is the main weight bearer as well as the source of the blood supply to the mandibular articular cartilage. Vascular occlusion is thought to be linked to sclerosis of the subchondral bone associated with disintegration of the articular cartilage. The aim of this study was to find out whether this model of haemolysis and disseminated thrombosis supports the vascular hypothesis of osteoarthritis. Six female rats were given BE orally for 4 consecutive days and the two control rats were given tap water alone. The rats were killed 26 days after the final dose. The mandibular condyles showed histological and radiological features consistent with osteoarthritis in three of the four experimental rats and in neither of the control rats. These results may support the need to explore the vascular mechanism of osteoarthritis further.     

Ubiquitin degradation with its substrate,or as a monomer in a ubiquitination-independent mode,provides clues to proteasome regulation

The mechanisms that regulate the ubiquitin (Ub)-proteasome system''s own components, although critically important, are largely unknown. Ub, a principal component of the system, must be maintained at adequate levels to support cellular homeostasis under basal and stressed conditions. It was suggested that Ub is degraded as part of the polyubiquitin chain along with its substrate. Here, we demonstrate in a direct manner that Ub is indeed degraded in a “piggyback” mechanism. Also, it has been shown that monomeric Ub can be rapidly degraded when a C-terminal tail of a minimal length is fused to it. The tail, which may represent the substrate or part of it, or a naturally occurring extended form of Ub, probably allows entry of the protein into the 20S catalytic chamber, while Ub serves as an anchor to the 19S complex. Here, we show that shorter-tailed Ubs, such as UBB⁺¹, bind to the proteasome but because they cannot be efficiently degraded, they inhibit the degradation of other Ub system''s substrates such as Myc, p21, Mdm2, and MyoD. The inhibition depends on the ability of the tailed Ubs to be ubiquitinated: their mere binding to the proteasome is not sufficient. Interestingly, the inhibition affects only substrates that must undergo ubiquitination for their degradation: ornithine decarboxylase that is targeted by the proteasome in a Ub-independent manner, is not affected by the short-tailed ubiquitinated Ubs, suggesting it binds to the 19S complex in a site different from that to which ubiquitinated substrates bind.     

Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine

BACKGROUNDThe significant risks posed to mothers and fetuses by COVID-19 in pregnancy have sparked a worldwide debate surrounding the pros and cons of antenatal SARS-CoV-2 inoculation, as we lack sufficient evidence regarding vaccine effectiveness in pregnant women and their offspring. We aimed to provide substantial evidence for the effect of the BNT162b2 mRNA vaccine versus native infection on maternal humoral, as well as transplacentally acquired fetal immune response, potentially providing newborn protection.METHODSA multicenter study where parturients presenting for delivery were recruited at 8 medical centers across Israel and assigned to 3 study groups: vaccinated (n = 86); PCR-confirmed SARS-CoV-2 infected during pregnancy (n = 65), and unvaccinated noninfected controls (n = 62). Maternal and fetal blood samples were collected from parturients prior to delivery and from the umbilical cord following delivery, respectively. Sera IgG and IgM titers were measured using the Milliplex MAP SARS-CoV-2 Antigen Panel (for S1, S2, RBD, and N).RESULTSThe BNT162b2 mRNA vaccine elicits strong maternal humoral IgG response (anti-S and RBD) that crosses the placenta barrier and approaches maternal titers in the fetus within 15 days following the first dose. Maternal to neonatal anti-COVID-19 antibodies ratio did not differ when comparing sensitization (vaccine vs. infection). IgG transfer ratio at birth was significantly lower for third-trimester as compared with second trimester infection. Lastly, fetal IgM response was detected in 5 neonates, all in the infected group.CONCLUSIONAntenatal BNT162b2 mRNA vaccination induces a robust maternal humoral response that effectively transfers to the fetus, supporting the role of vaccination during pregnancy.FUNDINGIsrael Science Foundation and the Weizmann Institute Fondazione Henry Krenter.