Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor

Aims/hypothesis  

Insulin analogues were developed to improve the pharmacological properties of injected insulin and to better mimic endogenous insulin output. However, certain insulin analogues have been suggested to display IGF-I-like biological activities. Furthermore, several recent epidemiological studies have suggested a potential increase in cancer risk for treatment of diabetes patients with long-acting analogue insulin glargine (A21Gly,B31Arg,B32Arg human insulin). Additional studies, however, reported no increased cancer risk. The purpose of the present study was to identify the receptor(s) and signal transduction pathways responsible for the biological actions of insulin glargine and insulin detemir (B29Lys[ε-tetradecanoyl],desB30 human insulin).     

Relevance of basic research to clinical data: Good answers, wrong questions!

What conclusions can be derived from experimental data on human epilepsies? This review discusses these issues, notably concerning human temporal lobe epilepsies (TLEs) and infantile epilepsies, where important advances have been achieved in both theory and the comprehension of epileptogenic mechanisms. A wide spectrum of human and animal data converge to show that the naive network transforms to one that generates seizures spontaneously. Thus, in TLE, experimental and human data suggest that the inaugurating status generates a sequence of events that lead to the sprouting of fibers and the formation of novel excitatory synapses. This reactive plasticity constitutes a basis for the generation of novel seizures by the epileptic network. Similarly, in vitro studies indicate that in immature hippocampal formation, the propagation of high- but not low-frequency seizures can transform a naive network into one that generates further seizures, thereby, giving an indication as to the types of seizure that are epileptogenic. In conclusion, it is suggested that although animal data cannot mimic human seizures in all their complex and variable etiologies, it provides essential indications on the mechanisms that enable seizure generation.     

Childbirth anxieties in the shadow of COVID-19: Self-compassion and social support among Jewish and Arab pregnant women in Israel

The study examined two angles of childbirth anxieties of Jewish and Arab pregnant women in Israel during the COVID-19 pandemic (March-April, 2020). Specifically, we examined the contribution of personal resources: self-compassion and perceived social support, as well as a couple of COVID-19-related fears of being infected and concern for the foetus, to both the woman's global fear of childbirth (FOC) and her COVID-19-related childbirth anxiety. Participants were Jewish and Arab pregnant women (n = 403) aged 20–47, who completed a set of structured self-report questionnaires from 18 March to 9 April 2020. Findings indicated that Arab women reported higher level of COVID-19-related childbirth anxiety and COVID-19-related fears of being infected and concern for the foetus. In addition, poorer health, being an Arab woman, being in the third trimester, lower self-compassion, and higher COVID-19-related fears contributed significantly to greater COVID-19-related childbirth anxiety. Furthermore, poorer health, being primiparous, at-risk pregnancy, lower self-compassion and higher fear of being infected contributed significantly to greater FOC. Importantly, social support was found to moderate the association between self-compassion and FOC. The results highlight the need to be attentive to pregnant women in times of crisis, and in particular to especially vulnerable subgroups, such as cultural minorities. They also highlight the importance of personal resources that may be applied in targeted interventions to reduce distress in vulnerable populations.     

Early sequential formation of functional GABA(A) and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus

During postnatal development of CA1 pyramidal neurons, GABAergic synapses are excitatory and established prior to glutamatergic synapses. As interneurons are generated before pyramidal cells, we have tested the hypothesis that the GABAergic interneuronal network is operative before glutamate pyramidal neurons and provides the initial patterns of activity. We patch-clamp recorded interneurons in foetal (69 neurons) and neonatal P0 (162 neurons) hippocampal slices and performed a morphofunctional analysis of biocytin-filled neurons. At P0, three types of interneurons were found: (i) non-innervated "silent" interneurons (5%) with no spontaneous or evoked synaptic currents; (ii) G interneurons (17%) with GABA(A) synapses only; and (iii) GG interneurons with GABA and glutamatergic synapses (78%). Relying on the neuronal capacitance, cell body size and arborization of dendrites and axons, the three types of interneurons correspond to three stages of development with non-innervated neurons and interneurons with GABA(A) and glutamatergic synapses being, respectively, the least and the most developed. Recordings from both pyramidal neurons and interneurons in foetuses (E18-20) revealed that the majority of interneurons (65%) had functional synapses whereas nearly 90% of pyramidal neurons were quiescent. Therefore, interneurons follow the same GABA-glutamate sequence of synapse formation but earlier than the principal cells. Interneurons are the source and the target of the first synapses formed in the hippocampus and are thus in a position to modulate the development of the hippocampus in the foetal stage.     

Treating Fragile X syndrome with the diuretic bumetanide: a case report

We report that daily administration of the diuretic NKCC1 chloride co‐transporter, bumetanide, reduces the severity of autism in a 10‐year‐old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double‐blind clinical trial is warranted to test the efficacy of bumetanide in FRX. Conclusion: This single case report showed an improvement of the scores of each test used after 3 months of treatment. Double‐blind clinical trials are warranted to test the efficacy of bumetanide in FRX.     

Epilepsy induced collateral sprouting of hippocampal mossy fibers: Does it induce the development of ectopic synapses with granule cell dendrites?

In the present study, using Golgi and electron microscopy techniques, experimentally induced epilepsy (kindling and kainate treatment) elicited collateral sprouting of mossy fibers in rat hippocampus. Collateral branches invade the hilus, cross the granule cell layer, and distribute throughout the inner third of the molecular layer. These newly developed collaterals may acquire the typical features of mossy fibers including giant fiber varicosities (mousses), although the mean surface of these mousses was thinner in these collaterals than in terminal branches. Granule cell dendrites may develop giant thorny excrescences, suggesting that the targets of these collaterals are granule cells. Giant synaptic boutons appear in the inner third of molecular layer of epileptic rats. These boutons acquire the morphological features of mossy fiber boutons and made multiple synaptic contacts with dendritic spines. The analysis of the profile types suggests that some of the newly developed collateral mossy fibers made hypotrophic synaptic contacts.