An evaluation of the polymorphisms Ins16bp and Arg72Pro in p53 as breast cancer risk modifiers in BRCA1 and BRCA2 mutation carriers

The close functional relationship between p53 and the breast cancer susceptibility genes BRCA1 and BRCA2 has promoted the investigation of various polymorphisms in the p53 gene as possible risk modifiers in BRCA1/2 mutation carriers. Specifically, two polymorphisms in p53, c.97-147ins16bp and p.Arg72Pro have been analysed as putative breast cancer susceptibility variants, and it has been recently reported that a p53 haplotype combining the absence of the 16-bp insertion and the presence of proline at codon 72 (No Ins-72Pro) was associated with an earlier age at the onset of the first primary tumour in BRCA2 mutation carriers in the Spanish population. In this study, we have evaluated this association in a series of 2932 BRCA1/2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.     

Homeostatic regulation of axonal Kv1.1 channels accounts for both synaptic and intrinsic modifications in the hippocampal CA3 circuit

Homeostatic plasticity of intrinsic excitability goes hand in hand with homeostatic plasticity of synaptic transmission. However, the mechanisms linking the two forms of homeostatic regulation have not been identified so far. Using electrophysiological, imaging, and immunohistochemical techniques, we show here that blockade of excitatory synaptic receptors for 2 to 3 d induces an up-regulation of both synaptic transmission at CA3–CA3 connections and intrinsic excitability of CA3 pyramidal neurons. Intrinsic plasticity was found to be mediated by a reduction of Kv1.1 channel density at the axon initial segment. In activity-deprived circuits, CA3–CA3 synapses were found to express a high release probability, an insensitivity to dendrotoxin, and a lack of depolarization-induced presynaptic facilitation, indicating a reduction in presynaptic Kv1.1 function. Further support for the down-regulation of axonal Kv1.1 channels in activity-deprived neurons was the broadening of action potentials measured in the axon. We conclude that regulation of the axonal Kv1.1 channel constitutes a major mechanism linking intrinsic excitability and synaptic strength that accounts for the functional synergy existing between homeostatic regulation of intrinsic excitability and synaptic transmission.

Chronic modulation of activity regimes in neuronal circuits induces homeostatic plasticity. This implicates a regulation of both intrinsic excitability (homeostatic plasticity of intrinsic excitability) and synaptic transmission (homeostatic plasticity of synaptic transmission) to maintain network activity within physiological bounds (1). In most cases, these two forms of homeostatic plasticity act synergistically but involve different molecular actors. Homeostatic intrinsic plasticity is associated with the regulation of voltage-gated ion channels (2–9), while homeostatic synaptic plasticity involves the regulation of postsynaptic receptors to neurotransmitters (10–17) or the regulation of the readily releasable pool of synaptic vesicles (18–20). However, the function of voltage-gated ion channels is not limited to the control of intrinsic excitability. Several studies point to the role of axonal voltage-gated channels in shaping presynaptic action potential (AP) waveform and subsequently controlling neurotransmitter release and synaptic transmission (21–35). Moreover, some studies describe homeostatic plasticity of the AP waveform via voltage-gated channel regulation (36–38), while other studies report an absence of this phenomenon (39).Kv1.1 channels are responsible for the fast-activating, slow-inactivating D-type current (I_D) in CA3 neurons. This current has been shown to create a delay in the onset of the first AP and to determine intrinsic excitability in various neuronal types, including CA1 and CA3 pyramidal neurons of the hippocampus (3, 40), L5 pyramidal neurons of the cortex (26, 34), and L2/3 fast-spiking interneurons of the somatosensory cortex (41, 42). Furthermore, Kv1.1 channels have been shown to control axonal AP width and subsequently presynaptic calcium entry and neurotransmitter release. In fact, pharmacological blockade of Kv1.1 channels broadens presynaptic APs and increases synaptic transmission at neocortical and hippocampal glutamatergic synapses and at cerebellar GABAergic synapses (21, 22, 26, 30, 32, 41, 43, 44). Moreover, Kv1.1 channels have been shown to be responsible for the phenomenon of depolarization-induced analog digital facilitation of synaptic transmission (d-ADF). In fact, at CA3–CA3 and L5–L5 synapses, a somatic subthreshold depolarization of the presynaptic cell leads to inactivation of axonal Kv1.1 channels, inducing the broadening of the presynaptic AP, an increase in spike-evoked calcium entry, and a facilitation of presynaptic glutamate release (26, 31, 33, 34, 45, 46). Therefore, Kv1.1 channels control both intrinsic excitability and glutamate release in CA3 pyramidal neurons.Kv1.1 channels have been shown to be involved in homeostatic regulation of neuronal excitability. Chronic activity enhancement by kainate application leads to an increase in I_D current and a decrease in excitability in dentate gyrus granule cells (47). Conversely, chronic sensory deprivation leads to Kv1.1 channel down-regulation and enhancement of excitability in the avian cochlear nucleus (48). In this study, we examined whether the increase in synaptic transmission could also be due to Kv1.1 channel down-regulation, which would possibly explain the observed synergy between homeostatic plasticity of excitability and synaptic transmission.We show here that chronic activity deprivation induced with an antagonist of ionotropic glutamate receptors (kynurenate) in hippocampal organotypic cultures provokes both an increase in CA3 pyramidal cells excitability and an enhancement of synaptic transmission at monosynaptically connected CA3 neurons. Deprived cultures display a decrease in Kv1.1 channel staining in the axon initial segment. Bath application of dendrotoxin-K (DTX-K), a selective blocker of Kv1.1 channels, leads to a larger excitability increase in control cultures than in deprived cultures. Focal puffing of DTX-K on the axon increases excitability in control but not in deprived cultures, showing that homeostatic plasticity of excitability in deprived cultures is partly due to the down-regulation of axonal Kv1.1 channels. In addition, we found that axonal Kv1.1 down-regulation in deprived cultures is responsible for a spike broadening in CA3 neurons, leading to elevated release probability at CA3–CA3 synapses. Consistent with these observations, d-ADF, a Kv1.1-dependent form of synaptic facilitation, is present in control cultures but not in deprived cultures. Altogether, these results show that chronic activity blockade of the hippocampal CA3 circuit induces the down-regulation of axonal Kv1.1 channels leading to a homeostatic increase in both excitability and presynaptic release probability.     

SARS-CoV-2 Omicron variant BA.2 neutralisation in sera of people with Comirnaty or CoronaVac vaccination,infection or breakthrough infection,Hong Kong, 2020 to 2022

BackgroundOmicron subvariant BA.2 circulation is rapidly increasing globally.AimWe evaluated the neutralising antibody response from vaccination or prior SARS-CoV-2 infection against symptomatic infection by BA.2 or other variants.MethodsUsing 50% plaque reduction neutralisation tests (PRNT₅₀), we assessed neutralising antibody titres to BA.2, wild type (WT) SARS-CoV-2 and other variants in Comirnaty or CoronaVac vaccinees, with or without prior WT-SARS-CoV-2 infection. Titres were also measured for non-vaccinees convalescing from a WT-SARS-CoV-2 infection. Neutralising antibodies in BA.2 and BA.1 breakthrough infections and in BA.2 infections affecting non-vaccinees were additionally studied.ResultsIn vaccinees or prior WT-SARS-CoV-2-infected people, BA.2 and BA.1 PRNT₅₀ titres were comparable but significantly (p < 10 ^− 5) lower than WT. In each group of 20 vaccinees with (i) three-doses of Comirnaty, (ii) two CoronaVac followed by one Comirnaty dose, or (iii) one dose of either vaccine after a WT-SARS-CoV-2 infection, ≥ 19 individuals developed detectable (PRNT₅₀ titre ≥ 10) antibodies to BA.2, while only 15 of 20 vaccinated with three doses of CoronaVac did. Comirnaty vaccination elicited higher titres to BA.2 than CoronaVac. In people convalescing from a WT-SARS-CoV-2 infection, a single vaccine dose induced higher BA.2 titres than three Comirnaty (p = 0.02) or CoronaVac (p = 0.00001) doses in infection-naïve individuals. BA.2 infections in previously uninfected and unvaccinated individuals elicited low (PRNT₅₀ titre ≤ 80) responses with little cross-neutralisation of other variants. However, vaccinees with BA.1 or BA.2 breakthrough infections had broad cross-neutralising antibodies to WT viruses, and BA.1, BA.2, Beta and Delta variants.ConclusionsExisting vaccines can be of help against the BA.2 subvariant.     

Neurosurgery in a patient with severe hemophilia B: an experience using eftrenonacog alfa as perioperative management

Extended half‐life FIX (EHL‐FIX) concentrates have been developed with the purpose of reducing the frequency of infusions in patients with severe or moderate hemophilia B. We describe the case of a 63‐year‐old patient with severe hemophilia B (sHB) treated with FIX‐Fc fusion protein (rFIXFc) who underwent neurosurgery.     

<Emphasis Type="Italic">CYP1A1</Emphasis>gene polymorphisms increase lung cancer risk in a high-incidence region of Spain: a case control study

Background  

A rural region in south-west Spain has one of the highest lung cancer incidence rates of the country, as revealed by a previous epidemiological 10-year follow-up study. The present work was undertaken to ascertain the role of CYP1A1 gene polymorphisms and their interaction with tobacco smoking in the development of the disease in this location.     

HIV-1-infection in a man who has sex with men despite self-reported excellent adherence to pre-exposure prophylaxis,the Netherlands,August 2021: be alert to emtricitabine/tenofovir-resistant strain transmission

In August 2021, a man who has sex with men was diagnosed with HIV-1 infection despite using event-driven pre-exposure prophylaxis for over 2 years with self-reported excellent adherence. Sequencing identified resistance-associated mutations (RAM) M184V and K65R, conferring resistance to emtricitabine and tenofovir, and RAM V108I and E138A. Background RAM prevalence was two of 164 (1.2%) new HIV diagnoses in Amsterdam (2017–19). We reiterate the need for frequent HIV testing among PrEP users and additional testing in case of symptoms.     

Effectiveness of Toothpastes on SARS-CoV-2 Viral Load in Saliva

IntroductionThe effect of toothpastes on viruses, such as SARS-CoV-2, is unknown. This study investigated the short-term effect of toothpastes containing antimicrobial properties in patients with novel coronavirus disease 2019 (COVID-19) to determine whether they could reduce the SARS-CoV-2 salivary viral load.MethodsHospitalised patients with COVID-19 (n = 83) were instructed to perform toothbrushing with 1 of 3 arms: a toothpaste containing 0.96% zinc (zinc oxide, zinc citrate) in a silica base (Test 1), a toothpaste containing 0.454% SnF₂ in a silica base (Test 2), and a nonantibacterial toothpaste (control). Saliva was collected before intervention (T0), immediately after intervention (T1), and 30 (T2) and 60 minutes (T3) after intervention. The SARS-CoV-2 salivary viral load was measured using quantitative real-time polymerase chain reaction (qRT-PCR) assays. For Test 1 and Test 2 toothpastes, the fold reductions were normalised to baseline and to the control toothpaste at each time point after brushing. A fold change of ≥2 is considered clinically effective.ResultsBrushing with the Test 1 toothpaste reduced the SARS-CoV-2 salivary viral load by 4.06-fold at T1, by 2.36-fold at T2, and by 1.42-fold at T3. Similarly, brushing with a Test 2 toothpaste reduced the SARS-CoV-2 salivary viral load by 2.33-fold at T1, by 2.38-fold at T2, and by 0.77-fold at T3.ConclusionsImmediately after brushing, the use of antimicrobial toothpastes reduced the salivary viral load of patients with COVID-19. The trial was registered on https://clinicaltrials.gov/ (NCT04537962).     

Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson's disease

We recently showed that mutation of the VPS35 gene can cause late-onset Parkinson's disease. In the present study we sequenced 702 affected subjects from the Mayo Clinic Parkinson's disease patient-control series for the VPS29 and VPS26A/B genes. We identified only 2 rare nonsynonymous variants in the VPS26A p.K93E and VPS29 p.N72H. The results show that mutations in the genes composing the retromer cargo recognition subunit are not a common cause of Parkinson's disease.