From Individual To Social Trauma: Sources Of Everyday Trauma In Italy, The US And UK During The Covid-19 Pandemic.

The heterogeneity of COVID-19 experience and response for each individual is irrefutable; nevertheless, similarities can be observed between countries with respect to people's psychological responses. The main aim of this Commentary is to provide a cultural perspective of the sources of trauma, at the individual and social level, in three different countries: Italy, US and UK. The evidence from previous outbreaks, such as SARS, H1N1 flu, Ebola, and the ongoing Italian, the US, and the UK experience of COVID-19 shows that COVID-19 has introduced not only an individual trauma but also a collective trauma, that researchers should attend to now and in future global emergencies. Future clinical interventions should aim to reconnect dissociated parts both in the individual and in society. This commentary discusses four potential sources of trauma: high-stakes decision fatigue in healthcare professionals, traumatic grief, and bereavement in people who have lost loved ones, loss of roles and identity, and social divisions related to economic shutdown.

Laboratory 20-km cycle time trial reproducibility.

This study evaluated the reproducibility of laboratory based 20-km time trials in well trained versus recreational cyclists. Eighteen cyclists (age = 34 +/- 8 yrs; body mass index = 23.1 +/- 2.2 kg/m (2); VO(2max) = 4.19 +/- 0.65 L/min) completed three 20-km time trials over a month on a Velotron cycle ergometer. Average power output (PO) (W), speed, and heart rate (HR) were significantly lower in the first time trial compared to the second and third time trial. The coefficients of variation (CV) between the second and third trial of the top eight performers for average PO, time to completion, and speed were 1.2 %, 0.6 %, 0.5 %, respectively, compared to 4.8 %, 2.0 %, and 2.3 % for the bottom ten. In addition, the average HR, VO(2), and percentage of VO(2max) were similar between trials. This study demonstrated that (1) a familiarization session improves the reliability of the measurements (i.e., average PO, time to completion and speed), and (2) the CV was much smaller for the best performers.

Differential sensitivity to apoptosis between the human small and large intestinal mucosae: linkage with segment-specific regulation of BCL-2 homologs and involvement of signaling pathways.

The small and large intestines differ in their expression profiles of Bcl-2 homologs. Intestinal segment-specific Bcl-2 homolog expression profiles are acquired as early as by mid-gestation (18-20 weeks) in man. In the present study, we examined the question whether such distinctions underlie segment-specific control mechanisms of intestinal cell survival. Using mid-gestation human jejunum and colon organotypic cultures, we analyzed the impact of growth factors (namely insulin; 10 microg/ml) and pharmacological compounds that inhibit signal transduction molecules/pathways (namely tyrosine kinases, Fak, P13-K/Akt, and MEK/Erk) on cell survival and Bcl-2 homolog expression (anti-apoptotic: Bcl-2, Bcl-X(L), Mcl-1; pro-apoptotic: Bax, Bak, Bad). The relative activation levels of p125Fak, p42Erk-2, and p57Akt were analyzed as well. Herein, we report that (1) the inhibition of signal transduction molecules/pathways revealed striking differences in their impact on cell survival in the jejunum and colon (e.g., the inhibition of p125Fak induced apoptosis with a significantly greater extent in the jejunum [approximately 43%] than in the colon [approximately 24%]); (2) sharp distinctions between the two segments were noted in the modulatory effects of the various treatments on Bcl-2 homolog steady-state levels (e.g., inhibition of tyrosine kinase activities in the jejunum down-regulated all anti-apoptotics analyzed while increasing Bax, whereas the same treatment in the colon down-regulated Bcl-X(L) only and increased all pro-apoptotics); and (3) in addition to their differential impact on cell survival and Bcl-2 homolog expression, the MEK/Erk and P13-K/Akt pathways were found to be distinctively regulated in the jejunum and colon mucosae (e.g., insulin in the jejunum increased p42Erk-2 activation without affecting that of p57Akt, whereas the same treatment in the colon decreased p42Erk-2 activation while increasing that of p57Akt). Altogether, these data show that intestinal cell survival is characterized by segment-specific susceptibilities to apoptosis, which are in turn linked with segmental distinctions in the involvement of signaling pathways and the regulation of Bcl-2 homolog steady-state levels. Therefore, these indicate that cell survival is subject to segment-specific control mechanisms along the proximal-distal axis of the intestine.

Early acquisition of bowel segment-specific Bcl-2 homolog expression profiles during development of the human ileum and colon.

The adult small and large intestines display distinct expression profiles of Bcl-2 homologs, known regulators of apoptosis. This is thought to indicate that control mechanisms of intestinal apoptosis are gut segment-specific. Little is known on the expression of Bcl-2 homologs during gut development. In man, intestinal features and functions are acquired largely by mid-gestation (18-20 wks); the question whether segment-specific controls of intestinal apoptosis are also acquired early during development remains open. In the present study, we approached this by investigating the expression of six Bcl-2 homologs (Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, Bad), and one nonhomologous associated molecule (Bag-1), during development of the human ileum and colon (12-20 wks of gestation). Beginning at 18 wks, we found that the epithelial localization of Bcl-2 homologs displayed differential patterns (or gradients) in both the ileum and colon; however, the patterns of some of the homologs differed between the two segments. For instance, Bag-1 and Bcl-2 exhibited crypt-villus decreasing gradients of expression in the ileum but not in the colon, whereas Mcl-1 displayed differing compartimentalizations between the two segments. Further analyses indicated that the steady-state expression levels of Bcl-2 homologs underwent modulations between 12 and 20 wks; however, the observed developmental profiles contrasted significantly between the two segments. For example, Bcl-2, Bag-1 and Bak levels increased in the colon, but the levels of these same homologs decreased in the ileum. Furthermore, by 18-20 wks, we found that the expression levels of each Bcl-2 homolog analyzed differed greatly between the ileum and colon. Altogether, these data indicate that the expression of Bcl-2 homologs is modulated differentially during human gut development in order to establish, by mid-gestation, distinct expression profiles for the small and large intestines. This in turn suggests that gut segment-specific control mechanisms of human intestinal apoptosis are acquired early during fetal life.

Human intestinal epithelial cell survival: differentiation state-specific control mechanisms.

To investigate whether human intestinal epithelial cell survival involves distinct control mechanisms depending on the state of differentiation, we analyzed the in vitro effects of insulin, pharmacological inhibitors of Fak, MEK/Erk, and PI3-K/Akt, and integrin (beta1, beta4)-blocking antibodies on the survival of the well-established human Caco-2 enterocyte-like and HIEC-6 cryptlike cell models. In addition, relative expression levels of six Bcl-2 homologs (Bcl-2, Bcl-X(L), Mcl-1, Bax, Bak, and Bad) and activation levels of Fak, Erk-2, and Akt were analyzed. Herein, we report that 1) the enterocytic differentiation process results in the establishment of distinct profiles of Bcl-2 homolog expression levels, as well as p125(Fak), p42(Erk-2), and p57(Akt) activated levels; 2) the inhibition of Fak, of the MEK/Erk pathway, or of PI3-K, have distinct impacts on enterocytic cell survival in undifferentiated (subconfluent Caco-2, confluent HIEC-6) and differentiated (30 days postconfluent Caco-2) cells; 3) exposure to insulin and the inhibition of Fak, MEK, and PI3-K resulted in differentiation state-distinct modulations in the expression of each Bcl-2 homolog analyzed; and 4) Fak, beta1 and beta4 integrins, as well as the MEK/Erk and PI3-K/Akt pathways, are distinctively involved in cell survival depending on the state of cell differentiation. Taken together, these data indicate that human intestinal epithelial cell survival is regulated according to differentiation state-specific control mechanisms.

Early establishment of epithelial apoptosis in the developing human small intestine.

In the adult small intestine, the dynamic renewal of the epithelium is characterized by a sequence of cell production in the crypts, cell maturation and cell migration to the tip of villi, where apoptosis is undertaken. Little is known about enterocytic apoptosis during development. In man, intestinal architectural features and functions are acquired largely by mid-gestation (18-20 wks); the question whether the establishment of enterocytic apoptotic processes parallels or not the acquisition of other intestinal functional features remains open. In the present study, we approached this question by examining enterocytic apoptosis during development of the human jejunum (9-20 wks gestation), using the ISEL (in situ terminal uridine deoxynucleotidyl nick-end labelling) method. Between 9 and 17 wks, apoptotic enterocytes were not evidenced. However, beginning at the 18 wks stage, ISEL-positive enterocytes were regularly observed at the tip of villi. Since the Bcl-2 family of proteins constitutes a critical checkpoint in apoptosis, acting upstream of the apoptotic machinery, we investigated the expression of six Bcl-2 homologs (Bcl-2, Bcl-X(L), Mcl-1, Bax, Bak, Bad) and one non-homologous associated molecule (Bag-1). By immunofluorescence, we found that all homologs analyzed were expressed by enterocytes between 9 and 20 wks. However, Bcl-2 homologs underwent a gradual compartmentalization of epithelial expression along the maturing crypt-villus axis, to establish gradients of expression by 18-20 wks. Western blot analyses indicated that the expression levels of Bcl-2 homologs were modulated during morphogenesis of the crypt-villus axis, in parallel to their gradual compartmentalization of expression. Altogether, these data suggest that regulatory mechanisms of human enterocytic apoptosis become established by mid-gestation (18-20 wks) and coincide with the maturation of the crypt-villus axis of cell proliferation, differentiation and renewal.

Quantitative and qualitative alterations of long-term culture-initiating cells in patients with acute leukaemia in complete remission.

Bone marrow (BM) samples from 24 patients with acute leukaemia (AML 17, ALL seven) in first complete remission were compared to samples from 10 normal donors with regard to their content in long-term culture-initiating cells (LTC-IC) as assessed by a limiting dilution assay and the clonogeneic capacity of these cells, in order to determine whether remission marrow cells displayed any specific defect at the primitive stem cell level. The frequency of LTC-IC in the whole patient group was 1 in 3487 +/- 3125 mononuclear cells (MNC) as compared to 1 in 794 +/- 492 MNC in normal controls (P = 0.0009), with no difference between AML and ALL. Moreover, the clonogeneic capacities were 2.66 +/- 0.7 (range 1.8-1.6) and 4.0 +/- 1.6 (range 2.2-7.9) CFC per LTC-IC in patients and controls respectively (P = 0.0015). These quantitative and qualitative defects were aggravated by treatment with mafosfamide at a dose of 50 microg/10(7) MNC/ml, where the mean recovery of LTC-IC after in vitro purging was 42%. In nine patients autografted with purged marrow following high-dose radiochemotherapy, no correlation could be detected between the dose of LTC-IC (mean 6742 +/- 7877/kg) and the kinetics of recovery of haemopoiesis. We concluded that, in acute leukaemia patients in complete remission, the presumably normal residual stem cell pool was not only quantitatively diminished but also qualitatively altered in its capacity to give rise to clonogeneic progenitor cells.

Comparison of the effects of M1 and M2 muscarinic receptor activation in the absence of GABAergic inhibition in immature rat hippocampal CA3 area.

We have reported previously that addition of carbachol (CCh, 25 microM) in the presence of the GABAA antagonist bicuculline (BMI, 10 microM), depresses evoked synaptic responses and significantly increases the frequency of spontaneous synchronous discharges in immature (postnatal days 10-20, P10-P20) hippocampus in vitro. The present experiments were designed in order to compare the activity of CCh with that of the selective muscarinic agonists McN-A-343 (M1 agonist) and oxotremorine-M (M2 agonist), in inducing the above-mentioned effects. Cholinergic agonists were tested in concentrations ranging from 2.5 nM to 5 microM and synaptic field potentials (evoked, spontaneous) were recorded from the CA3 pyramidal layer of hippocampal slices in the presence of BMI (10 microM). Depression of the evoked responses was measured as decrease (i) in their duration, (ii) in the number of population spikes/response, and (iii) in the amplitude of the first population spike of each sequence. Sigmoid dose-response curves were plotted, and the IC50s were calculated. For all three indexes, the profile of effectiveness was Oxotremorine-M>carbachol=McN-A-343. CCh and oxotremorine-M induced or increased the frequency of spontaneous synchronous discharges in the presence of BMI in a concentration-dependent manner. At the range of concentrations tested, McN-A-343 did not mimic this effect. In conclusion, our results suggest that M2 muscarinic receptors play a major role in both the depression of synaptic responses and the increase in the frequency of spontaneous synchronous discharges observed in the absence of GABAergic inhibition.

Decreased dopamine in the retinas of patients with Parkinson's disease.

Dopamine and it metabolites dihydroxyphenylacetic acid and homovanillic acid were measured in the retinas of eight patients with Parkinson's disease who died. They were divided into two groups according to their last dose of levodopa therapy. One group of three patients had not received levodopa therapy for at least 5 days before death, and the other group of five patients had received therapy 2-15 hours before death. Each patient was matched with controls for delay between death and freezing. In the three patients without levodopa therapy, the retinal dopamine content was lower than normal. In the five patients who received levodopa therapy before death, the retinal dopamine content was similar to that in the controls. This study is the first direct evidence to the authors' knowledge that retinal dopamine concentration is decreased in Parkinson's disease, as it is in the nigrostriatal pathway.

11p13 deletion, Wilms' tumour, and aniridia: unusual genetic, non-ocular and ocular features of three cases.

Three cases of Wilms' tumour and sporadic aniridia were followed up for periods ranging from 32 months to seven years. All had a deletion of the short arm of the eleventh chromosome 11p13, including one case with mosaicism, a cytogenetic feature that has not been previously described in the Wilms' tumour and sporadic aniridia association. Unusual non-ocular features found in all patients included tracheomalacia and delayed closure of the anterior fontanelle. In two cases tracheomalacia was responsible for respiratory distress after general anaesthesia. Wilms' tumour developed bilaterally in one patient and on the isthmus of a horseshoe kidney in another patient. In addition to the more commonly observed ocular features the presence of a corneal pannus was noted before 38 months of age in all patients and as early as 17 months in one case. An iridocorneal adherence with an overlying corneal opacity (presumably related to abnormal developmental cleavage of the anterior segment) was noted in one eye only of the mosaicism case.

Retinal dopamine sensitivity to MPP+ toxicity: electrophysiological and biochemical evaluation.

This study concerns the effect of intravitreal injection of 1-methyl-4-phenylpyridinium ion (MPP+) on the electroretinograms (ERG) and on the levels of retinal dopamine (DA) in rabbits. The right eye was injected intravitreously with MPP+ while the other received only the vehicle and served as control. The administration of 7, 40, 70 or 700 micrograms MPP+ resulted in a dose-related decrease of the amplitude of the a and b-waves as well as the oscillatory potentials (OPs) of the ERG, down to extinction. In contrast, the retinal DA content was decreased only with the 700 micrograms MPP+ dose. Fluorescein angiography demonstrated abnormalities in the retinal circulation of all MPP+-treated eyes. These observations indicate that MPP+ causes lesions to the retinal vessels at doses non-toxic to the retinal dopaminergic neurons. These data suggest that intravitreal injection of MPP+ cannot be used to study the physiological role of retinal DA.

Different sensitivities to MPTP toxicity in primate nigrostriatal and retinal dopaminergic systems: electrophysiological and biochemical evidence.

The influences of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on dopamine content in the retina and the striatum of monkeys, as well as retinal responses to flash stimulation were studied. Dopamine depletion was observed in the striatum, while retinal dopamine content was similar to controls. The electroretinograms and the oscillatory potentials remained normal, even in monkeys presenting a severe Parkinsonian syndrome, in concordance with the biochemical data. It is proposed that the retinal dopaminergic system is less sensitive to the toxic effects of MPTP than the nigro-striatal pathway.

Canthaxanthin retinopathy. Anatomic and functional reversibility.

Canthaxanthin intake is associated with golden yellow crystalline deposits in the retina around the macula and low static luminance threshold. Our study assesses the anatomic and functional reversibility of canthaxanthin retinopathy. The number of retinal deposits was evaluated in nine patients, two to four times over a mean period of 55 months. There was no significant difference after a nine-month follow-up. A statistically significant decrease in the number of retinal deposits was found after an observation period of 26 months. The deposits disappeared slowly, while some remained even seven years after canthaxanthin therapy was discontinued. Threshold static perimetry performed on eight patients with retinopathy and seven controls did not differ significantly between the two groups at the end of the follow-up period. The results demonstrate that canthaxanthin retinopathy is reversible.

Sporadic aniridia and Wilms' tumor: visual function evaluation of three cases.

The visual function of three infants with sporadic aniridia associated with Wilms' tumor and a deletion of the short arm of chromosome 11 was evaluated with electrophysiological tests. The patients presented nystagmus and photophobia. The electroretinograms (ERGs) were normal, as in other sporadic cases, but at variance with the familial cases. The latency of the flash visual evoked potentials (FVEPs) became shorter with time but remained longer than in age-matched controls, suggesting a delay in maturation of the nervous system. Poor visual function in our cases did not appear to be the result of gross retinal anomalies, as shown by the normal ERG, nor of an hypoplasia of the optic nerve. Contact lenses that provide an artificial pupil decreased photophobia and nystagmus and are therefore highly recommended to increase patient comfort.

Static perimetry in canthaxanthin maculopathy.

We performed threshold static perimetry on 19 patients who had ingested canthaxanthin; 11 had maculopathy and eight did not. Patients with no history of canthaxanthin ingestion served as controls. All patients had visual acuity of 6/9 or better. Threshold static perimetry was reevaluated two to three years after cessation of canthaxanthin ingestion. For both testing sessions, patients with maculopathy presented lower retinal sensitivity than controls, while patients without maculopathy did not differ significantly from the control group. These results suggest that canthaxanthin retinopathy can adversely affect the neurosensory retina.

Alteration of monkey retinal oscillatory potentials after MPTP injection.

We have investigated the functional role of dopamine in the monkey retina by recording the retinal responses to flash stimulations before and after destruction of dopaminergic cells by intravenous injection of N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). We evaluated specifically the oscillatory potentials (100 Hz-3 KHz) of the electroretinogram. By day 47 after MPTP injection, a selective decrease of the amplitude of the first oscillatory potential was observed. At that time the animals had been receiving antiparkinsonian therapy since day 15. These results suggest that retinal dopaminergic neurons may play a role in the generation of the first oscillatory potential, and moreover, that each oscillatory potential should be considered individually.

Assay of dopamine and its metabolites in human and rat retina.

Human and rat retina dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured after various delays in enucleation and freezing of the eyes. Human eyes were enucleated 45 min to 4 h after death, kept at 4 degrees C and frozen at -70 degrees C from 1.5 to 15 h after enucleation. In human retina, maximal DA concentration (4.85 ng/mg prot.) was obtained from eyes enucleated with a delay of 1 h and frozen with a delay of 2 h. After longer delays, DA concentrations decreased. Retinas of humans who died during the night had lower DA retina concentrations compared to those who died during daytime. Rats were decapitated and the eyes enucleated within 5 min or with a delay up to 8 h before freezing at -70 degrees C or kept at 4 degrees C for 5 min to 12 h before being frozen at -70 degrees C. Delays in enucleation of the rat eyes markedly decreased DA retinal concentrations with a minimal value reached as soon as 2 h after death. However, when the rat eyes were kept at 4 degrees C the minimal value was obtained after a longer period of time (about 7 h). Our results thus show that time of death and delays in enucleation and freezing significantly influence DA and its metabolite concentrations in retinas of rats and humans.

Converging cerebellofugal inputs to the thalamus. I. Mapping of monosynaptic field potentials in the ventrolateral nucleus of the thalamus.

The extent of thalamic projections from punctate sites in the cerebellar nuclei was examined in 22 acutely prepared cats by mapping monosynaptic field potentials evoked in the ventrolateral (VL) nucleus by stimulation of the interpositus and dentate nuclei (IN and DN). The monosynaptic field potentials were evoked in the VL by low current stimulating pulses applied at high frequency to these cerebellar nuclei. Quantification of the projections was possible since the conditions of stimulation and recording were strictly controlled. The incoming volley recorded in the brachium conjunctivum caudally to the VL was also analysed. It was composed of two amplitude peaks with different latencies, corresponding to two groups of fibres conducting at 60-90 m/s and 20-25 m/s respectively. The negative field potentials in VL also showed two amplitude peaks and different latencies. The differences in latency between the first and second peaks in the presynaptic and postsynaptic field potentials are compatible with the possibility that both groups of afferent fibres may be monosynaptically connected to VL relay cells. The cerebello-thalamic projections were mapped and their density gradient was established. Two or three small thalamic strips of dense projections surrounded by a large zone of weaker projections were observed to emerge from each punctate cerebellar site. In the discussion of the functional significance of these findings, it is suggested that this organization might constitute a modulatable morphological support for a mechanism focalizing the cerebello-cortical inputs.

Converging cerebellofugal inputs to the thalamus. II. Analysis and topography of thalamic EPSPs induced by convergent monosynaptic interpositus and dentate inputs.

A large number of projections from cerebellar nuclei converge onto individual neurones in the thalamic relay to the motor cortex. Among the thalamic cells receiving cerebellar inputs, 75 out of 153 (50%) were found to be influenced by monosynaptic inputs from at least two cerebellar nuclei and 2 (1.5%) from three nuclei (the interpositus, dentate and fastigial nuclei). The pathways of the inputs converging on the same unit were found to be monosynaptic in 67 thalamic neurons, and disynaptic in the eight others. The monosynaptic nature of the majority of the pathways was proved by analysing the synaptic delay and the spatial and temporal summation. The 67 thalamic neurons receiving direct convergent influences were found to be distributed within the central portion of the VL. Forty-four of them give off projections to all the cortical areas, although a slightly higher proportion is to be found within the motor cortex shoulder area than elsewhere (medial part of area 4). Consequently, the specific function of the neurons receiving direct, convergent cerebellar inputs is not to control one particular part of the musculature but on the contrary, to transmit reciprocal facilitatory effects between the interpositus and dentate nuclei to all the cortical motor subdivisions. Maps summarizing monosynaptic responses obtained with semi-chronic preparations were drawn at thalamic and cortical levels. Each VL neuron was found to be a point where the two cerebellar circuits converge and may interact: the cerebrocerebellar circuit, which passes through the dentate nucleus, generates a feedward motor command: this can either modify or be modified by the feedback peripheral loop, which passes through the interpositus nucleus.