Psychiatric presentations and admissions during the first wave of Covid-19 compared to 2019 in a psychiatric emergency department in Berlin, Germany: a retrospective chart review.

BACKGROUND: Most studies agree that the Covid-19 pandemic and the subsequent lockdown had a negative impact on mental health. On the other hand, international studies have shown that psychiatric emergency departments (pED) experienced a decrease in presentations and admissions. METHODS: Retrospective chart review of all pED presentations and admissions during the first wave of Covid-19 pandemic in Germany (Covid-19 period: 3/2/20 to 05/24/20) in a psychiatric hospital in Berlin compared to 1 year earlier (pre-Covid-19 period). Descriptive statistics and logistic regression were performed. RESULTS: We observed no statistical significant changes in overall pED presentations and overall hospital admissions during the Covid-19 period compared to the pre-Covid-19 period (813 vs. 894, - 9.1%, p = 0.064 and (363 vs. 437, - 16.9%, p = 0.080 respectively). In the subgroup analysis, less patients with depressive disorders (p = 0.035) and with personality disorders (p = 0.002) presented to the pED, a larger number of presentations with schizophrenia was observed (p = 0.020). In the Covid-19 period, less patients with substance use disorder and paranoid schizophrenia were admitted to the hospital via the pED than in the pre-Covid-19 period (p = 0.035 and p = 0.006, respectively). Bed capacity was reduced in the Covid-19 period by - 32.8% (p <  0.001). Presentations in police custody were 13.7% (p = 0.029) higher during the Covid-19 compared to pre-Covid-19 period, with higher rates in female presentations (p = 0.008) and suicide attempts (p = 0.012) and less hospital admissions (p = 0.048). Logistic regression analyses revealed that positive predictors for pED presentation during Covid-19 period were police custody (p <  0.001), being redirected from another hospital (p <  0.001), suicide attempt (p = 0.038), suicidal thoughts (p = 0.004), presentation with paranoid schizophrenia (p = 0.001) and bipolar and manic disorders (p = 0.004), negative predictors were hospital admission (p <  0.001), depressive disorders (p = 0.021) and personality disorders (p <  0.001). CONCLUSIONS: A larger number of presentations in police custody during the Covid-19 period may represent untreated medical needs. This was seen predominantly in female patients, suggesting this subgroup might have suffered particularly under lockdown measures. Patients with paranoid schizophrenia were the only subgroup, which increased in absolute numbers, also suggesting a particular lockdown effect. Reduced bed capacity due to infection curbing measures is suggestive to have played an important role in augmenting the threshold for hospital admissions.

rTMS affects working memory performance, brain activation and functional connectivity in patients with multiple sclerosis.

OBJECTIVE: To investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) on working memory performance, while measuring task-related brain activation and task-related brain connectivity in patients with multiple sclerosis (MS). METHODS: 17 patients with MS and 11 healthy controls (HCs) underwent 3 experimental sessions (baseline, real-rTMS, sham-rTMS), all including an N-back task (3 task loads: N1, N2, N3; control condition: N0) inside the MR scanner. Prior to imaging, real-rTMS (10 Hz) was applied to the right DLPFC. The stimulation site was defined based on individually assessed N-back task activation at baseline and located using neuronavigation. Changes in whole brain functional activation and functional connectivity with the right DLPFC were calculated. RESULTS: N-back task accuracy (N2 and N3) improved after real-rTMS (and not after sham-rTMS) compared with baseline (p=0.029 and p=0.015, respectively), only in patients. At baseline, patients with MS, compared with HCs, showed higher task-related frontal activation (left DLPFC, N2>N0), which disappeared after real-rTMS. Task-related (N1>N0) functional connectivity between the right DLPFC and the right caudate nucleus and bilateral (para)cingulate gyrus increased in patients after real-rTMS when compared with sham stimulation. CONCLUSIONS: In patients with MS, N-back accuracy improved while frontal hyperactivation (seen at baseline relative to HCs) disappeared after real-rTMS. Together with the changes in functional connectivity after real-rTMS in patients, these findings may represent an rTMS-induced change in network efficiency in patients with MS, shifting patients' brain function towards the healthy situation. This implicates a potentially relevant role for rTMS in cognitive rehabilitation in MS.

Gender differences in the histopathology of MS?

Multiple sclerosis (MS) lesions are histopathologically characterized by inflammation, demyelination/remyelination, axonal damage and gliosis. Animal experimental and in vitro studies suggest that sex hormones influence the immune system and contribute to the increased likelihood in women of developing MS. However, a variety of studies have also shown that remyelination is more marked in female rodents or that female sex hormones are beneficial for myelin repair. To determine whether gender influences the histopathology of MS lesions, we compared the extent of inflammation, axonal damage and remyelination in MS lesions of female and male MS patients. We observed no differences in the composition of inflammatory infiltrates, axonal damage or cortical pathology. Similar numbers of oligodendroglial progenitor cells and mature oligodendrocytes were present in MS lesions. Remyelination is slightly, but not significantly, more extensive in women than men in early MS lesions. The absence of significant differences in lesion pathology between female and male MS patients might be explained by a lack of a gender influence, but also might be due to the limited number of tissue samples available for histopathological analysis.

Remyelination capacity of the MS brain decreases with disease chronicity.

OBJECTIVE: To analyze and compare the extent of remyelination in lesions from patients with multiple sclerosis (MS) who have a short (early MS lesions) or a long (chronic MS lesions) disease duration and to determine the influence of anatomic localization on the extent of remyelination. In early MS lesions, remyelination has been described as a relatively frequent event, in contrast to chronic MS lesions, where remyelination is absent or limited to the lesion border in the majority of lesions. However, no studies have been published that have quantified and compared the extent of remyelination in early and chronic MS lesions. METHODS: We analyzed the occurrence of remyelination in 52 biopsies from 51 patients (early MS) and in 174 lesions from 36 autopsy cases (chronic MS) by immunohistochemistry for myelin proteins, and correlated our findings with anatomic localization, sex, age, and disease duration. RESULTS: Significantly more lesions were remyelinated in early than in chronic MS (80.7% vs 60%). In chronic MS, subcortical lesions showed more extensive remyelination than periventricular lesions. The majority of cerebellar lesions were completely demyelinated. CONCLUSION: In summary, our data demonstrate that remyelination is a frequent event in early multiple sclerosis lesions. Furthermore, the anatomic localization of a lesion might influence the extent of remyelination.

Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis.

Immunization of mice with type II collagen (CII) leads to collagen-induced arthritis (CIA), a model for rheumatoid arthritis. T cell recognition of CII is believed to be a critical step in CIA development. We have analyzed the T cell determinants on CII and the TCR used for their recognition, using twenty-nine T cell hybridomas derived from C3H.Q and DBA/1 mice immunized with rat CII. All hybridomas were specific for the CII(256-270) segment. However, posttranslational modifications (hydroxylation and variable O-linked glycosylation) of the lysine at position 264 generated five T cell determinants that were specifically recognized by different T cell hybridoma subsets. TCR sequencing indicated that each of the five T cell epitopes selected its own TCR repertoire. The physiological relevance of this observation was shown by in vivo antibody-driven depletion of TCR Valpha2-positive T cells, which resulted in an inhibition of the T cell proliferative response in vitro towards the non-modified CII(256-270), but not towards the glycosylated epitope. Most hybridomas (20/29) specifically recognized CII(256-270) glycosylated with a monosaccharide (beta-D-galactopyranose). We conclude that this glycopeptide is immunodominant in CIA and that posttranslational modifications of CII create new T cell determinants that generate a diverse TCR repertoire.

Dextran sulfate sodium (DSS) induced experimental colitis in immunodeficient mice: effects in CD4(+) -cell depleted, athymic and NK-cell depleted SCID mice.

Administration of dextran sulfate to mice, given in the drinking water results in acute or subacute colonic inflammation, depending on the administration protocol. This colonic inflammation exhibits ulceration, healing and repair, and a therapeutic response that makes it valuable for the study of mechanisms that could act in the pathogenesis of human ulcerative colitis, a disease thought to have an immunologically dependent pathogenesis. To investigate if immunological mechanisms were involved in the induction of colonic inflammation in this model, mice with different degrees of immunodeficiency were used. It was shown that dextran sulfate induced colitis could be induced in Balb/c mice depleted of CD4(+) helper T cells by treatment with monoclonal antibodies preceded by adult thymectomy. The depletion of CD4(+) was verified by flow cytometric analysis. Furthermore, the colonic inflammation could equally be induced in athymic CD-1 nu/nu mice lacking thymus-derived T cells, in T and B-cell deficient SCID mice, and also in SCID mice depleted of NK cells by treatment with anti-asialo GM1 antibodies. The NK-cell depletion was verified by measuring spleen NK-cell activity. The resulting colonic inflammation in all these types of deficient mice was qualitatively comparable, as shown by clinical and histological appearance. These results indicate that the presence of functional T, B and NK cells is not crucial for the induction of dextran sulfate colitis in mice.

Short-term administration of selected anti-T-cell receptor V beta chain specific MoAb reduces sialadenitis in MRL/lpr mice.

Sialadenitis develops spontaneously in MRL/Mp mice bearing a lymphoproliferative gene, lpr (MRL/Mp-lpr/lpr). Based on recent observations of an oligoclonal expansion of T-cell receptor (TCR) expressing V beta chain families (V beta 4, V beta 8.1,2, V beta 10b) in salivary glands of these mice we have initiated selective antibody therapy. Treatment with monoclonal antibodies (MoAb) specific for T cells expressing a mixture of TCR V beta 4, V beta 8.1,2 and V beta 10b was applied to MRL/lpr mice before and after the spontaneous development of sialadenitis. The in vivo treatment with V beta 4, V beta 8.1,2 and V beta 10b MoAb did not prevent the development of sialadenitis. However, in animals with established sialadenitis, treatment with the MoAb significantly decreased the inflammation compared with the control groups. Immunohistochemical staining of cell phenotypes demonstrated a change in the ratio of CD4/CD8 in the animals with established sialadenitis. Altogether, these findings illustrate that it is possible to modulate sialadenitis and infiltrate cell phenotypes in vivo in MRL/lpr mice with specific anti-TCR V beta MoAb treatment.

Early intervention with Portuguese mothers: a 2-year follow-up.

Results of a 2-year follow-up after an early intervention with low-middle-class primiparous Portuguese mothers are presented. On the 3rd day of their infants' lives, 40 mothers underwent a structured intervention using selected items of the Brazelton Neonatal Behavioral Assessment Scale. An additional 20 mothers randomized to the control group had a talk with a pediatrician about general problems of infant health care. On Day 28, the "sensory orientation" and "cuddliness" competencies of the infants in the experimental group were significantly enhanced when compared with the same competencies among the infants in the control group. In addition, dyads in the experimental group had established a more favorable pattern of interaction, particularly after short stressful situations (these situations included short separations from the mother in which a stranger was present, short separations in which no one was present, and a stillface situation). Short-term effects (the first month of life) were particularly noticeable, especially in terms of the babies' neurobehavioral development and mother-infant interaction. Long-term effects (3, 6, 9, 12, 15, 18, and 24 months), though less clear, were evident in the form of better interactive patterns among the dyads in the experimental group. This was particularly evident after the stressful situations to which they were submitted. These results are discussed in terms of both their scope and their clinical impact.

Therapeutic effects of monoclonal antibodies to alpha beta TCR but not to CD4 on collagen-induced arthritis in the rat.

The role which T cells play in the pathogenesis of the collagen-induced arthritis (CIA) model is not yet fully understood. Although CIA is most likely dependent on the activity of class II-restricted CD4+ T cells, only prophylactic but not therapeutic anti-CD4 treatments have been successful. The lack of therapeutically effective anti-T cell monoclonal antibody treatments has questioned the importance of T cells in ongoing CIA. However, recently we found that ongoing CIA in DA rats induced with homologous CII can be suppressed by injections with an anti-alpha beta TCR antibody. Having a CIA model where ongoing disease was clearly dependent on T cells, we addressed in the present work whether also an anti-CD4 treatment could suppress ongoing arthritis in this model. Although no CD4hi lymph node cells were seen after an anti-CD4 injection, the arthritis was suppressed only after treatment at immunization but not after treatment just before onset of disease. In comparison, the anti-TCR treatment at the time of onset was clearly suppressive even though a large fraction of the T cells was not depleted. This indicates that the different outcome of the anti-TCR and anti-CD4 treatment was not due to a different capacity to deplete T cells in vivo.

Extensive MHC variability in cichlid fishes of Lake Malawi.

Lake Malawi in East Africa harbours 500-1,000 endemic species of cichlid fishes, all presumably derived by adaptive radiation from a single founding population within the past two million years. The species of this 'flock' differ strikingly in their ecology and behaviour, moderately in their external morphology and very little in their molecular characteristics. Here we describe high sequence variability of class II major histocompatibility complex genes in a sample of species from Lake Malawi. The variability provides a set of molecular markers for studying adaptive radiation and should be useful for estimating the size of the population that founded the species flock.

Adsorption and helical coiling of amphipathic peptides on lipid vesicles leads to negligible protection from cathepsin B or cathepsin D.

The processing of antigenic peptides for presentation by MHC molecules to T cells, may depend upon the function of a second, consensus sequence in or near the T cell-presented epitope. One such processing-regulating sequence appears to be composed of amino acids Leu, Ile, Val, Phe, and Met recurring in a fashion to form a longitudinal, hydrophobic strip when the excised peptide is coiled as an alpha-helix. Such a hydrophobic strip-of-helix may: (a) scavenge peptides from lumens onto lipid membranes of digestion vesicles, (b) stabilize peptides there as protease-resistant helices, (c) specify recognition by the antigenic peptide-binding sites of chaperonin proteins, transmembranal transporters, or MHC molecules. By circular dichroism and electron paramagnetic resonance, we demonstrated that peptides with recurrent hydrophobic residues potentially forming longitudinal strips adsorbed to, and partially coiled as helices on, di-O-hexadecyl, D-L-alpha-phosphatidylcholine (DHPC) vesicles. Cathepsin B or cathepsin D cleavages of three such peptides were identified. With either enzyme, it made no significant difference whether a peptide substrate was in solution or bound to vesicles in terms of efficiency and specificity of peptide bond cleavages. We conclude that protease resistance, per se, of membrane-adsorbed, helically coiled peptides is not a major factor in the selection for T cell presentation of epitopes in peptides which have a motif with a longitudinal hydrophobic strip.

Arthritis induced in rats with adjuvant oil is a genetically restricted, alpha beta T-cell dependent autoimmune disease.

Adjuvant arthritis in rats is usually induced by injection of mycobacterium tubercle cell walls suspended in various adjuvant oils such as Freund's incomplete adjuvant (FIA) or pristane. We have recently shown that injection of adjuvant oils without inclusion of mycobacterium tubercle cell walls triggers arthritis [oil adjuvant-induced arthritis (OIA)] in the DA rat strain. The OIA is a genetically restricted disease since only DA rats are susceptible while Lewis, DA-fostered Lewis and F1 (Lew x DA) rats are relatively resistant. Activated alpha beta T cells infiltrate the affected joints of adjuvant oil-injected DA rats and treatment with monoclonal antibodies to the alpha beta T-cell receptor abrogates development of arthritis. These findings show that alpha beta T-cell activation is a critical event in the development of OIA.

Activated type II collagen reactive T cells are not eliminated by in vivo anti-CD4 treatment. Implications for therapeutic approaches on autoimmune arthritis.

Activation of CD4+ T cells plays an important role in type II collagen (CII) induced arthritis (CIA). The CD4+ T cell dependency is demonstrated by anti-CD4 antibody treatment which suppresses CIA in mice if injected before CII immunization. The same anti-CD4 treatment at a later stage does not suppress CIA, despite extensive elimination of peripheral CD4+ T cells. A possible explanation for this discrepancy is that activated T cells might not be as easily influenced by the anti-CD4 antibodies as resting T cells. To address this question, the proliferative capacity of CII reactive CD4+ lymph node (LN) T cells, in mice treated with anti-CD4 antibodies before or after the CII immunization, was analyzed. In mice treated before immunization the capacity of LN cells to proliferate in vitro was markedly suppressed while in mice receiving anti-CD4 treatment after immunization it was retained. Flow cytometric analysis revealed that the anti-CD4 treatment before and after immunization reduced the number of CD4+ LN T cells to the same level. The small population of CD4+ LN cells which were left after anti-CD4 treatment of naive mice all expressed CD44, a marker for previously activated T cells in mice. We propose that activation render CII reactive T cells more resistant to anti-CD4 treatment than virgin T cells are and suggest that the lack of therapeutic effect of late anti-CD4 treatment in CIA does not necessarily implicate that CD4+ T cells are unimportant in that stage of the disease.

Homologous collagen-induced arthritis in rats and mice are associated with structurally different major histocompatibility complex DQ-like molecules.

Collagen-induced arthritis (CIA) in rats, induced with homologous type II collagen (CII), is a genetically more restricted disease and has better resemblance to rheumatoid arthritis by its chronic disease course, than CIA induced with heterologous CII. The DA strain is highly susceptible to CIA induced with homologous CII, while the Lewis strain is resistant. (DAxLew)F1 is susceptible and backcrossing to Lewis reveals a close, but not complete, association of both arthritis and CII responsiveness to the RT1a haplotype. Analyses of congenic strains on DA and Lewis backgrounds suggest that expression of a major histocompatibility complex class II Ba molecule, encoded from the RT1Ba locus, is associated with arthritis susceptibility and CII responsiveness. The second exons coding for the first domains of the alpha and beta chains of both the RT1a and RT1l haplotypes were sequenced and the deduced amino acid sequences compared with the corresponding molecule associated with susceptibility to CIA in the mouse (H-2 Aq). The sequences of the respective alleles revealed no obvious structural homology explaining the extensive similarities in the development of chronic autoimmune arthritis. Instead, this finding implies that different trimolecular constituents (i.e. class II, T cell receptor, and CII peptides) may yield an antigen presentation event that is able to trigger a similar autoaggressiveness in the two rodent species.

Biophysical mechanism of the scavenger site near T cell-presented epitopes.

We seek to identify consensus sequences in digested fragments of antigenic proteins regulating selection and major histocompatibility complex (MHC)-restricted presentation to T cells of epitopes within those fragments. One such pattern, of recurrent, hydrophobic sidechains forming a longitudinal hydrophobic strip when a sequence is coiled as an alpha-helix, is found in or near most T cell-presented epitopes. Such recurrent hydrophobicity may lead to protease-protected coiling of the fragment against endosomal membranes and transfer to MHC molecules. This concept leads to better identification of T cell-presented sequences and possible to engineering of T cell-presented vaccines to affect their potency and MHC restriction.

Host defense against cholera toxin is strongly CD4+ T cell dependent.

This study investigates the role of CD4+ T cells in host defense against cholera enterotoxin-induced diarrhea. Antitoxin immunoglobulin A formation and gut protection against cholera toxin (CT) following oral immunizations with CT were evaluated in normal mice and mice that had been depleted of CD4+ T cells by in vivo treatment with specific anti-CD4 monoclonal antibodies. Flow cytometer analysis demonstrated that anti-CD4 monoclonal antibody effectively eliminated CD4+ T cells in the spleen, mesenteric lymph nodes, and Peyer's patches. In contrast, lamina propria lymphocytes demonstrated only some decrease in CD4+ T-cell numbers following antibody treatment. However, CD4 expression of individual lamina propria lymphocytes was strongly down-regulated. Depletion of CD4+ T cells performed prior to oral immunization with CT completely inhibited the ability to respond to CT. No antitoxin production, as detected at the single-cell level by the ELISPOT technique, was found in the spleen, mesenteric lymph nodes, or Peyer's patches, nor did we observe serum antitoxin responses in these mice. Control mice demonstrated strong antitoxin responses in all locations following oral immunization with CT. Anti-CD4 antibody treatment also effectively inhibited the antitoxin immunoglobulin A response in the lamina propria to CT as well as blocked the ability to develop gut protection against CT challenge of ligated intestinal loops after oral CT immunization. Thus, in vivo CD4+ T-cell depletion rendered these mice unable to develop protective immunity in the gut following oral immunization with CT. Moreover, CD4+ T-cell depletion effectively inhibited the antitoxin immune response in the gut lamina propria, mesenteric lymph nodes, Peyer's patches, and spleen when performed prior to both priming and booster immunizations with CT. This study clearly demonstrates the requirement of functional CD4+ T cells in the gut immune system for the development of host defense against CT-induced disease. Our data also reinforce the concept of a strong association between gut protection against CT and local production of neutralizing immunoglobulin A antitoxin.

T-cell receptor V beta haplotype and complement component C5 play no significant role for the resistance to collagen-induced arthritis in the SWR mouse.

The importance of T-cell receptor (TcR) V beta gene haplotype and complement component C5 deficiency for the resistance to collagen-induced arthritis (CIA) in the SWR mouse was studied. Firstly, the immune responses against heterologous and autologous type II collagen (CII) were compared between SWR mice and arthritis-susceptible and major histocompatibility complex (MHC)-identical DBA/1 mice. Secondly, F1 and F2 crosses were made between the two strains and studied for arthritis development, V beta gene usage and C5 presence. After immunization with heterologous rat CII, both strains reacted with a strong autoantibody response. Immunization with mouse CII, on the other hand, gave a much lower response in both strains, with DBA/1 mice having the strongest response. A collection of B-cell hybridomas was created from the draining lymph nodes of SWR mice 9 days after immunization with rat CII. This hybridoma collection showed similarity to previous data from the DBA/1 mouse, by its high frequency of B cells producing IgG specific for CII and with a high degree of cross-reactivity with autologous mouse CII. After immunization with heterologous CII, both T cells specific for heterologous CII as well as T cells cross-reacting with autologous CII could be demonstrated. F1 crosses between SWR and DBA/1 were relatively resistant to CIA (8%), while in the F2 generation 72% of the mice developed arthritis. No correlation between V beta haplotype or C5 and development of arthritis in the F2 mice was found. It is concluded that the resistance to CIA in the SWR mouse is not related to either V beta haplotype or C5 deficiency. Instead we postulate the involvement of two or more genes which are important for the induction and maintenance of tolerance to own CII.

Anti-T cell receptor antibody treatment of rats with established autologous collagen-induced arthritis: suppression of arthritis without reduction of anti-type II collagen autoantibody levels.

Activation of T cells is critical for the development of type II collagen (CII)-induced arthritis (CIA). However, the relative importance of T cells in their delivery of help to B cells, promoting autoantibody formation or acting as inflammatory initiating cells, is unclear. The effect of a monoclonal antibody directed to the alpha/beta T cell receptor (TcR) on the development of autologous CIA was studied. Two weeks after immunization with autologous CII the onset of severe arthritis occurred, followed by a chronic arthritis activity in the peripheral joints. Anti-TcR treatment before immunization suppressed the incidence of arthritis and the autoantibody response to CII. Treatment given immediately before the expected onset delayed the appearance of arthritis. Treatment given to already arthritic rats reduced the severity. In the latter two groups the serum levels of anti-CII autoantibodies were not affected. The duration of the ameliorating effect was limited and with the return of arthritis a concomitant antibody response towards the injected mouse anti-TcR antibody was observed. These results show that the role of T cells in both the induction and perpetuation of CIA is essential and not limited to the triggering of production of pathogenic anti-CII autoantibodies.