Intra-gastric balloon with lifestyle modification: a promising therapeutic option for overweight and obese patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Data on effects of intra-gastric balloon (IGB) on metabolic dysfunction-associated steatotic liver disease (MASLD) are scarce, in part with contradictory results, and mainly obtained in tertiary care patients with diabetes and other comorbidities. We here explore effects of IGB in patients with MASLD referred to a first-line obesity clinic. METHODS: In this prospective cohort study, patients with at least significant fibrosis (≥ F2) and/or severe steatosis (S3) according to screening transient elastography (FibroScan®) were offered a second FibroScan® after 6 months lifestyle modification with or without IGB (based on patient preference). RESULTS: 50 of 100 consecutively screened patients (generally non-diabetic) qualified for repeated evaluation and 29 (58%) of those had a second FibroScan®. At baseline, at least significant fibrosis was present in 28% and severe steatosis in 91%. IGB was placed in 19 patients (59%), whereas 10 patients (41%) preferred only lifestyle modification (no differences in baseline characteristics between both groups). After 6 months, liver stiffness decreased markedly in the IGB group (median: from 6.0 to 4.9 kPa, p = 0.005), but not in the lifestyle modification only group (median: from 5.5 to 6.9 kPa, p = 0.477). Steatosis improved in both groups, (controlled attenuation parameter values; IGB, mean ± SD: from 328 ± 34 to 272 ± 62 dB/m, p = 0.006: lifestyle modification only, mean ± SD: from 344 ± 33 to 305 ± 43 dB/m: p = 0.006). CONCLUSION: Both steatosis and fibrosis improve markedly in overweight/obese patients with MASLD after 6 months IGB combined with lifestyle modification. Our results warrant further research into long-term effect of IGB in these patients.

Resting energy expenditure in children at risk of hypothalamic dysfunction.

Objective: Children with suprasellar brain damage are at risk of hypothalamic dysfunction (HD). HD may lead to decreased resting energy expenditure (REE). Decreased REE, however, is not present in all children with HD. Our aim was to assess which children suspect for HD have low REE, and its association with clinical severity of HD or radiological hypothalamic damage. Patients and methods: A retrospective cohort study was performed. Measured REE (mREE) of children at risk of HD was compared to predicted REE (pREE). Low REE was defined as mREE <90% of predicted. The mREE/pREE quotient was associated to a clinical score for HD symptoms and to radiological hypothalamic damage. Results: In total, 67 children at risk of HD (96% brain tumor diagnosis) with a mean BMI SDS of +2.3 ± 1.0 were included. Of these, 45 (67.2%) had low mREE. Children with severe HD had a significant lower mean mREE/pREE quotient compared to children with no, mild, or moderate HD. Mean mREE/pREE quotient of children with posterior hypothalamic damage was significantly lower compared to children with no or anterior damage. Tumor progression or tumor recurrence, severe clinical HD, and panhypopituitarism with diabetes insipidus (DI) were significant risk factors for reduced REE. Conclusion: REE may be lowered in children with hypothalamic damage and is associated to the degree of clinical HD. REE is, however, not lowered in all children suspect for HD. For children with mild or moderate clinical HD symptoms, REE measurements may be useful to distinguish between those who may benefit from obesity treatment that increases REE from those who would be better helped using other obesity interventions.

Transforming nursing home-based day care for people with dementia into socially integrated community day care: process analysis of the transition of six day care centres.

BACKGROUND: The community-based Meeting Centres Support Programme for people with dementia and their carers has been proven more effective in influencing behaviour and mood problems of people with dementia and improving sense of competence of carers compared to nursing home-based day care centres for people with dementia. Six Dutch nursing home-based day care centres were transformed into Community-based day care centres with carer support, according to this Meeting Centres model. OBJECTIVES: To determine which factors facilitate or impede the transition to Community-based day care. DESIGN: A process evaluation was conducted with a qualitative study design. SETTINGS: Six nursing home-based day care centres transformed into Community-based day care centres for people with dementia and their carers. STUDY PARTICIPANTS: Stakeholders (n=40) that were involved during the transition. METHODS: Factors that facilitated or impeded the transition were traced by means of (audiotaped and transcribed) interviews with stakeholders and document analysis. All data were coded by two independent researchers and analyzed using thematic analysis based on the Theoretical framework of adaptive implementation. RESULTS: Six nursing home-based day care centres successfully made the transition to Community-based day care with carer support. Success factors for the start of the project were: the innovation being in line with the current trend towards more outpatient care and having motivated pioneers responsible for the execution of the transition. Barriers were difficulties reaching/recruiting the target group (people with dementia and carers), inflexible staff and little or no experience with collaboration with community-based care and welfare organizations. Facilitating factors during the implementation phase were: finding a suitable location in the community, positive changes in staff attitude and adoption of the new vision, and good cooperation with care and welfare organizations. Barriers were insufficient involvement of, and support from the managers of the responsible organizations, and communication problems with referrers of other organizations, including the GPs and case managers. CONCLUSIONS: The transition from nursing home-based psychogeriatric day care support to a community-based combined support programme for people with dementia and their informal carer is shown to be feasible. Successful implementation of this community-based combined support programme requires - besides motivated pioneers, a change in staff attitude and working style, a suitable pleasant location and collaboration with other care and welfare organizations - special attention for effective communication with the target user group and the referrers, and also how the management of the pioneer organizations can facilitate the staff during the transition process.

[TRANSITION OF A PSYCHOGERIATRIC DAY CARE IN THE NURSING HOME TO EASY-ACCESS DAY CARE PLUS CAREGIVER SUPPORT IN THE COMMUNITY: A PILOT STUDY]. / Transitie van een psychogeriatrische dagbehandeling in het verpleeghuis naar een laagdrempelige dagbehandeling in de wijk: een pilotonderzoek.

BACKGROUND: In this study, the transition of a nursing home based psychogeriatric day care centre to an easy-access community day care centre plus caregiver support (DC-plus CS) is followed closely. The transition was based on the proven effective Meeting Centres Support Program. METHOD: By means of qualitative analysis of documents and interviews with key persons (n=11) we investigate facilitating and impeding factors for making this transition. Besides, we evaluate the satisfaction of participants and informal caregivers that used the new support program longer than 6 months. RESULTS: Several characteristics of the innovation (DC-plus CS) help to establish cooperation with other care and welfare services in the region, such as: the easy-access location, the social integration in the community, and the focus on combined support for people with dementia and their informal carers. The good cooperation and the suitable location in the community facilitate the implementation. At first, the presence of other community care-centres for people with dementia and their informal carers in the neighbourhood impedes the recruitment of new participants for the DC-plus CS. In general, the satisfaction of participants and informal carers about the support program is high. CONCLUSION AND DISCUSSION: The transition is made successfully and this study gives other psychogeriatric day care centres in the nursing home insight in how to make a similar transition to DC-plus CS.

[Theatre as communication method in psychogeriatric care: effects on behaviour, mood and quality of life of people with dementia ]. / Theater als contactmethode in de psychogeriatrische zorg: effecten op gedrag, stemming en kwaliteit van leven van mensen met dementie.

BACKGROUND: Recently, a new communication method was introduced in nursing homes for people with dementia. This so-called Veder Method, developed by professional actors with former educational background in care,combines proven effective emotion-oriented care methods, like reminiscence,with theatrical stimuli like songs and poetry. The method is applied during theatre shows and living room theatre activities. In this exploratory study the surplus value of a living room theatre activity according to the Veder method compared to a reminiscence group activity was evaluated. METHOD: Within a quasi experimental design, three groups of nursing home residents with dementia were compared: Experimental group 1 (E1; N=64)joined a 'living room theatre activity' offered by trained caregivers. Experimental group 2 (E2; N=31) joined a 'living room theatre activity' offered by professional actors. The control group (N=52) received a reminiscence group activity. Behaviour, mood and quality of life were measured using standardized observation scales at three points in time: (T1) pretest; (T2)during the intervention and; (T3) posttest, two hours after the intervention. RESULTS: During and after the intervention, positive effects were found in favour of E2 on behaviour (i.e. laughing, recalled memories), mood (i.e. happy/content) and quality of life (i.e. social involvement, feeling at home). CONCLUSION: A living room theatre activity according to the Veder Method has more positive effect on nursing home residents compared to a normal reminiscence group activity, if offered by professional actors.This article is a slightly edited translation of Does theatre improve the quality of life of people with dementia? International Psychogeriatrics2012;24: 36r381 by the same authors.

Determination of helper T-cell precursor frequencies against non-haemopoietic cells: comparison of co-stimulation provided by anti-CD28 antibody versus the cellular ligand B7-1.

Helper T-cell precursor frequency assays (HTLp-assays) are commonly used in transplantation to examine the frequency of T cells reactive against donor or host alloantigens. In these assays, peripheral blood mononuclear cells (PBMCs) are most often used as stimulator cells. However, cells targeted after transplantation do not always belong to the haematopoietic lineage and may express different alloantigens, especially minor histocompatibility antigens (mHags). Non-haematopoietic cells lack expression of the B7 co-stimulatory molecules needed to activate primary T cells that can be supplied by anti-CD28 (alphaCD28) antibodies or transfection with B7-1 coding sequences. At present, it is not known how these two ways of supplied co-stimulation compare in HTLp assays. B7-1-transfected A431 keratinocytes (A431B7-1) induced higher proliferative responses in allogeneic primary T cells and more interleukin (IL) 2 production than that induced by A431 cells plus alphaCD28, whereas the kinetics of proliferation and IL-2 production were similar. Neither cross-linking of alphaCD28 bound to T cells nor prevention of IL-2 resorption by the anti-IL-2 receptor resulted in improved proliferation or IL-2 production. Results of HTLp assays indicated that A431B7-1 activated on average 7.5 times more alloreactive IL-2-producing T cells than A431 cells plus alphaCD28. We conclude that primary T-cell alloresponses against major histocompatibility complexes (MHCs) and mHags expressed on non-haematopoietic cells can be measured in HTLp assays using supplied co-stimulation, although alphaCD28 yields an intrinsic underestimation of actual frequencies.

Selective depletion of major and minor histocompatibility antigen reactive T cells: towards prevention of acute graft-versus-host disease.

Development of acute graft-versus-host disease (aGVHD) following HLA-identical sibling bone marrow transplantation (BMT) remains a serious complication. A selective depletion of T cells has proved to be effective in preventing aGVHD but is associated with relapse and increased incidence of infection. As aGVHD is directed mainly against epithelial tissues we examined whether it would be feasible to selectively deplete T cells reactive with epithelial cells whilst preserving other specificities. Donor T cells which express HLA-DR, CD25, CD69 and CD71 activation markers after cocultivation with patient keratinocytes were depleted using magnetic cell separation techniques. Depletion of major as well as minor histocompatibility antigen activated T cells revealed a significant (P = 0.004 and P = 0.031, respectively) 10-fold decrease in the frequency of donor T lymphocyte precursors reactive with patient keratinocytes. The frequency reactive with third-party and patient peripheral blood mononuclear cells, including leukaemia cells, remained unchanged, supporting the notion that aGVHD and graft-versus-leukaemia (GVL) may be separable. This alloantigen-specific depletion may be used in matched unrelated as well as HLA-identical sibling BMT for reducing aGVHD whilst conserving GVL.

CD28 induces cell cycle progression by IL-2-independent down-regulation of p27kip1 expression in human peripheral T lymphocytes.

CD28 is the primary T cell costimulatory receptor, and upon ligation with its ligands, it enhances T cell proliferation and IL-2 synthesis. In this study we examined the role of CD28 in the initial proliferative response and cell cycle entry of T lymphocytes. Stimulation through CD3 alone resulted in a poor proliferative response, while in the presence of CD28 costimulation a strong increase in the number of cells in S-phase could be detected after 48 h of stimulation. CD28 costimulation enhanced expression of cyclin D3 and induced down-regulation of p27kip1 expression. Cross-linking CD28 was much more effective in inducing cyclin D3 expression and in down-regulating p27kip1 expression than addition of IL-2. Blocking experiments, using antibodies that neutralize IL-2 or the IL-2 receptor, showed that the effects induced by CD28 are independent of endogenous IL-2. Moreover, using a variety of immunosuppressants that interfere with IL-2 signaling pathways, we were able to show that IL-2 is not required for cell cycle entry induced by CD28 costimulation. From these experiments it can be concluded that CD28 and IL-2 use different signaling pathways for down-regulation of p27kip1 expression. We hypothesize that costimulation through CD28 is responsible for initial cell cycle entry of T lymphocytes, while IL-2, which is produced after costimulation, might be involved in sustaining proliferation.

Human B7-1 is more efficient than B7-2 in providing co-stimulation for alloantigen-specific T cells.

Besides a signal via the T cell receptor/CD3 complex, an additional costimulatory signal is required for optimal T cell activation. This signal can be delivered by interaction of either B7-1 or B7-2 expressed by antigen-presenting cells with CD28 on the T cells. Comparison of the function of B7-1 and B7-2 in different experimental animal systems generated conflicting data on the roles for the co-stimulatory molecules. We therefore investigated whether there are differences between B7-1 and B7-2-mediated co-stimulation in an alloantigen-specific primary T cell response induced by B7-transfected human cell lines of epithelial origin. Both transfected keratinocyte cell lines efficiently induce T cell proliferation and the ratios of stimulator versus responder cells are similar. The kinetics of proliferation and interleukin (IL)-2, IL-4 and interferon-gamma production are also comparable between both transfectant lines. However, despite equal B7 expression levels, it is consistently found that the magnitude of the B7-1-induced T cell proliferation was higher than that of B7-2. Comparison of precursor frequencies of helper T lymphocytes responsive with either B7-1 or B7-2 revealed that the frequency of B7-1-responsive T cells was higher than that of B7-2, and that the frequency of cells activated by a combination of B7-1 and B7-2 did not differ significantly from that of B7-1 alone. We therefore conclude that the B7-2-responsive T cells are part of the B7-1-responsive population, and that B7-1 on keratinocytes is more efficient in providing co-stimulation for alloantigen-specific T cells.

A peptide variant of an arthritis-related T cell epitope induces T cells that recognize this epitope as a synthetic peptide but not in its naturally processed form.

The immune system has the potential to utilize a diverse T cell repertoire for the recognition of Ag in the context of MHC molecules. Here we describe the analysis of two rat T cell clones, both of which recognize a synthetic peptide comprised of the arthritis-associated 180-188 amino acid sequence of the mycobacterial 65-kDa heatshock protein (hsp65 180-188), but which differ in the recognition of the naturally processed hsp65. The arthritogenic T cell clone A2b, generated by immunization with whole Mycobacterium tuberculosis, recognized the hsp65 180-188 synthetic peptide as well as the processed hsp65, whereas T cell clone ATL11, generated after immunization with a single amino acid substituted peptide analog of hsp65 180-188, recognized peptide hsp65 180-188 but not the processed hsp65. For both T cell clones the minimal stimulatory sequence was hsp65 180-186. However, within this minimal stimulatory sequence marked differences between the clones were found with regard to peptide residues interacting with the TCR. Furthermore, addition of extra residues at the N terminus of the hsp65 180-186 sequence abrogated the recognition by clone ATL11, but not by A2b. These findings demonstrate that, upon in vivo immunization with a synthetic peptide comprised of a single amino acid variant of a T cell epitope, T cells can be triggered that recognize a peptide comprised of the original epitope sequence, but that do not recognize this epitope in its naturally processed protein fragment. The possibility of triggering such T cells by immunization with synthetic peptides, may well have consequences for the design of peptide vaccines or peptide immunomodulatory agents.

Characterization of single isolated vascular smooth muscle cells from bovine coronary artery.

Single smooth muscle cells from bovine coronary artery were obtained by enzymatic digestion. 20.1 +/- 3.2% (mean value of seven experiments) of the dispersed cells were in a relaxed, noncontracted state. These cells responded to electrically induced depolarization with a graded contraction to a maximum shortening of 47.8% of initial length; the corresponding maximum for K+-induced depolarization was 61.7% of initial length. Cells relaxed only a small percentage (approximately equal to 20%) of the amount of shortening, but could be restimulated several times to contract to even shorter lengths. The decrease in mean cell length of dispersed cells exposed to serotonin, acetylcholine, and ergonovine maleate was 21.0, 23.0 and 25.5%, respectively (p less than 0.05). No significant decrease in cell length was obtained with norepinephrine. The ultrastructure of the relaxed cells seemed to be unaltered, suggesting that the accuracy of the physiological results is not impaired by induced structural damage.

GTP-sensitive phosphorylation of proteins in a postmitochondrial supernatant from rat brainstem affected by ACTH1-24.

The effect of ACTH1-24 and cyclic nucleotides on the endogenous phosphorylation of proteins from a postmitochondrial supernatant from rat brainstem was investigated in the presence and absence of GTP. Phosphorylation and its modulation by these compounds were studied in vitro by incorporation of labeled phosphate from [gamma-32P]ATP added to the incubation mixture. Phosphoproteins were subsequently analyzed by autoradiography after one- and two-dimensional separation. Eight ACTH-sensitive phosphoproteins of molecular weights 75 (IEP 4.0), 67, 64, 50 (IEP 4.7), 47 (IEP 4.8), 38, 34, and 24K were found. The effects of ACTH on phosphorylation were mainly inhibitory, and the affected protein bands did not coincide with the phosphoproteins sensitive to cyclic AMP and cyclic GMP. Phosphorylation of those phosphoprotein bands and its ACTH sensitivity appeared to be highly sensitive to GTP. It is suggested that the activity of protein kinases involved in hormone-sensitive phosphorylation in a postmitochondrial rat brainstem fraction is regulated by GTP-dependent mechanisms.

Brain adrenocorticotrophin after adrenalectomy and sham-operation of rats.

The influence of adrenalectomy on the level of immunoreactive 18-24 ACTH extracted from hypothalamus, hippocampus and pituitary gland of rats was investigated. Brain ACTH was further characterized by fractionation by gel-permeation chromatography. Porcine 1-39 ACTH was exposed to synaptic plasma membranes in vitro in order to evaluate the role of metabolic conversion in changes of brain ACTH content. Removal of the adrenals, when compared with sham-adrenalectomy, resulted in a transient depletion of ACTH content in the anterior pituitary gland and the hippocampus, but not in the hypothalamus and the neurointermediate lobe. However, sham-adrenalectomy caused a transient reduction in levels of ACTH when compared with levels before operation in all tissues studied. The effects of adrenalectomy on hippocampal ACTH content persisted in hypophysectomized rats. Treatment of adrenalectomized rats with corticosterone failed to restore the reduced ACTH content when it was administered in doses that completely suppressed the release of pituitary ACTH. Adrenal steroids, however, may exert a direct effect on the metabolism of ACTH in the brain as judged from the in-vitro studies with porcine 1-39 ACTH exposed to a synaptosomal plasma membrane fraction of hippocampal tissue. The present study suggests that control of brain ACTH occurs independently of the control of pituitary ACTH release.

Involvement of ACTH and MSH in active and passive avoidance behavior.

Intracerebroventricular injection of antiserum to alpha--MSH induces a weak reduction of passive avoidance latencies after administration prior to retention testing. Administration of antiserum to ACTH 1--24 induces a more marked effect in this respect, whereas injection of a combination of these antisera results in the strongest reduction of passive avoidance retention. No effect of this treatment is observed when these antisera are injected immediately after the learning trial. In active avoidance behavior a facilitation of extinction of the response is observed after intracerebroventricular administration of the antisera prior to each extinction session. This effect is comparable with the one observed in passive avoidance behavior. From these data it is suggested that ACTH and alpha-MSH play an important role in processes related to the retrieval of information stored in the brain.