In search of a dose-response relationship in SSRIs-a systematic review, meta-analysis, and network meta-analysis.

OBJECTIVE: Recent meta-analyses on dose-response relationships of SSRIs are largely based on indirect evidence. We analyzed RCTs directly comparing different SSRI doses. METHOD: Systematic literature search for RCTs. Two raters independently screened articles and extracted data. Across SSRIs, doses defined as low, medium, and high doses, based on drug manufacturers' product monographs, were analyzed in pairwise random-effects meta-analyses and in a sensitivity network meta-analysis with regard to differences in antidepressive efficacy (primary outcome). We also analyzed all direct comparisons of different dosages of specific SSRIs. (Prospero CRD42018081031). RESULTS: Out of 5333 articles screened, we included 33. Comparisons of dosage groups (low, medium, and high) resulted in only small and clinically non-significant differences for SSRIs as a group, the strongest relating to medium vs low doses (SMD: -0.15 [95%-CI: -0.28; -0.01) and not sustained in a sensitivity analysis. Among different doses of specific SSRIs, no statistically significant trend emerged for efficacy at higher doses, but 60 mg/day fluoxetine are statistically significantly inferior to 20 mg/day. Paroxetine results are inconclusive: 10 mg/day are inferior to higher doses, but 30 and 40 mg/day are inferior to 20 mg/day. Meaningful effects cannot be ruled out for certain drugs and dosages, often investigated in only one trial. Dropout rates increase with dose-particularly due to side effects. Network meta-analyses supported our findings. CONCLUSIONS: There is no conclusive level I or level II evidence of a clinically meaningful dose-response relationship of SSRIs as a group or of single substances. High SSRI doses are not recommended as routine treatment.

Experimental peri-implant mucositis around titanium and zirconia implants in comparison to a natural tooth: part 2-clinical and microbiological parameters.

The aim of this study was to assess the clinical and microbiological parameters around dental zirconia and titanium implants compared with natural teeth during experimental plaque accumulation. Clinical parameters were evaluated (gingival index, plaque index, bleeding on probing, and probing pocket depth). Microbiological samples were analyzed for total bacterial cell counts, as well as Tannerella forsythia and Prevotella intermedia counts. A statistically significant difference over time was observed in the groups in terms of the gingival index (P<0.001), plaque index (P<0.001), and bleeding on probing (P=0.039). The lowest mean total number of bacterial cells was measured around the teeth, followed by the zirconia implants; the highest values were found around the titanium implants. T. forsythia and P. intermedia values showed significant changes over time and sessions around the titanium implants. Compared to the soft tissues around zirconia implants and the teeth, those around titanium implants developed a stronger inflammatory response to experimental plaque accumulation in terms of the total number of bacterial cells and T. forsythia and P. intermedia values.

Main biomarkers associated with age-related plasma zinc decrease and copper/zinc ratio in healthy elderly from ZincAge study.

PURPOSE: Zinc (Zn) plays an essential role in many biological processes including immune response. Impaired Zn status promotes immune dysfunction, and it has been associated with enhanced chronic inflammation during aging. It has been suggested that the measurement of circulating Zn by itself could not reflect the real Zn status of an individual. It is therefore necessary to identify other determinants associated with plasma Zn to better understanding how physiopathological conditions during aging may affect the concentration of this metal. METHODS: We have investigated the association between Zn levels and some biomarkers in 1090 healthy elderly from five European countries to increase the accuracy in the assessment of the Zn status. Stepwise multivariate linear regression models were used to analyze the influence of factors such as age, dietary intake, inflammatory mediators, laboratory parameters and polymorphisms previously associated with Zn homeostasis. RESULTS: Plasma Zn decrement was most strongly predicted by age, while positive correlations were found with albumin, RANTES and Zn intake after adjustment for multiple confounders. HSP70 +1267 AA genotype was an independent factor associated with Zn plasma concentrations. Cu/Zn ratio was positively associated with markers of systemic inflammation and age and negatively associated with albumin serum levels. CONCLUSIONS: Our findings show the most important independent determinants of plasma Zn concentration and Cu/Zn ratio variability in elderly population and suggest that the decline with age of Zn circulating levels is more dependent on physiopathological changes occurring with aging rather than to its nutritional intake.

Effects of a short-term reduction in brain serotonin synthesis on the availability of the soluble leptin receptor in healthy women.

Serotonin (5-HT) and the hormone leptin have been linked to the underlying neurobiology of appetite regulation with evidence coming from animal and cellular research, but direct evidence linking these two pathways in humans is lacking. We examined the effects of reduced brain 5-HT synthesis due to acute tryptophan depletion (ATD) on levels of soluble leptin receptor (sOb-R), the main high-affinity leptin binding protein, in healthy adults using an exploratory approach. Women, but not men, showed reduced sOb-R concentrations after ATD administration. With females showing reduced baseline levels of central 5-HT synthesis compared to males diminished brain 5-HT synthesis affected the leptin axis through the sOb-R in females, thereby potentially influencing their vulnerability to dysfunctional appetite regulation and co-morbid mood symptoms.

The biochemical effects of extracellular Zn(2+) and other metal ions are severely affected by their speciation in cell culture media.

Investigations of physiological and toxicological effects of metal ions are frequently based on in vitro cell culture systems, in which cells are incubated with these ions in specialized culture media, instead of their physiological environment. This allows for targeted examination on the cellular or even molecular level. However, it disregards one important aspect, the different metal ion speciation under these conditions. This study explores the role of culture conditions in investigations with zinc ions (Zn(2+)). Their concentration is buffered by several orders of magnitude by fetal calf serum. Due to the complexity of serum and its many zinc-binding components, zinc speciation in culture media cannot be completely predicted. Still, the primary effect is due to the main Zn(2+)-binding protein albumin. Buffering reduces the free Zn(2+) concentration, thereby diminishing its biological effects, such as cytotoxicity and the impact on protein phosphorylation. This is not limited to Zn(2+), but is also observed with Ag(+), Cu(2+), Pb(2+), Cd(2+), Hg(2+), and Ni(2+). Usually, the serum content of culture media, and thereby their metal buffering capacity, is only a fraction of that in the physiological cellular environment. This leads to systematic over-estimation of the effects of extracellular metal ions when standard cell culture conditions are used as model systems for assessing potential in vivo effects.

Association among 1267 A/G HSP70-2, -308 G/A TNF-α polymorphisms and pro-inflammatory plasma mediators in old ZincAge population.

Proinflammatory cytokines and heat shock proteins play relevant roles in the pathogenesis of inflammatory diseases. We investigated whether Hsp70 1267 A/G and TNF-α -308 G/A polymorphisms are associated with proinflammatory mediators, zinc status and laboratory parameters in 1,078 healthy elderly from ZincAge study. Hsp70 1267 A/G genotype and allele distribution were similar among various European countries, while a TNF-α genetic heterogeneity was observed between the Northern and the Southern European populations, with a major frequency of the -308 A variant in France, Germany and Poland. We used linear regression models to test additive, dominant or recessive associations of each SNP with proinflammatory mediators, laboratory parameters, metallothioneins and zinc status. Hsp70 1267 A/G SNP, but not TNF-α -308 G/A SNP, influences TNF-α and IL-6 plasma levels under additive, dominant and recessive models (for TNF-α only). An association between Hsp70 1267 A/G SNP and zinc plasma levels was observed in the dominant model. In particular, G allele carriers showed increased circulating pro-inflammatory cytokines and zinc. Moreover, both these SNPs affect creatinine levels suggesting a possible influence on renal function. In conclusion, Hsp70 1267 A/G SNP is associated with pro-inflammatory cytokine production in healthy elderly and might represent a possible determinant of individual susceptibility to inflammatory diseases.

Zinc deficiency adversely influences interleukin-4 and interleukin-6 signaling.

Zinc deficiency is accompanied by a severe impairment of the immune system, causing a high risk for infections and autoimmune diseases due to altered functionality of B- and T- cells. The influence of zinc deficiency on T- and B- cells via alteration of cytokine expression is well established. The aim of this study was to examine potential direct effects of zinc deficiency on the reactivity of B- and T- cells. Zinc deficient B- and T- cells revealed divergent reaction patterns compared to zinc sufficienT-cells. This was manifested by a stronger proliferative response following IL-6 and IL-2 stimulation on the one hand, but less proliferation following IL-4 stimulation on the other hand. Moreover, these results were supported by the finding that the B- and T-cell signaling cascades activated by IL-4 or IL-6, respectively, were affected directly by zinc deficiency, resulting in reduced Stat6 phosphorylation and increased Stat3 phosphorylation. Whereas the transcription factor Stat6 is involved in IL-4 signaling, Stat3 is activated by IL-6 signaling. Consequently, these results show opposing effects of zinc deficiency on IL-4 and IL-6/IL-2 signaling pathways, thus underlying the importance of zinc for proper immune function.

A nonrandom association of gastrointestinal stromal tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28 patients.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) and desmoid tumors (DTs) are two rare mesenchymal tumor. Anecdotal reports of individuals with both diseases led us to make the hypothesis that the association is a nonrandom event as the probability would be extremely low to observe such cases if they were independent events. PATIENTS AND METHODS: We evaluated the existence of patients with GIST and DT in a large multicenter cohort at 10 institutions in the United States, Australia and Europe. Data on gender, age at diagnosis, KIT, PDGFRA, CTNNB1 mutation status and follow-up time after diagnosis were collected. RESULTS: We identified 28 patients diagnosed with both tumors. DT was diagnosed after GIST in 75% of patients and concomitantly in 21%. In only one case (4%), GIST was diagnosed after DT. KIT or PDGFRA mutations were detected in 12 of 14 GIST, 9 in KIT exon 11, 2 in KIT exon 9 and 1 in PDGFRA. CONCLUSION: A statistical analysis of these 28 cases suggests a nonrandom association between GIST and DT. Further studies may be able to elucidate the underlying biology responsible for this association.

Effects of zinc supplementation on antioxidant enzyme activities in healthy old subjects.

A large body of experimental research indicates that oxidative stress contributes to the processes related to aging and age-related diseases. Trace elements, particularly zinc (Zn), are essential components of the endogenous enzymatic antioxidant defenses. The aim of this study was to determine the activity of three main antioxidant enzymes in plasma [i.e. superoxide dismutase (pSOD), catalase (CAT), glutathione peroxidase (GPx)] and of SOD in erythrocyte (eSOD) in a group of 1108 healthy elderly subjects from different European countries. The same enzymatic activities were evaluated in a subgroup of 108 subjects before and after Zn supplementation. We observed that eSOD activity increased with age, whereas plasma Zn decreased. Moreover, we found that women showed higher eSOD activity and lower plasma Zn compared to men. There were no age and gender-related differences in the activities of pSOD, CAT and GPx. After Zn supplementation, the activities of Zn-dependent enzymes (pSOD and eSOD), as well as plasma Zn concentration, were significantly higher than before supplementation. These results were not influenced by age, gender, plasma Zn variations (Delta Zn) and geographic area. These data suggest the potential beneficial effects of Zn supplementation on Zn-dependent antioxidant enzymes in healthy elderly subjects.

Zinc in pharmacological doses suppresses allogeneic reaction without affecting the antigenic response.

Zinc is an essential trace element for the immune system. Previously it was shown that zinc inhibits alloreactivity. In our present in vitro experiments, it is shown that zinc maintains the antigenic potency of the host while blocking the allogeneic response. These results were observed in experiments using tetanus toxoid as a well-established recall antigen and the mixed lymphocyte culture as an in vitro model for allogeneic reaction. To prove the in vivo relevance, an ex vivo experimental setup was established. This involved participants taking zinc orally for 1 week. Here it is shown that in vivo zinc application induced the same effect of blocking the mixed lymphocyte culture without influencing tetanus toxoid stimulation. So far, no clinical application studies have been performed, but the observed selective suppression of allogeneic reaction by zinc is the first step towards a new generation of immunosuppressants.

Impaired serum cortisol stress response is a predictor of early relapse.

AIMS: to investigate a possible association of cortisol stress response during early abstention with relapse. METHODS: Thirty-six alcohol-dependent males, half of them with a comorbid anxiety disorder, and 15 healthy controls were exposed to a standardized psychosocial stress test. Thirty-one of the patients were assessed for relapse 6 weeks after discharge. RESULTS: The relapsers showed almost no cortisol responses in the stress test. Comorbid anxiety disorder influenced neither stress response nor relapse. CONCLUSIONS: During early abstention from alcohol, reduced stress-responsivity of the hypothalamo-pituitary-adrenocortical axis seems to be connected to early relapse.

Inter-individual differences in cytokine release in patients undergoing cardiac surgery with cardiopulmonary bypass.

Cardiac surgery with cardiopulmonary bypass (CPB) leads to a systemic inflammatory response with secretion of cytokines (e.g. IL-6, TNF-alpha, IL-1 beta and sIL-2R). The objective of the following study was to investigate in vitro and in vivo cytokine responses and white blood cell counts (WBC) of patients with high versus low cytokine secretion after a coronary artery bypass grafting (CABG) procedure. Twenty male patients undergoing elective CABG surgery with CPB under general anaesthesia were enrolled in the study. On the day of surgery (postoperatively), serum levels of TNF-alpha and IL-1 beta were significantly higher in patients of the high IL-6 level group compared to the respective values in the patient group with low IL-6 levels. The inter-individual differences in IL-6 release in patients undergoing CABG surgery with CPB were accompanied by differences in the release of other cytokines, such as TNF-alpha, IL-1 beta and sIL-2R. To understand whether genetic background plays a role in influencing cytokine plasma levels under surgical stress, we examined the distribution of polymorphic elements within the promoter regions of the TNF-alpha and IL-6 genes, and determined their genotype regarding the BAT2 gene and TNF-beta intron polymorphisms. Our preliminary data suggests that regulatory polymorphisms in or near the TNF locus, more precisely the allele set 140/150 of the BAT2 microsatellite marker combined with the G allele at -308 of the TNF-alpha gene, could be one of the genetic constructions providing for a less sensitive response to various stimuli. Our results suggest: (1) close relationships between cytokine release in the postoperative period, and (2) inter-individually varying patterns of cytokine release in patients undergoing CABG surgery with CPB.

Induction of interleukin-8 in human neutrophils after MHC class II cross-linking with superantigens.

Neutrophils have been shown to express major histocompatibility complex class II (MHC II) after stimulation. However, reports concerning the functional effect of MCH II expression are still lacking. In our hands, granulocyte-monocyte colony-stimulating factor (GM-CSF) alone and in combination with interferon (IFN)-gamma, but not IFN-gamma or interleukin (IL)-3, induced a significant level of expression of human leukocyte antigen DR on neutrophils. The addition of staphylococcal enterotoxin E to neutrophils resulted in a significant increase in IL-8 production only after prestimulation with GM-CSF alone or in combination with IFN-gamma but had no effect on neutrophils preincubated with IFN-gamma alone or IL-3. Staphylococcal enterotoxin A, another bivalent superantigen, also stimulated production of IL-8 by preincubated polymorphonuclear neutrophils, whereas staphylococcal enterotoxin A mutants that are not able to cross-link MHC II molecules failed to induce IL-8 production. Taken together, our results clearly demonstrate that after induction of MHC II, neutrophils are able to respond to MHC II-specific stimulation. These findings support the ideas that the induced MHC II complex is completely functional and that neutrophils may be able to present antigens.

Human neutrophils produce macrophage inhibitory protein-1beta but not type i interferons in response to viral stimulation.

Several cell types have been shown to produce type I interferons (IFN). Of human leukocytes, monocytes and especially type 2 dendritic cell precursors (pDC2) seem to be the main producers and also have a wide spectrum of cytokine production. However, neutrophils seem to have a limited capacity for cytokine production but possess efficient defense mechanisms vs. bacterial infection by phagocytosis and degranulation. To determine whether they also have antiviral functions, IFN-alpha and IFN-beta were measured in preparations of pure neutrophils. The capacity of neutrophils to produce type I IFN is controversial. Additionally, macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta were measured, as they are described to have indirect or direct antiviral activity. As stimulants, active and inactivated Newcastle disease virus (NDV), Sendai virus, and granulocyte colony-stimulating factor (G-CSF) were used. Peripheral blood mononuclear cells (PBMC) from the same donors were highly reactive to viral stimulation, whereas neutrophils failed to produce IFN but produced MIP-1beta in response to NDV. We conclude that neutrophils fail to prevent viral infection by IFN production but probably possess alternative mechanisms, such as secreting MIP-1beta in response to viruses.

Zinc inhibits the mixed lymphocyte culture.

The mixed lymphocyte culture (MLC) is an established clinical method for bone marrow transplantation, as it serves as an in vitro model for allogenic reaction and transplantation. We previously showed that cytokine release into the supernatant is a more specific and sensitive parameter for cross-reactivity in the MLC than the common measurement of cell proliferation. Therefore we tried to find an inhibitor of the MLC in vitro with the least side effects in vivo, measuring interferon (IFN)-gamma as one of the most important cytokines in posttransplant medicine. Earlier studies showed that zinc is an important trace element for immune function with both stimulatory and inhibitory effects on immune cells. We found that slightly elevated zinc concentrations (three to four times the physiological level), which do not decrease T-cell proliferation in vitro nor produce immunosuppressive effects in vivo, suppress alloreactivity in the mixed lymphocyte culture. In this report we analyzed the mechanism whereby zinc influences the MLC to possibly find a nontoxic way of immunosuppression.

Leucocyte response and anti-inflammatory cytokines in community acquired pneumonia.

BACKGROUND: In the host defence of the lung neutrophils (PMN) play a central role. Apart from antimicrobial properties, recent data indicate that PMN also exert anti-inflammatory effects by stimulation and release of cytokine antagonists such as interleukin-1 receptor antagonist (IL-1ra). METHODS: Cytokine release from lipopolysaccharide stimulated whole blood was studied in 18 patients with community acquired pneumonia (CAP) and severe co-morbidities at admission and after 24 hours. Release of IL-1ra, interleukin-1beta (IL-1beta), tumour necrosis factor alpha (TNFalpha), soluble TNF receptor type I (sTNF-RI), and IL-8 was determined by ELISA. RESULTS: The mean (SD) leucocyte level at admission was 12.5 (4.1)/nl. There was a significant correlation between the release of anti-inflammatory cytokines such as IL-1ra and sTNF-RI and the leucocyte count at admission and after 24 hours. Additional in vitro experiments showed that co-incubation of peripheral blood mononuclear cells with autologous PMN led to a marked dose dependent increase in IL-1ra and sTNF-RI release. CONCLUSION: These results indicate that PMN may be responsible for the increase in anti-inflammatory cytokines in CAP. Strategies to increase neutrophil counts may exert beneficial effects, not only by augmenting the antimicrobial activity but also by modulating the inflammatory cytokine response.

Extracellular and immunological actions of zinc.

Zinc is an essential trace element for the immune system, but also very important in other organ systems. Every highly proliferating cell system is dependent on sufficient availability of zinc. During the last decades the influence of zinc on various cell systems have been investigated. Multiple effects of exogenously added zinc have been described in in vitro culture systems and in in vivo systems. However, most of these effects are so far poorly understood, and the dosages used in the in vitro systems are not comparable and sometimes unphysiologically high. Especially in the immune system a number of effects were described and over the last ten years we have come to understand some molecular mechanisms of zinc in this cell system. A zinc deficiency is accompanied by an immunodeficiency, resulting in an increased number of infections. However, the immune function is delicately regulated by zinc, since both increased and decreased zinc levels result in a disturbed immune function. Therefore, zinc supplementation must be accurately supervised. In this review, we discuss the activity of extracellular zinc in four sections. 1. The effect of zinc on different in vitro cell systems, including keratinocytes, osteocytes and leukocytes, and the concentrations of zinc needed for a specific cell response. 2. The modulation of the innate immune system in vitro and in vivo. 3. The role of zinc in the B cell response and antibody production. 4. Effects of zinc on the development and function of T cells.

[The immune system in aging]. / Das Immunsystem im Alter.

The immune system changes during life time. In this article we review which kinds of alterations take place. To exclude changes based on illnesses or chronical diseases, the SENIEUR protocol was performed, which defines "healthy elderly people". We focus on alterations in lymphocyte subsets, immunoglobulins and the cytokine network. Monocytes, eosinophils and basophils are without change during life, whereas the number of neutrophils and natural killer (NK) cells increase with aging. T- and B-lymphocytes are diminished in number as well as in function. The serum levels of immunoglobulins are mostly increased. The balance between TH1- and TH2-cells is disturbed and also TH1- and TH2-specific cytokines. Theses changes and their effects on the health status of the elderly are discussed in detail.

Evidence for presence of IgG4 anti-immunoglobulin autoantibodies in all human beings.

IgG4 anti-IgG autoantibodies were found to be present in all serum samples from a group of healthy people; IgG4 ant-IgA and anti-IgE were present In only 13 of 218 (6%) and 8 of 218 (3.5%) samples, respectively. These antibodies also showed affinities towards animal immunoglobulins. We suggest that IgG4 anti-IgA antibodies (the strongest found heterophilic Immunoglobulins) are responsible for most artifacts obtained with commercial EUSA systems.

Zinc-altered immune function and cytokine production.

Although the intriguing role of zinc as an essential trace element for immune function is well established, particular progress in determining the molecular principles of action of this ion was made recently. Leukocyte responsiveness is delicately regulated by zinc concentration. Zinc deficiency as well as supraphysiologic levels impair immune function. Furthermore, the activities of many immunostimulants frequently used in immunologic studies are influenced by zinc concentration. Therefore, our knowledge from in vitro studies is widely dependent on the zinc concentration, and when not in physiologic range, immunologic responses are artificially low. Decreased production of TH1 cytokines and interferon-alpha by leukocytes in the healthy elderly person is correlated with low zinc serum level. The defect in interferon-alpha production is reconstituted by the addition of physiologic amounts of zinc in vitro. Interestingly, zinc induces cytokine production by isolated leukocytes. Zinc induces monocytes to produce interleukin-1, interleukin-6 and tumor necrosis factor-alpha in peripheral blood mononuclear cells and separated monocytes. This effect is higher in serum-free medium. However, only in the presence of serum does zinc also induce T cells to produce lymphokines. This effect on T cells is mediated by cytokines produced by monocytes. Stimulation also requires cell-to-cell contact of monocytes and T cells. Information is presented to illustrate the concepts that the zinc concentration must be taken into account whenever in vitro studies are made or complex alterations of immune functions are observed in vivo.