IL-1, IL-18, and IL-33 families of cytokines

Summary: The interleukin-1 (IL-1), IL-18, and IL-33 families of cytokines are related by mechanism of origin, receptor structure, and signal transduction pathways utilized. All three cytokines are synthesized as precursor molecules and cleaved by the enzyme caspase-1 before or during release from the cell. The NALP-3 inflammasome is of crucial importance in generating active caspase-1. The IL-1 family contains two agonists, IL-1α and IL-1β, a specific inhibitor, IL-1 receptor antagonist (IL-1Ra), and two receptors, the biologically active type IL-1R and inactive type II IL-1R. Both IL-1RI and IL-33R utilize the same interacting accessory protein (IL-1RAcP). The balance between IL-1 and IL-1Ra is important in preventing disease in various organs, and excess production of IL-1 has been implicated in many human diseases. The IL-18 family also contains a specific inhibitor, the IL-18-binding protein (IL-18BP), which binds IL-18 in the fluid phase. The IL-18 receptor is similar to the IL-1 receptor complex, including a single ligand-binding chain and a different interacting accessory protein. IL-18 provides an important link between the innate and adaptive immune responses. Newly described IL-33 binds to the orphan IL-1 family receptor T1/ST2 and stimulates T-helper 2 responses as well as mast cells.     

Multicenter Evaluation of the Mycobacteria Growth Indicator Tube for Testing Susceptibility of Mycobacterium tuberculosis to First-Line Drugs

In a multicenter study involving three reference centers for mycobacteria, the reliability of the Mycobacteria Growth Indicator Tube (MGIT) for rapid antimicrobial susceptibility testing (AST) of Mycobacterium tuberculosis was evaluated and compared to the radiometric method (BACTEC 460TB). Test cultures for which the results of the MGIT and BACTEC 460TB tests were discordant were checked by the conventional proportion method on solid medium. Four hundred forty-one isolates have been tested for susceptibility to isoniazid (INH), rifampin (RMP), ethambutol (EMB), and streptomycin (SM). Discrepant results were obtained for three isolates (0.7%) with INH (susceptible by MGIT, resistant by BACTEC 460TB), for four isolates (0.9%) with RMP (susceptible by MGIT, resistant by BACTEC 460TB), for six isolates (1.9%) with EMB (four susceptible by MGIT, resistant by BACTEC 460TB; two resistant by MGIT, susceptible by BACTEC 460TB), and for four isolates (0.9%) with SM (two susceptible by MGIT, resistant by BACTEC 460TB; two resistant by MGIT, susceptible by BACTEC 460TB). When cultures with discordant results were tested by the conventional proportion method, about half of the cultures yielded results similar to the BACTEC 460TB results, while the other half yielded results similar to the MGIT results. Turnaround times were 3 to 14 days (median, 8.8 days) for MGIT and 3 to 15 days (median, 7.8 days) for BACTEC 460TB. There was no statistically significant difference between the susceptibility testing results of the two methods (P > 0.05). These data demonstrate that the MGIT system is an accurate, nonradiometric alternative to the BACTEC 460TB method for rapid susceptibility testing of M. tuberculosis.     

The Factor Structure of the Illness Attitude Scales in A German Population

Background  The illness attitudes scales (IAS) were developed to identify different dimensions of hypochondrical attitudes, fears, beliefs, and abnormal illness behavior (Kellner 1986). Although there are several studies which focus on the scale structure of the IAS, the factor structure has not yet been made quite clear. Purpose  Therefore, the aim of this study was to investigate the factor structure of the IAS on a large representative sample. Method  Participants (N = 1,575) comparable with the general German population regarding sex, age, and education level completed the IAS. For the data analyses, a principal components analyses with subsequent oblique rotations was used. Results  The minimum average partial method suggested a three-factor solution. The three factors were named (1) health anxiety, (2) health behavior, and (3) health habits. Internal consistency (Cronbach’s alpha) for the three scales were (1) α = 0.88, (2) α = 0.75, and (3) α = 0.56. Conclusion  The results support previous findings, namely that the IAS factor structure appears to be less complex than originally suggested by the author. For a sample of the general German population, a three-factor solution fit best. Further items should be added to improve the internal consistency, especially for the third scale (health habits).     

PSGL‐1 and E/P‐selectins are essential for T‐cell rolling in inflamed CNS microvessels but dispensable for initiation of EAE

T‐cell migration across the blood‐brain barrier is a crucial step in the pathogenesis of EAE, an animal model for MS. Live cell imaging studies demonstrated that P‐selectin glycoprotein ligand‐1 (PSGL‐1) and its endothelial ligands E‐ and P‐selectin mediate the initial rolling of T cells in brain vessels during EAE. As functional absence of PSGL‐1 or E/P‐selectins does not result in ameliorated EAE, we speculated that T‐cell entry into the spinal cord is independent of PSGL‐1 and E/P‐selectin. Performing intravital microscopy, we observed the interaction of WT or PSGL‐1^?/? proteolipid protein‐specific T cells in inflamed spinal cord microvessels of WT or E/P‐selectin^?/? SJL/J mice during EAE. T‐cell rolling but not T‐cell capture was completely abrogated in the absence of either PSGL‐1 or E‐ and P‐selectin, resulting in a significantly reduced number of T cells able to firmly adhere in the inflamed spinal cord microvessels, but did not lead to reduced T‐cell invasion into the CNS parenchyma. Thus, PSGL‐1 interaction with E/P‐selectin is essential for T‐cell rolling in inflamed spinal cord microvessels during EAE. Taken together with previous observations, our findings show that T‐cell rolling is not required for successful T‐cell entry into the CNS and initiation of EAE.     

Impact of HIV-1 replication on immunological evolution during long-term dual-boosted protease inhibitor therapy

To explore CD4-cell and viral evolution in relation to different levels of HIV-1 replication, as observed during protease inhibitor (PI)-based antiretroviral therapy. Adult HIV-1 infected cohort patients, receiving historical salvage therapy with daily doses of saquinavir (2,000 mg), ritonavir (200 mg) and either lopinavir (800 mg) or atazanavir (300 mg) for >36 weeks were retrospectively analysed for highest detectable viral load up to week 96 and assigned to groups according to the viral load level: always <50 copies/ml (1), 50–199 copies/ml (2), 200–499 copies/ml (3) and ≥500 copies/ml (4). A total of 126 patients were evaluated; at baseline, median CD4-cell count was 204/mm³, HIV-1 RNA was 5.13 Log10-copies/ml and duration of prior HIV-1 infection was 11.7 years. Patients were assigned by 43, 30, 7 and 20 % to groups 1–4. Median observation time was 136 weeks (range: 38–304); at weeks 48/96, the CD4-cell gains for groups 1–4 were +88/+209, +209/+349, +67/+300 and +114.5/+ 128, respectively. After fitting data in a linear fixed effect model, ascending CD4 slopes were continuously increasing for group 1, similarly for 2 and clearly decreasing for 3–4 (p = 0.0006). Of 25 individuals from group 4, patient number with major IAS-USA protease mutations increased from 5 to 10 before and after failing PI therapy, whereas minor mutations remained stable (n = 18). On double-boosted PI therapy, CD4-cell increases through week 96 were similar for patients at always undetectable or with detection of low viral load. Viral detection >200 copies/ml was associated with decreasing CD4-cell slopes and emergence of major mutations, supporting this as benchmark for virological failure definition on PI therapy.     

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.     

Cellular diversity of human placental stem villi: an ultrastructural and immunohistochemical study

The aim of the study was to investigate the distribution and differentiation of cell types in the stroma of human placental stem villi (SV). A total of 14 human term placental tissues were studied. Double immunolabeling was performed for desmin-vimentin, desmin--smooth actin and vimentin--smooth actin. Cytokeratin 7, proliferating cell nuclear antigen immunolabeling was also performed. Parallel tissue samples were examined by transmission electron microscopy. HSCORE was performed for the semi-quantitative analysis of distribution of cells in the stroma of SV. Vimentin-labeled cells were mostly distributed in the subtrophoblastic area. Desmin-vimentin double immunolabeling was mainly localized in the triangular area and to a lesser degree in the perivascular area and vessel walls (p=<0.001). However, desmin- smooth actin labeling was observed predominantly in the vessel wall and perivascular area. Vimentin- smooth actin immunoreactivity was significantly stronger in the triangular and perivascular areas compared to the vessel walls (p=0.003).

Ultrastructurally, cells in the stroma of SV were mesenchyme cells, reticulum cells, fibroblasts, myofibroblasts, smooth muscle cells, and Hofbauer cells, filamented and vacuolated cells. The differentiation of myofibroblasts in the triangular and perivascular areas may play a role in maturation of SV and villous contractility, modulation of the intervillous space and this may have effects on maternofetal placental circulation.     

Surgical Outcomes after Colorectal Surgery for Endometriosis: A Systematic Review and Meta-analysis

ObjectiveTo assess the impact of type of surgery for colorectal endometriosis—rectal shaving or discoid resection or segmental colorectal resection—on complications and surgical outcomes.Data SourcesWe performed a systematic review of all English- and French-language full-text articles addressing the surgical management of colorectal endometriosis, and compared the postoperative complications according to surgical technique by meta-analysis. The PubMed, Clinical Trials.gov, Cochrane Library, and Web of Science databases were searched for relevant studies published before March 27, 2020. The search strategy used the following Medical Subject Headings terms: (“bowel endometriosis” or “colorectal endometriosis”) AND (“surgery for endometriosis” or “conservative management” or “radical management” or “colorectal resection” or “shaving” or “full thickness resection” or “disc excision”) AND (“treatment”, “outcomes”, “long term results” and “complications”).Methods of Study SelectionTwo authors conducted the literature search and independently screened abstracts for inclusion, with resolution of any difference by 3 other authors. Studies were included if data on surgical management (shaving, disc excision, and/or segmental resection) were provided and if postoperative outcomes were detailed with at least the number of complications. The risk of bias was assessed according to the Cochrane recommendations.Tabulation, Integration, and ResultsOf the 168 full-text articles assessed for eligibility, 60 were included in the qualitative synthesis. Seventeen of these were included in the meta-analysis on rectovaginal fistula, 10 on anastomotic leakage, 5 on anastomotic stenosis, and 9 on voiding dysfunction <30 days. The mean complication rate according to shaving, disc excision, and segmental resection were 2.2%, 9.7%, and 9.9%, respectively. Rectal shaving was less associated with rectovaginal fistula than disc excision (odds ratio [OR] = 0.19; 95% confidence interval [CI], 0.10–0.36; p <.001; I² = 33%) and segmental colorectal resection (OR = 0.26; 95% CI, 0.15–0.44; p <.001; I² = 0%). No difference was found in the occurrence of rectovaginal fistula between disc excision and segmental colorectal resection (OR = 1.07; 95% CI, 0.70–1.63; p = .76; I² = 0%). Rectal shaving was less associated with leakage than disc excision (OR = 0.22; 95% CI, 0.06–0.73; p = .01; I² = 86%). No difference was found in the occurrence of leakage between rectal shaving and segmental colorectal resection (OR = 0.32; 95% CI, 0.10–1.01; p = .05; I² = 71%) or between disc excision and segmental colorectal resection (OR = 0.32; 95% CI, 0.30–1.58; p = .38; I² = 0%). Disc excision was less associated with anastomotic stenosis than segmental resection (OR = 0.15; 95% CI, 0.05–0.48; p = .001; I² = 59%). Disc excision was associated with more voiding dysfunction <30 days than rectal shaving (OR = 12.9; 95% CI, 1.40–119.34; p = .02; I² = 0%). No difference was found in the occurrence of voiding dysfunction <30 days between segmental resection and rectal shaving (OR = 3.05; 95% CI, 0.55–16.87; p = .20; I² = 0%) or between segmental colorectal and discoid resections (OR = 0.99; 95% CI, 0.54–1.85; p = .99; I² = 71%).ConclusionColorectal surgery for endometriosis exposes patients to a risk of severe complications such as rectovaginal fistula, anastomotic leakage, anastomotic stenosis, and voiding dysfunction. Rectal shaving seems to be less associated with postoperative complications than disc excision and segmental colorectal resection. However, this technique is not suitable for all patients with large bowel infiltration. Compared with segmental colorectal resection, disc excision has several advantages, including shorter operating time, shorter hospital stay, and lower risk of postoperative bowel stenosis.     

Prehospital endotracheal intubation in patients with severe traumatic brain injury: Guidelines versus reality

The international Brain Trauma Foundation guidelines recommend prehospital endotracheal intubation in all patients with traumatic brain injury (TBI) and a Glasgow Coma Scale (GCS) ≤ 8. Close adherence to these guidelines is associated with improved outcome, but not all severely injured TBI patients receive adequate prehospital airway support. Here we hypothesized that guideline adherence varies when skills are involved that rely on training and expertise, such as endotracheal intubation.We retrospectively studied the medical records of CT-confirmed TBI patients with a GCS ≤ 8 who were referred to a level 1 trauma centre in Amsterdam (n = 127). Records were analyzed for demographic parameters, prehospital treatment modalities, involvement of an emergency medical service (EMS) and respiratory and metabolic parameters upon arrival at the hospital.Patients were mostly male, aged 45 ± 21 years with a median injury severity score (ISS) of 26. Of all patients for whom guidelines recommend endotracheal intubation, only 56% were intubated. In 21 out of 106 severe cases an EMS was not called for, suggesting low guideline adherence. Especially those TBI patients treated by paramedics tended to develop higher levels of stress markers like glucose and lactate.We observed a low degree of adherence to intubation guidelines in a Dutch urban area. Main reasons for low adherence were the unavailability of specialized care, scoop and run strategies and absence of a specialist physician in cases where intubation was recommended. The discrepancy between guidelines and reality warrants changing practice to improve guideline compliance and optimize outcome in TBI patients.