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Background & Aims: CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance in both rodents and humans. Low-dose IL-2 (LDIL-2) can expand human endogenous circulating Tregs in vivo, but its role in suppressing antigen-specific responses and promoting Treg trafficking to the sites of inflammation is unknown. Likewise, whether LDIL-2 facilitates the induction of allograft tolerance has not been investigated in humans., Methods: We conducted a clinical trial in stable liver transplant recipients 2-6 years post-transplant to determine the capacity of LDIL-2 to suppress allospecific immune responses and allow for the complete discontinuation of maintenance immunosuppression (ClinicalTrials.gov NCT02949492). One month after LDIL-2 was initiated, those exhibiting at least a 2-fold increase in circulating Tregs gradually discontinued immunosuppression over a 4-month period while continuing LDIL-2 for a total treatment duration of 6 months., Results: All participants achieved a marked and sustained increase in circulating Tregs. However, this was not associated with the preferential expansion of donor-reactive Tregs and did not promote the accumulation of intrahepatic Tregs. Furthermore, LDIL-2 induced a marked IFNγ-orchestrated transcriptional response in the liver even before immunosuppression weaning was initiated. The trial was terminated after the first 6 participants failed to reach the primary endpoint owing to rejection requiring reinstitution of immunosuppression., Conclusions: The expansion of circulating Tregs in response to LDIL-2 is not sufficient to control alloimmunity and to promote liver allograft tolerance, due, at least in part, to off-target effects that increase liver immunogenicity. Our trial provides unique insight into the mechanisms of action of immunomodulatory therapies such as LDIL-2 and their limitations in promoting alloantigen-specific effects and immunological tolerance., Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT02949492)., Impact and Implications: The administration of low-dose IL-2 is an effective way of increasing the number of circulating regulatory T cells (Tregs), an immunosuppressive lymphocyte subset that is key for the establishment of immunological tolerance, but its use to promote allograft tolerance in the setting of clinical liver transplantation had not been explored before. In liver transplant recipients on tacrolimus monotherapy, low-dose IL-2 effectively expanded circulating Tregs but did not increase the number of Tregs with donor specificity, nor did it promote their trafficking to the transplanted liver. Low-dose IL-2 did not facilitate the discontinuation of tacrolimus and elicited, as an off-target effect, an IFNγ-orchestrated inflammatory response in the liver that resembled T cell-mediated rejection. These results, supporting an unexpected role for IL-2 in regulating the immunogenicity of the liver, highlight the need to carefully evaluate systemic immunoregulatory strategies with investigations that are not restricted to the blood compartment and involve target tissues such as the liver., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Research Question: How are perinatal outcomes of live-born singletons after stimulated and unstimulated IVF different from perinatal outcomes in (i) children born in a tertiary centre and (ii) all children born in Switzerland?, Methods: This cohort study compared the perinatal outcomes of two birth cohorts and the national live birth registry. Relative risks were calculated using modified Poisson regression and clustering for siblings and adjustment for maternal age, parity and childs sex., Results: Of the 636,639 live births, 311 were in the Bern IVF Cohort (144 stimulated, 167 unstimulated), 2332 in the tertiary centre and 633,996 in the Swiss Live Birth Registry (SLBR). Perinatal outcomes following IVF did not differ compared with births in the SLBR (adjusted relative risk [aRR]; 95% confidence interval [CI]), with the exception of the increased risk of small for gestational age (1.31; 1.01 to 1.70, P = 0.04; aRR 1.12; 0.87 to 1.45, P = 0.39). Children born following stimulated IVF had a higher risk of low birthweight (2.17; 1.27 to 3.69, P < 0.01; aRR 1.72; 1.01 to 2.93, P = 0.05), and of being small for gestational age (1.50; 1.05 to 2.14, P = 0.03; aRR 1.31; 0.92 to 1.87; P = 0.13), whereas children born after unstimulated IVF had no increased risks compared with the SLBR. Higher Caesarean rate after IVF was mainly associated with higher maternal age., Conclusion: Singletons in the Bern IVF Cohort do not show less favourable perinatal outcomes. Gonadotrophin stimulation seems to have an effect, because lower risks were associated with unstimulated IVF., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The aim is assessing the in vivo efficacy of annulus fibrosus (AF) cells seeded into collagen by enhancing the reparative process around annular defects and preventing further degeneration in a rat-tail model., Summary of Background Data: Treating disc herniation with discectomy may relieve the related symptoms but does not address the underlying pathology. The persistent annular defect may lead to re-herniation and further degeneration. We recently demonstrated that riboflavin crosslinked high-density collagen gels (HDC) can facilitate annular repair in vivo., Methods: 42 rats, tail disc punctured with an 18-gauge needle, were divided into 3 groups: untreated (n = 6), injected with crosslinked HDC (n = 18), and injected with AF cell-laden crosslinked HDC (n = 18). Ovine AF cells were mixed with HDC gels prior to injection. X-rays and MRIs were conducted over 5 weeks, determining disc height index (DHI), nucleus pulposus (NP) size, and hydration. Histological assessments evaluated the viability of implanted cells and degree of annular repair., Results: Although average DHIs of both HDC gel groups were higher than those of the puncture control group at 5 weeks, the retention of disc height, NP size and hydration at 1 and 5 weeks was significant for the cellular group compared to the punctured, and at 5 weeks to the acellular group. Histological assessment indicated that AF cell-laden HDC gels have accelerated reparative sealing compared to acellular HDC gels., Conclusions: AF cell-laden HDC gels have the ability of better repairing annular defects than acellular gels after needle puncture., Statement of Significance: This project addresses the compelling demand of a sufficient treatment strategy for degenerative disc disease (DDD) perpetuated by annulus fibrosus (AF) injury, a major cause of morbidity and burden to health care systems. Our study is designed to answer the question of whether injectable, photo-crosslinked, high density collagen gels can seal defects in the annulus fibrosus of rats and prevent disc degeneration. Furthermore, we investigated whether the healing of AF defects will be enhanced by the delivery of AF cells (fibrochondrocytes) to these defects. The use of cell-laden collagen gels in spine surgery holds promise for a wide array of applications, from current discectomy procedures to future nucleus pulposus reparative therapies, and our group is excited about this potential., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Two-dimensional radiographic methods have been proposed to evaluate the radiographic outcome after indirect decompression through extreme lateral interbody fusion (XLIF). However, the assessment of neural decompression in a single plane may underestimate the effect of indirect decompression on central canal and foraminal volumes. The present study aimed to assess the reliability and consistency of a novel 3-dimensional radiographic method that assesses neural decompression by volumetric analysis using a new generation of intraoperative fan-beam computed tomography scanner in patients undergoing XLIF., Methods: Prospectively collected data from 7 patients (9 levels) undergoing XLIF was retrospectively analyzed. Three independent, blind raters using imaging analysis software performed volumetric measurements pre- and postoperatively to determine central canal and foraminal volumes. Intrarater and Interrater reliability tests were performed to assess the reliability of this novel volumetric method., Results: The interrater reliability between the three raters ranged from 0.800 to 0.952, P < 0.0001. The test-retest analysis on a randomly selected subset of three patients showed good to excellent internal reliability (range of 0.78-1.00) for all 3 raters. There was a significant increase in mean volume ≈20% for right foramen, left foramen, and central canal volumes postoperatively (P = 0.0472; P = 0.0066; P = 0.0003, respectively)., Conclusions: Here we demonstrate a new volumetric analysis technique that is feasible, reliable, and reproducible amongst independent raters for central canal and foraminal volumes in the lumbar spine using an intraoperative computed tomography scanner., (Copyright © 2017. Published by Elsevier Inc.)

Background: Recently, novel mobile intraoperative fan-beam computed tomography (CT) was introduced, allowing for real-time navigation and immediate intraoperative evaluation of neural decompression in spine surgery. This study sought to investigate whether intraoperatively assessed neural decompression during minimally invasive spine surgery (MISS) has a predictive value for clinical and radiographic outcome., Methods: A retrospective study of patients undergoing intraoperative CT (iCT)-guided extreme lateral interbody fusion or transforaminal lumbar interbody fusion was conducted. 1) Preoperative, 2) intraoperative (after cage implantation, 3) postoperative, and 4) follow-up radiographic and clinical parameters obtained from radiography or CT were quantified., Results: Thirty-four patients (41 spinal segments) were analyzed. iCT-based navigation was successfully accomplished in all patients. Radiographic parameters showed significant improvement from preoperatively to intraoperatively after cage implantation in both MISS procedures (extreme lateral interbody fusion/transforaminal lumbar interbody fusion) (P ≤ 0.05). Radiologic parameters for both MISS fusion procedures did not show significant differences to the assessed radiographic measures at follow-up (P > 0.05). Radiologic outcome values did not decrease when compared intraoperatively (after cage implantation) to latest follow-up., Conclusions: Intraoperative fan-beam CT is capable of assessing neural decompression intraoperatively with high accuracy, allowing for precise prediction of radiologic outcome and earliest possible feedback during MISS fusion procedures. These findings are highly valuable for routine practice and future investigations toward finding a threshold for neural decompression that translates into clinical improvement. If sufficient neural decompression has been confirmed with iCT imaging studies, additional postoperative and/or follow-up imaging studies might no longer be required if patients remain asymptomatic., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Morbidity and mortality from cardiovascular diseases have decreased since the 1970s in most Western societies. However, it is unclear if this positive trend can also be found in younger women suffering from acute coronary syndrome (ACS)., Methods: This is a prospective single center registry study including 11.015 women and men hospitalized for a first ACS between the years 2001 and 2010. We analyzed ACS rates according to sex and age group using Poisson regression in order to assess temporal trends., Results: Overall ACS hospitalization rates per 100.000 inhabitants increased by 31% between 2001 and 2010 (Rate Ratio (RR) of 1.31, 95% CI 1.20-1.43; p<0.001) with a similar increase in men (RR 1.29, p<0.00001) and women (RR 1.35, p<0.0001). Analyses of age-specific ACS rates showed a significant increase in ACS hospitalization rates only for the age groups 70-79years (p=0.003) and 80+ years (p<0.00001). None of the age matched subgroups showed a sex related significant difference in trend for ACS hospitalization rates. Temporal trends for recorded risk factors showed a significant increase in smoking (p=0.03), and a trend to increased obesity prevalence (p=0.06) in females in the age group 60-69years., Conclusions: In contrast to other studies, we found no evidence for a particular increase in the number of younger women referred for a first ACS during the years 2001 and 2010. Potential negative effects of smoking and obesity on ACS incidence may be delayed to women older than 70years., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Novel tissue engineered and biomaterial approaches to treat intervertebral disc (IVD) degeneration focus on single aspects of the progressive disease and hence are insufficient repair strategies. In this study, annulus fibrosus (AF) and nucleus pulposus (NP) biomaterial repair strategies were used individually and combined to treat IVD degeneration modeled in ex vivo rat-tail motion segments by annulotomy and nucleotomy. An injectable riboflavin cross-linked high-density collagen gel patched defects in the AF, while NP repair consisted of injections of a modified hyaluronic acid (HA) hydrogel. Qualitative imaging showed the annulotomy and nucleotomy successfully herniated NP material, while the HA NP injections restored intact NP morphology and the collagen AF patches sealed AF defects. Assessed by quantitative T2 magnetic resonance imaging, combined repair treatments yielded disc hydration not significantly different than intact hydration, while AF and NP repairs alone only restored ∼1/3 of intact hydration. Mechanical testing showed NP injections alone recovered on average ∼35% and ∼40% of the effective instantaneous and equilibrium moduli. The combined treatment comprising biomaterial AF and NP repair was effective at increasing NP hydration from NP repair alone, however HA injections alone are sufficient to improve mechanical properties., Statement of Significance: Intervertebral disc degeneration affects an estimated 90% of individuals throughout their life, and is a candidate pathology for tissue engineered repair. The current standard of clinical care reduces spinal articulation and leads to further degeneration along the spine, hence great interest in a regenerative medicine therapy. Literature studies focused on biomaterial repair strategies for treating degenerated discs have partially restored native disc function, however no studies have reported the use of combined therapies to address multiple aspects of disc degeneration. This initial investigation screened injectable biomaterial repair strategies ex vivo, and through complementary outcome measures showed a combined therapy restores disc function better than individual approaches. This study is the first of its kind to address multiple aspects of disc degeneration, using clinically-oriented biomaterials in a well-established animal model., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Portable intraoperative computed tomography (iCT) with integrated 3-dimensional navigation (NAV) offers new opportunities for more precise navigation in spinal surgery, eliminates radiation exposure for the surgical team, and accelerates surgical workflows. We present the concept of "total navigation" using iCT NAV in spinal surgery. Therefore, we propose a step-by-step guideline demonstrating how total navigation can eliminate fluoroscopy with time-efficient workflows integrating iCT NAV into daily practice., Methods: A prospective study was conducted on collected data from patients undergoing iCT NAV-guided spine surgery. Number of scans, radiation exposure, and workflow of iCT NAV (e.g., instrumentation, cage placement, localization) were documented. Finally, the accuracy of pedicle screws and time for instrumentation were determined., Results: iCT NAV was successfully performed in 117 cases for various indications and in all regions of the spine. More than half (61%) of cases were performed in a minimally invasive manner. Navigation was used for skin incision, localization of index level, and verification of implant position. iCT NAV was used to evaluate neural decompression achieved in spinal fusion surgeries. Total navigation eliminates fluoroscopy in 75%, thus reducing staff radiation exposure entirely. The average times for iCT NAV setup and pedicle screw insertion were 12.1 and 3.1 minutes, respectively, achieving a pedicle screw accuracy of 99%., Conclusions: Total navigation makes spine surgery safer and more accurate, and it enhances efficient and reproducible workflows. Fluoroscopy and radiation exposure for the surgical staff can be eliminated in the majority of cases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Skin conductance (SC) has been previously used to measure acute post-operative pain in adults and older children (>1year old).We have investigated the ability of SC to predict the severity of post-operative pain scores in the exclusively infant population., Methods: Infants (ages 6-12months) scheduled for elective surgery were recruited for the study. Data for behavioral pain scores and SC values - frequency of electrodermal responses per second (EDR/s), peak and basal levels, were recorded in the post-anesthesia care unit (PACU). Blood samples were collected for genomic studies, including single nucleotide polymorphisms (SNP) in morphine opioid receptor (MOR) A118G and the catechol-O-methyltransferase (COMT) G1947A genes., Results: 31 infants, mean age 8.9months (±1.9); mean weight 8.5kg (±1.1) were included in the final study analysis. With every 0.1 unit increase in peak values noted on SC, the odds of higher pain scores were found to be 5% greater (p=0.03). For predictability of moderate to severe pain, the area under the curve, sensitivity and specificity were 0.64, 90.9% and 51.4% respectively for peak values and 0.66, 54.5% and 79.4% respectively for EDR/s values. Genotyping performed in 16 out of 31 infants demonstrated that the carriers of MOR 118G allele had consistently higher basal SC values in the PACU., Conclusion: Peak SC values may serve as indicators of unmitigated pain. Further studies are needed to fully investigate the effect of MOR A118G SNP on the post operative pain scores and SC values in the larger infant population in order to validate both the clinical significance of the skin conductance for routine pain assessment in infants and the observed genetic effect., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Regulatory T cells (Tregs) play a fundamental role in the suppression of different immune responses; however, compartments at which they exert suppressive functions in vivo are unknown. Although many groups have described the presence of Tregs within inflammatory sites, it has not been shown that inflamed tissues are, indeed, the sites of active suppression of ongoing immune reactions. Here, by using alpha(E)+ effector/memory-like Tregs from fucosyltransferase VII-deficient animals, which lack E/P-selectin ligands and fail to migrate into inflamed sites, we analyzed the functional importance of appropriate Treg localization for in vivo suppressive capacity in an inflammation model. Lack of suppression by Tregs deficient in E/P-selectin ligands demonstrates that immigration into inflamed sites is a prerequisite for the resolution of inflammatory reactions in vivo because these selectin ligands merely regulate entry into inflamed tissues. In contrast, control of proliferation of naive CD4+ T cells during the induction phase of the immune response is more efficiently exerted by the naive-like alpha(E)-CD25+ Treg subset preferentially recirculating through lymph nodes when compared with its inflammation-seeking counterpart. Together, these findings provide the first conclusive evidence that appropriate localization is crucial for in vivo activity of Tregs and might have significant implications for anti-inflammatory therapies targeting recruitment mechanisms.

A continuous microtiter plate nucleotidyltransferase substrate screening assay (NUSSA) is described which allows the identification of nucleotide sugar-synthesizing enzyme activities. The assay is accomplished by the determination of the common product of these enzymes PPi with a PPi-dependent phosphofructokinase. A subsequent enzyme reaction cascade leads to the production of 2 mol NAD per mol PPi. PPi-dependent phosphofructokinase was purified from potato with respect to contaminating enzyme activities which would disturb NUSSA performance. NUSSA allows the quick, simultaneous, and comprehensive check of different sugar 1-phosphate and nucleoside triphosphate substrates using purified pyrophosphorylases or crude extracts of plants, microorganisms, and mammalian tissues. Moreover, NUSSA will assist to evaluate these enzymes for the synthesis of important nucleotide sugars which serve as substrates of glycosyltransferases in carbohydrate syntheses.

A fluorometric method for determining bethanidine in blood plasma is described. The bethanidine is extracted into chloroform, a drug-dye complex with eosin Y is formed, and the fluorescence is measured (excitation, 535 nm; fluorescence, 560 nm). The assay detects 0.02 muM bethanidine (4 ng/ml) in plasma. The relative fluorescence of several body constituents and antihypertensive drugs is negligible. The plasma levels of bethanidine in four hypertensive patients receiving this drug were measured.

In a previous study of the comprehension of linguistic prosody in brain-damaged subjects, S. R. Grant and W. O. Dingwall (1984. The role of the right hemisphere in processing linguistic prosody, presentation at the Academy of Aphasia, 1984) demonstrated that the right hemisphere (RH) of nonaphasic patients plays a prominent role in the processing of stress and intonation. The present study examines laterality for affective and linguistic prosody using the dichotic listening paradigm. Both types of prosody elicited a significant left ear advantage. This advantage was more pronounced for affective than for linguistic prosody. These findings strongly support previously documented evidence of RH involvement in the processing of affective prosody (R. G. Ley & M. P. Bryden, 1982. A dissociation of right and left hemispheric effects for recognizing emotional tone and verbal content, Brain and Cognition, 1, 3-9). They also provide support for the previously mentioned demonstration of RH involvement in the processing of linguistic intonation (S. Blumstein & W. E. Cooper, 1974. Hemispheric processing of intonation contours, Cortex, 10, 146-158; Grant & Dingwall, 1984).

Anti-RNA polymerase I antibodies were detected by radioimmunoassay in the sera of 8 out of 9 Sjögren's syndrome patients, 11 out of 19 individuals with scleroderma, and 19 out of 19 systemic lupus erythematosus patients. The results of the radioimmunoassay were confirmed by demonstrating the ability of the patients' IgG to inhibit RNA polymerase I activity in vitro. Sera from four patients in each category were also tested for reaction with individual subunits of RNA polymerase I. All 4 SLE sera, 3 out of 4 scleroderma sera and 1 out of 4 Sjögren's syndrome sera contained antibodies against the 65 kDa (S3) subunit of RNA polymerase I in addition to antibodies against one other subunit. Sera from the remaining scleroderma and Sjögren's syndrome patients tested in this assay contained only anti-S3 antibodies. These results demonstrate that anti-RNA polymerase I antibodies are characteristic of a variety of rheumatic autoimmune sera.