Serum concentration-guided intravenous magnesium sulfate administration for neuroprotection in patients with aneurysmal subarachnoid hemorrhage: a retrospective evaluation of a 12-year single-center experience.

Delayed cerebral infarction (DCI) is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). The benefits of magnesium sulfate as an alternative treatment are controversial, and most previous studies examined its benefits only as adjunctive treatment to traditional nimodipine. We retrospectively analyzed aSAH patients records with magnesium sulfate between 2010 and 2021. We aimed for a serum magnesium concentration of 2-2.5 mmol/l between post-hemorrhage days 3 and 12. The patients were separated in three groups based on average serum magnesium concentration (magnesium >2 mmol/l, reduced magnesium 1.1-1.9 mmol/l, and no magnesium). Additionally, we assessed delayed cerebral infarction (DCI) and clinical outcome at follow-up, using the modified Rankin Scale (mRS), categorized in favorable (0-3) and unfavorable outcome (4-5). In this analysis, 548 patients were included. Hereof, radiological evidence of DCI could be found in 23.0% (n = 126) of patients. DCI rates were lower if patients' average serum magnesium was higher than 2 mmol/l (magnesium 18.8%, n = 85; reduced magnesium 38.3%, n = 23; no magnesium 51.4%, n = 18; p < 0.001). Also, at the last follow-up, patients in the group with a higher serum magnesium concentration had better outcome (favorable outcome: magnesium 64.7%, n = 293; reduced magnesium 50.0%, n = 30; no magnesium 34.3%, n = 12; p < 0.001). This 12-year study reveals the value of serum concentration-guided magnesium administration in aSAH patients. Our findings demonstrate the safety and efficacy when titrated to a serum concentration of 2-2.5 mmol/l. We observed higher rates of delayed cerebral infarction and unfavorable outcomes in patients with serum concentrations below 2 mmol/l.

Discovery of inhibitors against mycobacterium branched-chain amino acid aminotransferases through in silico screening and experimental evaluation.

Tuberculosis (TB) is one of the most dangerous infectious diseases and is caused by Mycobacterium bovis (Mb) and Mycobacterium tuberculosis (Mt). Branched-chain amino acid aminotransferases (BCATs) were reported to be the key enzyme for methionine synthesis in Mycobacterium. Blocking the methionine synthesis in Mycobacterium can inhibit the growth of Mycobacterium. Therefore, in silico screening of inhibitors can be a good way to develop a potential drug for treating TB. A pyridoxal 5'-phosphate (PLP)-form of Mycobacterium bovis branched-chain amino acid aminotransferases (MbBCAT), an active form of MbBCAT, was constructed manually for docking approximately 150 000 compounds and the free energy was calculated in Autodock Vina. The 10 compounds which had the highest affinity to MbBCAT were further evaluated for their inhibitory effects against MbBCAT. Within the selected compounds, compound 4 (ZINC12359007) was found to be the best inhibitor against MbBCAT with the inhibitory constant Ki of 0·45 µmol l-1 and IC50 of 2·37 µmol l-1 . Our work provides potential candidates to develop effective drugs to prevent TB since the well-known structural information would be beneficial in the structure-based modification and design.

Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes.

BACKGROUND: Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. METHODS: To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. RESULTS: Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. CONCLUSION: We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.

First report of the oil palm disease fungus Marasmius palmivorus from Taiwan causing stem rot disease on native Formosa palm Arenga engleri as new host.

Basidiomata were found on dead stems of wild native Formosa palm (Arenga engleri) in Taiwan. The fungus was identified based on morphology and internal transcribed spacer sequence comparison as the oil palm pathogen Marasmius palmivorus. A pathogenicity test with cultivated mycelium of M. palmivorus positively produced disease symptoms and death of non-wounded Formosa palm tree seedlings under excessive moisture conditions. These results indicate that mycelial inoculum may be more important for pathogenesis than spore inoculum and that the fungus does not require wounds for entry into the plant. Host records in the literature are critically revised. The extended geographical and host distribution indicate a greater risk by M. palmivorus in palm plantations than hitherto anticipated. SIGNIFICANCE AND IMPACT OF THE STUDY: Certain palm species are susceptible to disease caused by Marasmius palmivorus, particularly in oil and coconut palm plantations in tropical countries. Hitherto, there is no published information on the morphology and pathogenicity of the species in Taiwan.

Comparative Analysis and Long-Term Results of Various Septal Extension Graft Types.

Shape, tip projection, and position can be controlled by the use of septal extension grafts (SEG). A retrospective cohort study of patients undergoing primary and secondary rhinoplasty was reviewed. The purpose of this study was to analyze maintenance of nasal length, dorsal length, and nasolabial angle postoperatively comparing different types of SEG using standardized photography and digital measurement. Two-hundred twenty-one patients undergoing rhinoplasty were included. There was a statistically significant change regarding the nasolabial angle during the time of follow-up decreasing from 97.53 to 95.30 degrees. No changes could be found in dorsal and nasal length. There was no significant difference among the techniques used to fixate the SEG. The nasolabial angle appeared to decrease from the position 2 weeks postoperatively without changes in the dorsal and nasal length. This means that the decrease in the nasolabial angle depends on the swelling effect and not on drooping of the tip confirming the reliability of SEG over time.

The plant growth-promoting potential of the mesophilic wood-rot mushroom Pleurotus pulmonarius.

AIMS: To demonstrate the plant growth-promoting potential of a wood-decay mushroom. METHODS AND RESULTS: A wild strain of a white rot fungus (Pleurotus pulmonarius) was found to convert 10 mmol l-1 L-tryptophan (TRP) to approximately 15 µg ml-1 indole-3-acetic acid (IAA) under the optimal growth conditions of 30°C and pH 5 for 15 days. Results of gas chromatography-mass spectrometry indicated IAA synthesis through the indole-3-pyruvic acid pathway when using cellulose as a sole carbon source. The mycelium as well as the culture filtrate promoted the growth and chlorophyll content of seedlings. In a monocotyledonous plant (rice), the number of lateral roots was increased experimentally, whereas in a dicotyledonous plant (tomato), the fungus led to an increased length of shoots and roots. CONCLUSIONS: TRP-dependent IAA production was demonstrated for the first time for P. pulmonarius and may be responsible for enhancing plant growth in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: Synthesis of IAA as the most prevalent phytohormone in plants has been demonstrated for soil microfungi. Pleurotus pulmonarius is reported as an IAA-producing wood-decay macrofungus. The higher temperature optimum of P. pulmonarius isolated from subtropical environment compared to other Pleurotus species from temperate regions makes it more suitable for application in subtropical/tropical regions.

Occurrence of Melibiose-Containing Glycosphingolipids in a Sample of a Sponge-Coral Association (Desmapsamma anchorata/Carijoa riisei).

In our research on biologically active compounds from Vietnamese marine invertebrates, rare melibiose-containing glycosphingolipids were found in a sample of a sponge-coral association (Desmapsamma anchorata/Carijoa riisei). Melibiosylceramides were analyzed as constituents of some multi-component RP-HPLC fractions, and the structures of 14 new (1b, 3b, 4a-4c, 6a-6c, 8b, 9a, 9b, 10b, 11a, 11b) and five known (2b, 5a-5c, 7b) natural compounds were elucidated using NMR, mass spectrometry, optical rotation, and chemical transformations. These α-d-Galp-(1→6)-ß-d-Glcp-(1 ↔ 1)-ceramides (presumably sponge-derived compounds) were shown to contain phytosphingosine-type n-t17:0 (1), (6E)-n-t17:1 (2), i-t17:0 (3), n-t18:0 (4), (6E)-n-t18:1 (5), i-t18:0 (6), (6E)-i-t18:1 (7), i-t19:0 (8), (6E)-i-t19:1 (9), ai-t19:0 (10), and (6E)-ai-t19:1 (11) backbones N-acylated with saturated straight-chain (2R)-2-hydroxy C21 (a), C22 (b), and C23 (c) acids. Characteristic trends in the fragmentations of the terminal parts of tetraacetylated normal-chain and iso- and anteiso-branched sphingoid bases were observed using GC/MS. The total sum of melibiosylceramides and compound 5b caused a reduction in colony formation of human melanoma cells.

[Entrapment and non-entrapment syndromes at the elbow]. / Entrapment- und Non­Entrapment-Syndrome am Ellenbogen.

CLINICAL/METHODICAL ISSUE: Entrapment syndromes of peripheral nerves at the elbow are common and are often diagnostically challenging disorders. Difficulties consist in lesion localization and recognition of complex spatial lesion patterns as well as in differentiation of focal and multifocal disorders. STANDARD DIAGNOSTIC METHODS: Medical history taking, neurological examination and neurophysiological tests represent the gold standard in the diagnosis of peripheral nerve lesions at the elbow, but have known methodical limitations. METHODICAL INNOVATIONS: Additional diagnostic imaging tools recently developed for high-resolution visualization of extended peripheral nerve segments include 3 T magnetic resonance neurography (MRN) and neurosonography. PERFORMANCE: MRN and neurosonography can directly visualize and thus precisely localize focal and nonfocal peripheral nerve lesions of various origins with high spatial resolution at the anatomical level of nerve fascicles. ACHIEVEMENTS: MRN can cover peripheral nerve structures at the elbow, evaluate spatial nerve lesion patterns and partly disclose underlying causes. PRACTICAL RECOMMENDATIONS: Imaging of peripheral nerves is a valuable addition in the diagnostic work-up of entrapment syndromes at the elbow and provides important assistance in the differentiation of nonfocal differential diagnoses, especially in cases that cannot be clarified using standard diagnostic methods. The evaluation of spatial nerve lesion pattern may give additional information on the origin of the underlying disease, which is essential for further treatment.

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PURPOSE: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Roles of texture and latent hardening on plastic anisotropy of face-centered-cubic materials during multi-axial loading.

This study investigates the joint impact of preferred texture and latent hardening on the plastic anisotropy of face centered cubic (FCC) materials. The main result is that both aspects have significant impact on the anisotropy, but the two can either counteract each other or synergistically reinforce each other to maximize anisotropy. Preferred texture results in significant anisotropy in plastic yielding. However, the latent hardening significantly alters the texture-induced anisotropy. In addition, one latent hardening type can cancel out the anisotropy of another type. Consequently, if all dislocation-based latent hardening types are included at the same level as the self-hardening, the result might not reveal the complexity of plastic anisotropy. The present study of the synergistic influence of detailed latent hardening and texture presented helps provide new insights into the complex anisotropic behavior of FCC materials during multi-axial forming.

Thoracic outlet syndrome in 3T MR neurography-fibrous bands causing discernible lesions of the lower brachial plexus.

OBJECTIVES: To investigate whether targeted magnetic resonance neurography (MRN) of the brachial plexus can visualise fibrous bands compressing the brachial plexus and directly detect injury in plexus nerve fascicles. METHODS: High-resolution MRN was employed in 30 patients with clinical suspicion of either true neurogenic thoracic outlet syndrome (TOS) or non-specific TOS. The protocol for the brachial plexus included a SPACE (3D turbo spin echo with variable flip angle) STIR (short tau inversion recovery), a sagittal-oblique T2-weighted (T2W) SPAIR (spectral adiabatic inversion recovery) and a 3D PDW (proton density weighted) SPACE. Images were evaluated for anatomical anomalies compressing the brachial plexus and for abnormal T2W signal within plexus elements. Patients with abnormal MR imaging findings underwent surgical exploration. RESULTS: Seven out of 30 patients were identified with unambiguous morphological correlates of TOS. These were verified by surgical exploration. Correlates included fibrous bands (n = 5) and pseudarthrosis or synostosis of ribs (n = 2). Increased T2W signal was detected within compressed plexus portion (C8 spinal nerve, inferior trunk, or medial cord) and confirmed the diagnosis. CONCLUSIONS: The clinical suspicion of TOS can be diagnostically confirmed by MRN. Entrapment of plexus structures by subtle anatomical anomalies such as fibrous bands can be visualised and relevant compression can be confirmed by increased T2W signal of compromised plexus elements. KEY POINTS: • MR neurography (MRN) can aid the diagnosis of thoracic outlet syndrome (TOS). • Identifiable causes of TOS in MRN include fibrous bands and bony anomalies. • Increased T2W signal within brachial plexus elements indicate relevant nerve compression. • High positive predictive value allows confident and targeted indication for surgery.

Effect of thrombus size on recanalization by bridging intravenous thrombolysis.

BACKGROUND AND PURPOSE: Thrombus length has been reported as an important predictor of successful recanalization by intravenous thrombolysis but its influence on bridging thrombolysis has not been investigated yet. The effect of thrombus length on recanalization rates evaluated by catheter angiography early after intravenous bridging thrombolysis was analyzed. METHODS: Ninety-six consecutive patients with acute cerebral artery occlusion were included. Occlusion site and thrombus length on initial computed tomography angiography or magnetic resonance angiography were related to recanalization after intravenous bridging thrombolysis on the initial series of catheter angiography. RESULTS: Eleven of 96 patients (11.5%) showed successful recanalization (TICI 2a, 2b or 3) after intravenous bridging thrombolysis. Mean thrombus length in these patients was 10.8 mm as opposed to 15.6 mm in patients without successful recanalization. No thrombus longer than 16 mm showed complete recanalization. Binary logistic regression demonstrated a significant influence of thrombus length on probability of recanalization (odds ratio 0.78, 95% confidence interval 0.65-0.95; P = 0.014). CONCLUSIONS: Thrombus length is a significant predictor of recanalization rates after bridging thrombolysis. Overall recanalization rate within the time frame until interventional treatment is started was 11.5% after bridging thrombolysis.

An innovative strategy for direct electrochemical detection of microRNA biomarkers.

We report an electrochemical method for direct, reagentless, and label-free detection of microRNA, based on a conjugated copolymer, poly(5-hydroxy-1,4-naphthoquinone-co-5-hydroxy-2-carboxyethyl-1,4-naphthoquinone), acting as hybridization transducer. Hybridization between the oligonucleotide capture probe and a microRNA target of 22 base pairs generates an increase in the redox current ("signal-on"), which is evidenced by square wave voltammetry. Selectivity is good, with little hybridization for non-complementary targets, and the limit of detection reaches 650 fM. It is also evidenced that this sensitivity benefits from the high affinity of DNA for RNA.

The LVIS Jr. microstent to assist coil embolization of wide-neck intracranial aneurysms: clinical study to assess safety and efficacy.

INTRODUCTION: This study was aimed to assess clinical safety and efficacy of the LVIS Jr. microstent in stent-assisted coil embolization of wide-neck intracranial aneurysms. METHODS: IRB approved single-center interventional clinical study in 22 patients (10 females, 12 males, mean age 55, age range 33-74 years) for the endovascular treatment of wide-neck aneurysms. After obtaining informed consent, patients were included according to the following criteria: aneurysm fundus-to-neck ratio < 2 or neck diameter > 4 mm, and a parent vessel diameter of ≤3.5 mm. Primary end point for clinical safety was absence of death, absence of major or minor stroke, and absence of transient ischemic attack. Primary end point for treatment efficacy was complete angiographic occlusion according to the Raymond-Roy Occlusion Classification (RROC) immediately after the procedure and at follow-up after 3 and 6 months on magnetic resonance imaging (MRI). RESULTS: In 20/22 (91 %) of patients, the primary end point of safety was reached; in the two remaining patients, transient ischemic attack, but no permanent deficit was observed; in 16/22 (73 %), efficient occlusion (RROC1) was reached, and in 6/22 (27 %), a residual neck remained (RROC2). Single [seven with antegrade, two in crossover configuration, and four with "first-balloon-then-stent" (FBTS) technique] or double-stent (eight patients with Y configuration and one patient with X configuration) deployment was technically successful in all cases. CONCLUSION: Deployment of the LVIS Jr. microstent in various single- or double-stent configurations is safe and effective to assist the treatment of intracranial wide-neck aneurysms.

[MR neurography for lesion localization in the peripheral nervous system. Why, when and how?]. / MR-Neurographie zur Läsionslokalisation im peripheren Nervensystem. Warum, wann und wie?

Peripheral neuropathies are frequent disorders which are often challenging in the diagnostic work-up. Diagnostic difficulties first and foremost arise with regard to lesion localization and the precise definition of spatial lesion patterns. Magnetic resonance (MR) neurography as a diagnostic imaging tool directly visualizes nerve lesions thereby facilitating lesion localization not only in traumatic nerve lesions but also in the large and heterogeneous group of intrinsic, spontaneously occurring non-focal neuropathies. The major diagnostic sign for lesion detection and localization is the T2 lesion which can be evaluated with high spatial resolution at the anatomical level of nerve fascicles. Lesion detection at the fascicular level by MR neurography advances the diagnostic work-up in the peripheral nervous system (PNS), because fascicular and partial nerve lesions of spontaneously occurring intrinsic neuropathies and polyneuropathies present a classical diagnostic pitfall for traditional localization by means of physical findings and electrophysiology. With the appropriate techniques and strategies MR neurography can now cover large anatomical areas of the PNS in a single examination session.

Multi-detector fusion and Bayesian smoothing for tracking viral and chromatin structures.

Automatic tracking of viral and intracellular structures displayed as spots with varying sizes in fluorescence microscopy images is an important task to quantify cellular processes. We propose a novel probabilistic tracking approach for multiple particle tracking based on multi-detector and multi-scale data fusion as well as Bayesian smoothing. The approach integrates results from multiple detectors using a novel intensity-based covariance intersection method which takes into account information about the image intensities, positions, and uncertainties. The method ensures a consistent estimate of multiple fused particle detections and does not require an optimization step. Our probabilistic tracking approach performs data fusion of detections from classical and deep learning methods as well as exploits single-scale and multi-scale detections. In addition, we use Bayesian smoothing to fuse information of predictions from both past and future time points. We evaluated our approach using image data of the Particle Tracking Challenge and achieved state-of-the-art results or outperformed previous methods. Our method was also assessed on challenging live cell fluorescence microscopy image data of viral and cellular proteins expressed in hepatitis C virus-infected cells and chromatin structures in non-infected cells, acquired at different spatial-temporal resolutions. We found that the proposed approach outperforms existing methods.

A new certified reference material IAEA-465 for radionuclides in Baltic Sea sediment.

Certified reference material (CRM) for natural (40K,210Pb,210Po,226Ra,228Ra,228Th,230Th,232Th,234U,235U, and238U) and anthropogenic (137Cs,239+240Pu, and241Am) radionuclides in marine sediment from the Baltic Sea (IAEA-465) has been developed. Information values are given for 238Pu,239Pu and240Pu. Altogether 27 laboratories participated in this exercise. Radiometric (alpha-spectrometry, gamma-spectrometry and beta counting, as well as mass spectrometry (ICP-MS and AMS) techniques were applied in measurements. The CRM is intended to be used for Quality Assurance/Quality Control of radionuclide analyses, for the development and validation of analytical methods, for the development of reference methods and for training purposes.

Progress towards elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission update.

The top 20 highest burdened countries (in disability-adjusted life years) account for more than 75% of the global burden of viral hepatitis. An effective response in these 20 countries is crucial if global elimination targets are to be achieved. In this update of the Lancet Gastroenterology & Hepatology Commission on accelerating the elimination of viral hepatitis, we convene national experts from each of the top 20 highest burdened countries to provide an update on progress. Although the global burden of diseases is falling, progress towards elimination varies greatly by country. By use of a hepatitis elimination policy index conceived as part of the 2019 Commission, we measure countries' progress towards elimination. Progress in elimination policy has been made in 14 of 20 countries with the highest burden since 2018, with the most substantial gains observed in Bangladesh, India, Indonesia, Japan, and Russia. Most improvements are attributable to the publication of formalised national action plans for the elimination of viral hepatitis, provision of publicly funded screening programmes, and government subsidisation of antiviral treatments. Key themes that emerged from discussion between national commissioners from the highest burdened countries build on the original recommendations to accelerate the global elimination of viral hepatitis. These themes include the need for simplified models of care, improved access to appropriate diagnostics, financing initiatives, and rapid implementation of lessons from the COVID-19 pandemic.

Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes.

AIMS/HYPOTHESIS: Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes. METHODS: The beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at -5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-α), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-ß1-3) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA1c and fasting blood glucose. RESULTS: High fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-α were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p < 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-ß1 and TGF-ß2 were associated with lower fasting and stimulated C-peptide levels (p < 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-α increased (p < 0.001) while those of IL-10 and TGF-ß1 decreased (p < 0.02) and IL-1RA and TGF-ß2 remained unchanged. CONCLUSIONS/INTERPRETATION: The association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.