Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme

Glucagon‐like peptide‐1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose‐dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta‐cell function (as measured by HOMA2‐%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide‐treated patients from AWARD‐1, AWARD‐3 and AWARD‐6 clinical studies were categorised based on their homeostatic model assessment of beta‐cell function (HOMA2‐%B) tertiles. Changes in glycaemic measures in response to treatment with once‐weekly dulaglutide were evaluated in each HOMA2‐%B tertile. Patients with low HOMA2‐%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB‐2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; ?1.55% vs. ?0.98% [?16.94 vs. ?10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; ?1.00 vs. ?1.18% [?10.93 vs. ?12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C‐peptide were observed in the low tertile. Similar increases in HOMA2‐%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta‐cell function.     

Effect of hip dislocation on the blood supply to the femoral head. An experimental study in rabbits

This work consists of a series of experiments which were made in order: a) to examine the possible alterations of blood flow to the reduced femoral heads of rabbits, after inducing a closed dislocation of their hips and b) to determine the influence of the early or late reduction of the dislocated femoral heads on their blood flow. The estimations of blood flow to the normal and reduced femoral heads were made using radioactive microspheres. The findings are as follows: a) The blood flow of the femoral heads of the reduced hips was never interrupted completely. b) The initially decreased femoral head blood flow progressively increased, in association to the time elapsed from the reduction. c) No statistically significant difference was found in the femoral head blood flow between hips reduced in early and those reduced late. d) Pure traumatic dislocation of the hip can only rarely be the cause of aseptic necrosis of the femoral head.     

Effect of Hip Dislocation on the Blood Supply to the Femoral Head: An Experimental Study in Rabbits

This work consists of a series of experiments which were made in order: a) to examine the possible alterations of blood flow to the reduced femoral heads of rabbits, after inducing a closed dislocation of their hips and b) to determine the influence of the early or late reduction of the dislocated femoral heads on their blood flow. the estimations of blood flow to the normal and reduced femoral heads were made using radioactive microspheres.

The findings are as follows: a) the blood flow of the femoral heads of the reduced hips was never interrupted completely, b) the initially decreased femoral head blood flow progressively increased, in association to the time elapsed from the reduction, c) No statistically significant difference was found in the femoral head blood flow between hips reduced in early and those reduced late, d) Pure traumatic dislocation of the hip can only rarely be the cause of aseptic necrosis of the femoral head.     

Preparation and First Preclinical Evaluation of [18F]FE@SNAP: A Potential PET Tracer for the Melanin-Concentrating Hormone Receptor-1 (MCHR1)

The melanin-concentrating hormone (MCH) system is a new target for the treatment of human disorders. Since the knowledge of the MCH system’s involvement in a variety of pathologies (obesity, diabetes, and deregulation of metabolic feedback mechanism) is based on in vitro or preclinical studies, a suitable positron emission tomography (PET) tracer needs to be developed. We herein present the preparation and first preclinical evaluation of [¹⁸F]FE@SNAP – a new PET tracer for MCH receptor-1 (MCHR1). The synthesis was performed using a microfluidic device. Preclinical evaluation included binding affinity, plasma stability, plasma free fraction, stability against the cytochrome P-450 (CYP450) system using liver microsomes, stability against carboxyl-esterase, and methods to assess the penetration of the blood-brain barrier (BBB) such as logD analysis and immobilized artificial membrane (IAM) chromatography. Levels at 374 ± 202 MBq [¹⁸F]FE@SNAP were obtained after purification. The obtained K_d value of [¹⁸F]FE@SNAP was 2.9 nM. [¹⁸F]FE@SNAP evinced high stability against carboxylesterase, CYP450 enzymes, and in human plasma. LogD (3.83) and IAM chromatography results (P_m=0.51) were in the same range as for known BBB-penetrating compounds. The synthesis of [¹⁸F]FE@SNAP was reliable and successful. Due to high binding affinity and stability, [¹⁸F]FE@SNAP is a promising tracer for MCHR1.     

Baseline levels of CD8+ T cells against survivin and survivin-2B in the blood of lung cancer patients and cancer-free individuals

Survivin and its variant survivin-2B have been considered as potential candidates for cancer immunotherapy. The magnitude however of spontaneously occurring CD8(+) T cells circulating precursor CTLs (pCTL), has never been evaluated. We set out to measure in 20 patients with lung carcinomas and 5 aged matched healthy male individuals (expressing HLA-A2 and/or -A24), the frequency of pCTLs specific for two naturally processed and presented peptides of survivin (LTLGEFLKL presented by HLA-A2) and survivin-2B (AYACNTSTL presented by HLA-A24) since these peptides are the only ones used in immunotherapeutic trials. The frequency of peptide-specific pCTLs was estimated using a sensitive method that combines HLA-multimer flow cytometric technology with a previous step of in vitro amplification under limiting dilution conditions. Anti-survivin or anti-survivin-2B specific CTL clones were not detected in 17 out of the 21 tested patients, and in none of the healthy individuals. In a number of peripheral blood mononuclear cell microcultures of the remaining 4 patients, diffuse clusters stained weakly by the HLA-multimers were observed which were not amplified after further stimulation and, therefore, they were finally considered as negative. The significance of the levels of spontaneously occurring CTL-responses against survivin and survivin-2B peptides, in cancer patients and cancer-free subjects, remains to be elucidated and it would be interesting to be considered in relation to the clinical efficacy of anti-cancer vaccination protocols.     

Platelet labeling with 67Ga chelates.

68Ga-labeled platelets could be useful for positron emission tomographic (PET) studies. In order to identify the optimal chelate for radiolabeling of platelets with 68Ga, we investigated the platelet uptake of 67Ga-oxine, -tropolone and -MPO. The platelet uptake of 67Ga-oxine and -tropolone is very low (< 5%). The platelet uptake of 67Ga-MPO, in contrast, increases with platelet density (highest at 10(9) platelets/ml) up to 18%. Our data provide evidence that only 68Ga-MPO could be useful for PET-studies.     

Radioactive contamination of contact lenses during radioiodine therapy

Although the secretion of radioiodine in tears is not unexpected, there are only few investigations in that field. We report the measurement of 131I in disposable contact lenses for daily use during radioiodine treatment. After administration of 740 MBq 131I, all contact lenses of a 59-year-old female used the day before and 5 days after radioiodine therapy were collected and measured in a gamma counter. Activities of 124 Bq (right) and 139 Bq (left) were measured in the contact lenses used during the first day after administration of radioiodine. The activity in the contact lenses of the following days was significantly lower. An initial dose rate of approximately 0.31 microSv x h(-1) was caused by the radioactivity resulting in a total dose of 13 microSv to the patient's eye lens. That dose is negligible compared to the dose caused by the incorporated radioactivity.     

CD4/CD8 T‐Cell Ratio in Peritoneal Dialysis Effluents Predicts the Outcome of Peritonitis in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis

This study aimed to clarify the role of peritoneal T‐lymphocytes in peritoneal immune defense mechanisms. This study was designed to examine the changes in T‐cell subpopulations during peritonitis in patients treated with continuous ambulatory peritoneal dialysis (CAPD). Our observations were correlated to responses to treatment and with outcomes. The present study was carried out in 20 patients (8 males, 12 females) under CAPD. Peritonitis was diagnosed according to the criteria defined by the Ad Hoc Advisory Committee on Peritonitis Management. Peritoneal dialysate effluent (PDE) samples were collected from our patients, and lymphocyte subsets (CD2+, CD3+, CD3+/4+, CD3+/8+, CD3?/16+56+, CD4/CD8 ratio) were quantitated by using monoclonal antibodies. CD4/CD8 ratio was measured every day during peritonitis until the patients had completely recovered. The serial measurements of the CD4/CD8 ratio made in the PDE during peritonitis followed two patterns: the first pattern was characterized by a progressive increase in the CD4/CD8 ratio. The CD4/CD8 ratios on days 5, 6, and 7 were significantly higher than those on day 1 (P < 0.05). Overall, the patients who exhibited pattern 1 had favorable clinical courses. The second pattern was characterized by high initial CD4/CD8 ratios, which progressively decreased significantly (P < 0.05). This second pattern was associated with a delayed clinical response to treatment. Symptoms and signs of peritonitis persisted beyond 72 h. The pattern of the CD4/CD8 ratio in PDE may determine the outcome of peritonitis in CAPD patients.     

Dominant TCR V alpha usage by virus and tumor-reactive T cells with wide affinity ranges for their specific antigens

We have studied the TCR features and functional responses of three sets of human cytolytic T cell (CTL) clones, recognizing antigenic peptides presented by HLA-A2 and derived from the Epstein-Barr virus proteins BMLF1 and BRLF1 and from the melanoma protein Melan-A/MART-1. Within each set, a majority of clones used a recurrent V alpha region, even though they expressed highly diverse TCR beta chains and V(D)J junctional sequences. Functional assays and peptide/MHC multimer binding studies indicated that this restricted V alpha usage was not associated with the affinity/avidity of the CTL clones. The V alpha dominance, which may be a frequent feature of antigen-specific T cells, likely reflects a restricted geometry of TCR/peptide/MHC complexes, primarily determined by V alpha CDR.