Acute allograft rejection and immunosuppression: influence on endogenous melatonin secretion

Abstract: Melatonin displays a dose‐dependent immunoregulatory effect in vitro and in vivo. Exogenous high‐dose melatonin therapy exerted an immunosuppressive effect, abrogating acute rejection (AR), significantly prolonging transplant survival. Endogenous melatonin secretion, in response to heterotopic rat cardiac allograft transplantation (Tx), was investigated during the AR response and under standardized immunosuppressive maintenance therapy with cyclosporin A (CsA) and rapamycin (RPM). Recipients of syngeneic transplants, and recipients of allogeneic grafts, either untreated or receiving immunosuppressive therapy constituted the experimental groups. Endogenous circadian melatonin levels were measured at 07:00, 19:00, and 24:00 hr, using a novel radioimmunoassay (RIA) procedure, under standardized 12‐hr‐light/dark‐conditions (light off: 19:00 hr; light on: 07:00 hr), before and after Tx. Neither the operative trauma, nor the challenge with a perfused allograft or the AR response influenced endogenous melatonin peak secretion. Immunosuppressive therapy with CsA led to a significant increase in peak secretion, measured for days 7 (212 ± 40.7 pg/mL; P < 0.05), 14 (255 ± 13.9 pg/mL; P < 0.001), and 21 (219 ± 34 pg/mL; P < 0.01) after Tx, as compared with naïve animals (155 ± 25.8 pg/mL). In contrast, treatment with RPM significantly decreased the melatonin peak post‐Tx up to day 7 (87 ± 25.2 pg/mL; P < 0.001), compared with naïve animals (155 ± 25.8 pg/mL). These findings imply a robust nature of the endogenous circadian melatonin secretion kinetics, even against the background of profound allogeneic stimuli. Immunosuppressive maintenance therapy with CsA and RPM modulated early melatonin secretion, indicating a specific secondary action of these drugs. Further studies are necessary to disclose the long‐term effect of immunosuppressive therapy on circadian melatonin secretion in transplant recipients.     

Assessment of the lactulose-mannitol test in Crohn's disease.

The mannitol-lactulose intestinal permeability test was evaluated in 100 healthy controls and 47 patients with Crohn's disease. These patients were further separated into three subgroups of increased activity (Harvey-Bradshaw index) and in two subgroups, with elective colonic lesions and associated ileal and colonic lesions. Results were given as percentages of urinary recoveries for mannitol (M), lactulose (L), and L/M ratio. As a whole, patients with Crohn's disease have lower mean M and higher mean L and mean L/M ratios than controls. The magnitude of alterations in M, L, and L/M increased with activity. The sensitivity of the test, however, reached interesting figures (67%:L and 86%:L/M) only in subgroup III which was composed of relapsing patients. Mean M was lower in patients with associated ileal lesion but, whatever the criterion (M, L, or L/M), the test does not provide any clue for the detection of a possible infraclinical associated ileal localisation.     

Osteomyelitis of the Patella Caused by Legionella anisa

A 51-year-old man with a history of stage IV angioimmunoblastic T-cell lymphoma was diagnosed with osteomyelitis of the patella. Legionella anisa was identified by 16S rRNA gene sequencing and culture. The patient had pneumonia 2 months prior to this osteomyelitis episode. L. anisa was retrospectively detected in his lung tissue by 16S rRNA gene sequencing and was considered the source of the L. anisa that caused his patella osteomyelitis.     

Ischemic lesion water homeostasis after thrombectomy for large vessel occlusion stroke within the anterior circulation: The impact of age

The effect of age on lesion pathophysiology in the context of thrombectomy has been poorly investigated. We aimed to investigate the impact of age on ischemic lesion water homeostasis measured with net water uptake (NWU) within a multicenter cohort of patients receiving thrombectomy for anterior circulation large vessel occlusion (LVO) stroke. Lesion-NWU was quantified in multimodal CT on admission and 24 h for calculating Δ-NWU as their difference. The impact of age and procedural parameters on Δ-NWU was analyzed. Multivariable regression analysis was performed to identify significant predictors for Δ-NWU. Two hundred and four patients with anterior circulation stroke were included in the retrospective analysis. Comparison of younger and elderly patients showed no significant differences in NWU on admission but significantly higher Δ-NWU (p = 0.005) on follow-up CT in younger patients. In multivariable regression analysis, higher age was independently associated with lowered Δ-NWU (95% confidence interval: −0.59 to −0.16, p < 0.001). Although successful recanalization (TICI ≥ 2b) significantly reduced Δ-NWU progression by 6.4% (p < 0.001), younger age was still independently associated with higher Δ-NWU (p < 0.001). Younger age is significantly associated with increased brain edema formation after thrombectomy for LVO stroke. Younger patients might be particularly receptive targets for future adjuvant neuroprotective drugs that influence ischemic edema formation.     

Frontotemporal Regulation of Subjective Value to Suppress Impulsivity in Intertemporal Choices

Impulsive decisions arise from preferring smaller but sooner rewards compared with larger but later rewards. How neural activity and attention to choice alternatives contribute to reward decisions during temporal discounting is not clear. Here we probed (1) attention to and (2) neural representation of delay and reward information in humans (both sexes) engaged in choices. We studied behavioral and frequency-specific dynamics supporting impulsive decisions on a fine-grained temporal scale using eye tracking and MEG recordings. In one condition, participants had to decide for themselves but pretended to decide for their best friend in a second prosocial condition, which required perspective taking. Hence, conditions varied in the value for themselves versus that pretending to choose for another person. Stronger impulsivity was reliably found across three independent groups for prosocial decisions. Eye tracking revealed a systematic shift of attention from the delay to the reward information and differences in eye tracking between conditions predicted differences in discounting. High-frequency activity (175-250 Hz) distributed over right frontotemporal sensors correlated with delay and reward information in consecutive temporal intervals for high value decisions for oneself but not the friend. Collectively, the results imply that the high-frequency activity recorded over frontotemporal MEG sensors plays a critical role in choice option integration.SIGNIFICANCE STATEMENT Humans face decisions between sooner smaller rewards and larger later rewards daily. An objective benefit of losing weight over a longer time might be devalued in face of ice cream because they prefer currently available options because of insufficiently considering long-term alternatives. The degree of contribution of neural representation and attention to choice alternatives is not clear. We investigated correlates of such decisions in participants deciding for themselves or pretending to choose for a friend. Behaviorally participants discounted less in self-choices compared with the prosocial condition. Eye movement and MEG recordings revealed how participants represent choice options most evident for options with high subjective value. These results advance our understanding of neural mechanisms underlying decision-making in humans.     

Association between tDCS computational modeling and clinical outcomes in depression: data from the ELECT-TDCS trial

European Archives of Psychiatry and Clinical Neuroscience - Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention investigated for the treatment of...     

Shoulder Isokinetic Strength Balance Ratio in Overhead Athletes: A Cross-Sectional Study

BackgroundStudies have grouped different overhead sports and evaluated together the isokinetic strength of shoulder internal (IR) and external (ER) rotator muscles. However, muscular adaptations could be a consequence of the specific sport, and some strength imbalance between these muscles may exist as a consequence of the muscular demand unique to the sport. Therefore, grouping different overhead sports together may not be adequate.PurposeTo compare strength balance ratios between different overhead sports (volleyball, handball, swimming, judo, baseball, softball, functional movements performed at high-intensity interval training, and tennis) with a control athletic group (no overhead group).Study designCross-sectional study.MethodsA total of 237 athletes were submitted to isokinetic shoulder strength tests. The isokinetic concentric and eccentric peak torque values of shoulder internal IR and external ER rotator muscles were measured. Conventional (CR) and functional strength ratios (FR) were calculated.ResultsThere were no significant differences between the sports for the CR in the male group. Female softball athletes (90.4±13.6%) had a significantly higher CR than judo (67.3±6.9%), volleyball (74.9±15.9%), and swimming athletes (70.3±8.7%). In the female group, judo athletes had lower FR values (0.76±0.19) than soccer athletes (1.31±0.35), volleyball athletes (1.24±0.27), functional movements performed at high intensity (1.10±0.1), and softball athletes (1.40±0.39). Female handball athletes also had a lower FR (0.99±0.25) than soccer athletes (1.31±0.35) and softball athletes (1.40±0.39). Male handball (0.90±0.23), tennis (0.86±0.30), and judo (0.68±0.22) athletes had lower FR values than soccer athletes (1.20±0.21) and volleyball athletes (1.25±0.28).ConclusionsCR for males may be analyzed together, as there were no significant differences between them. However, for females, the CR for softball athletes should be analyzed individually. As there were several differences between the overhead sports according to the FRs, the authors suggest caution in grouping overhead athletes across multiple sports. These results could have important implications for the design of injury prevention and rehabilitation programs associated with the shoulder joint in overhead sports.Level of Evidence3     

Orthopaedic Surgeons Receive the Most Industry Payments to Physicians but Large Disparities are Seen in Sunshine Act Data

Background

Industry payments made to physicians by drug and device manufacturers or group purchasing organizations are now reported to the Centers for Medicare and Medicaid Services (CMS) as a part of the Physician Payments Sunshine Act. Initial reports from the program show that orthopaedic surgeons lead all physician specialties in total and average industry payments. However, before further discussion of these payments and their implications can take place, it remains to be seen whether these figures are a true reflection of the field of orthopaedic surgery in general, rather than the result of a few outlier physicians in the field. In addition, the nature and sources of these funds should be determined to better inform the national dialogue surrounding these payments.

Questions/Purposes

We asked: (1) How do industry payments to orthopaedic surgeons compare with payments to physicians and surgeons in other fields, in terms of median payments and the Gini index of disparity? (2) How much do payments to the highest-receiving orthopaedic surgeons contribute to total payments? (3) What kind of industry payments are orthopaedic surgeons receiving? (4) How much do the highest-paying manufacturers contribute to total payments to orthopaedic surgeons?

Materials and Methods

We reviewed the most recent version of the CMS Sunshine Act Open Payments database released on December 19, 2014, containing data on payments made between August 1, 2013 and December 31, 2013. Data on total payments to individual physicians, physician specialty, the types of payments made, and the manufacturers making payments were reviewed. The Gini index of statistical dispersion was calculated for payments made to orthopaedic surgeons and compared with payments made to physicians and surgeons in all other medical specialties. A Gini index of 0 indicates complete equality of payments to everyone in the population, whereas an index of 1 indicates complete inequality, or all income going to one individual.

Results

A total of 15,376 orthopaedic surgeons receiving payments during the 5-month period were identified, accounting for USD 109,846,482. The median payment to orthopaedic surgeons receiving payments was USD 121 (interquartile range, USD 34–619). The top 10% of orthopaedic surgeons receiving payments (1538 surgeons) received at least USD 4160 and accounted for 95% of total payments. Royalties and patent licenses accounted for 69% of all industry payments to orthopaedic surgeons.

Conclusions

Even as a relatively small specialty, orthopaedic surgeons received substantial payments from industry (more than USD 110 million) during the 5-month study period. Whether there is a true return of value from these payments remains to be seen; however, future ethical and policy discussions regarding industry payments to orthopaedic surgeons should take into account the large disparities in payments that are present and also the nature of the payments being made. It is possible that patients and policymakers may view industry payments to orthopaedic surgeons more positively in light of these new findings.

Level of Evidence

Level III, Economic and Decision Analysis.