Synthetic chemerin-derived peptides suppress inflammation through ChemR23

Chemerin is a chemotactic protein that binds to the G protein-coupled receptor, ChemR23. We demonstrate that murine chemerin possesses potent antiinflammatory properties that are absolutely dependent on proteolytic processing. A series of peptides was designed, and only those identical to specific C-terminal chemerin sequences exerted antiinflammatory effects at picomolar concentrations in vitro. One of these, chemerin15 (C15; A(140)-A(154)), inhibited macrophage (MPhi) activation to a similar extent as proteolyzed chemerin, but exhibited reduced activity as a MPhi chemoattractant. Intraperitoneal administration of C15 (0.32 ng/kg) to mice before zymosan challenge conferred significant protection against zymosan-induced peritonitis, suppressing neutrophil (63%) and monocyte (62%) recruitment with a concomitant reduction in proinflammatory mediator expression. Importantly, C15 was unable to ameliorate zymosan-induced peritonitis in ChemR23(-/-) mice, demonstrating that C15's antiinflammatory effects are entirely ChemR23 dependent. In addition, administration of neutralizing anti-chemerin antibody before zymosan challenge resulted in a significant exacerbation of peritoneal inflammation (up to 170%), suggesting an important endogenous antiinflammatory role for chemerin-derived species. Collectively, these results show that chemerin-derived peptides may represent a novel therapeutic strategy for the treatment of inflammatory diseases through ChemR23.     

Effectiveness of chlorhexidine bathing to reduce catheter-associated bloodstream infections in medical intensive care unit patients

OBJECTIVE: To determine whether patients bathed daily with chlorhexidine gluconate (CHG) have a lower incidence of primary bloodstream infections (BSIs) compared with patients bathed with soap and water. METHODS: The study design was a 52-week, 2-arm, crossover (ie, concurrent control group) clinical trial with intention-to-treat analysis. The study setting was the 22-bed medical intensive care unit (MICU), which comprises 2 geographically separate, similar 11-bed units, of the John H. Stroger Jr (Cook County) Hospital, a 464-bed public teaching hospital in Chicago, Illinois. The study population comprised 836 MICU patients. During the first of 2 study periods (28 weeks), 1 hospital unit was randomly selected to serve as the intervention unit in which patients were bathed daily with 2% CHG-impregnated washcloths (Sage 2% CHG cloths; Sage Products Inc, Cary, Illinois); patients in the concurrent control unit were bathed daily with soap and water. After a 2-week wash-out period at the end of the first period, cleansing methods were crossed over for 24 more weeks. Main outcome measures included incidences of primary BSIs and clinical (culture-negative) sepsis (primary outcomes) and incidences of other infections (secondary outcomes). RESULTS: Patients in the CHG intervention arm were significantly less likely to acquire a primary BSI (4.1 vs 10.4 infections per 1000 patient days; incidence difference, 6.3 [95% confidence interval, 1.2-11.0). The incidences of other infections, including clinical sepsis, were similar between the units. Protection against primary BSI by CHG cleansing was apparent after 5 or more days in the MICU. CONCLUSION: Daily cleansing of MICU patients with CHG-impregnated cloths is a simple, effective strategy to decrease the rate of primary BSIs.     

Thumb function and appearance in thrombocytopenia: absent radius syndrome

PURPOSE: To evaluate thumb function and appearance in patients with thrombocytopenia absent radius (TAR) syndrome. METHODS: The size and shape of the 14 thumbs in 7 patients with TAR syndrome were quantified and compared with age-matched normals. Function was assessed using a series of standardized tasks. RESULTS: The thumb length averaged 73% relative to the length of the index finger proximal phalanx (normal, 70%) and 36% relative to the length of the entire index finger (normal, 32%). The thumb/index nail width and girth ratios measured 138% and 101%, respectively (normal, 133% and 105%, respectively). The relative thumb/index thumbnail width-to-girth ratio was 1.36, which was significantly greater than the normal average of 1.27, suggesting the TAR thumbs are relatively wide and flat compared with normal thumbs. The thumb interphalangeal joint was held in a neutral posture and did not show active motion in any patient; the metacarpophalangeal joint was held in a position of flexion and had an average of 32 degrees of extension lag. Patients had difficulty with all activities tested, especially grasping large objects. CONCLUSIONS: The thumb in TAR syndrome patients is of relatively normal size and shape; however, the thumb is held in a position of metacarpophalangeal flexion in most patients and function is impaired.     

A Double-Blind,Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease

Background

Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD.

Objectives

To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement.

Methods

The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (³¹P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment.

Results

UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain ³¹P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups.

Conclusions

High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Unpacking the Cinderella black box of complex intervention development through the Partners at Care Transitions (PACT) programme of research

Introduction

Complex intervention development has been described as the ‘Cinderella’ black box in health services research. Greater transparency in the intervention development process is urgently needed to help reduce research waste.

Methods

We applied a new consensus-based framework for complex intervention development to our programme of research, in which we developed an intervention to improve the safety and experience of care transitions for older people. Through this process, we aimed to reflect on the framework's utility for intervention development and identify any important gaps within it to support its continued development.

Findings

The framework was a useful tool for transparent reporting of the process of complex intervention development. We identified potential ‘action’ gaps in the framework including ‘consolidation of evidence’ and ‘development of principles’ that could bracket and steer decision-making in the process.

Conclusions

We consider that the level of transparency demonstrated in this report, aided through use of the framework, is essential in the quest for reducing research waste.

Patient or Public Contribution

We have involved our dedicated patient and public involvement group in all work packages of this programme of research. Specifically, they attended and contributed to co-design workshops and contributed to finalizing the intervention for the pilot evaluation. Staff also participated by attending co-design workshops, helping us to prioritize content ideas for the intervention and supporting the development of intervention components outside of the workshops.