Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis - pilot study.

BACKGROUND: Sepsis remains a major cause of mortality in critical care, for which specific treatments are lacking. The dysregulated response to infection seen in sepsis includes features of lymphocyte dysfunction and exhaustion, suggesting that immune-stimulatory therapy may improve outcomes in certain patient groups. Monoclonal antibodies targeting checkpoint molecules, such as programmed-death 1 protein (PD-1) and its ligand PD-L1, have shown success in stimulating the immune response in patients with cancer, and are being considered for future sepsis trials. The aims of this pilot study were to compare lymphocyte subset expression of PD-1 and its ligands between patients with sepsis and controls; to characterize serum levels of PD-1 and PD-L1 in patients with sepsis and controls, and determine if serum concentrations correlated with cell surface expression. METHODS: Expression levels of PD-1, PD-L1 and PD-L2 on four lymphocyte subsets (CD27 + CD19+ B cells, CD27-CD19+ B cells, CD27 + CD4+ T cells and CD27-CD4+ T cells) were compared between 22 patients with sepsis (including 11 survivors and 11 non-survivors) and 11 healthy controls using flow cytometry. Levels of soluble PD-1 and PD-L1 were also compared using commercially available ELISA kits. RESULTS: Expression of PD-1 and PD-L1 was higher on all lymphocyte subsets in patients with sepsis compared to controls (p < 0.05). PD-L2 expression on CD27+ B cells was also higher in patients with sepsis (p = 0.0317). There was differential expression of PD-1 by CD27 status, with expression being higher in the B and T cell subsets associated with memory status (CD27+ and CD27-, respectively; p < 0.001). Higher PD-1 and PD-L1 expression was not associated with mortality or with a higher risk of nosocomial infection. There were no differences in levels of soluble PD-1 or PD-L1 between patients with sepsis and controls. CONCLUSIONS: Higher expression of PD-1 by memory subpopulations of B cells and CD4+ T cells, with normal soluble PD-1 and PD-L1 in patients with sepsis, are novel findings. This information may be useful to enrich sepsis populations for trials of PD-1/PD-L1 blockade.

Enhanced amylin-mediated body weight loss in estradiol-deficient diet-induced obese rats.

In rodents, ovariectomy (OVX) elicits weight gain and diminished responsiveness to homeostatic signals. Here we characterized the response of obese OVX rats to peripheral amylin. Rats received sham surgery (SHAM), OVX, or OVX with hormonal replacement (17ß-estradiol, 2 µg per 4 d; OVX+E) and were infused with vehicle or amylin (50 µg/kg · d) for 28 d. Amylin reduced body weight (5.1 ± 1.1%) and food intake (10.9 ± 3.4%) in SHAM rats but was twice as efficacious in OVX rats in reducing weight (11.2 ± 1.9%) and food intake (23.0 ± 2.0%). There were no differences between amylin-treated SHAM and OVX+E rats. OVX decreased metabolic rate (∼24%) and increased respiratory exchange ratio relative to SHAM. Amylin partially normalized metabolic rate (13% increase) in OVX rats and decreased respiratory exchange ratio in OVX and SHAM rats. Regarding central mechanisms, amylin infusion corrected the OVX-induced decrease in hippocampal neurogenesis and increased immobility in the forced swim test. Additionally, amylin increased neurogenesis (∼2-fold) within the area postrema of OVX rats. To assess the contribution of endogenous leptin to amylin-mediated weight loss in OVX rats, amylin was administered to SHAM or OVX Zucker diabetic fatty rats. In SHAM rats, amylin infusion reduced food intake but not body weight, whereas in OVX Zucker diabetic fatty rats, food intake, body weight, and insulin were reduced. Overall, amylin induced greater body weight loss in the absence of estradiol via central and peripheral actions that did not require leptin. These findings support the clinical investigation of amylin in low estradiol (e.g. postmenopausal) states.

The industrial athlete?

Many similarities can be drawn between the athletic and industrial population. It is time for a shift in the approach toward injured workers utilizing a sports medicine perspective. We must think of workers as industrial athletes and recognize that the sports medicine model can be appropriately adapted to the injured worker. This model includes prevention, early intervention/identification, training and conditioning, and progressive treatment. Sports medicine rehabilitation concepts include treating the entire kinetic chain that is associated with a specific injury and the SAID principle (Specific Adaptations to Imposed Demands).

Innovative approach for the treatment of cumulative trauma disorders.

Cumulative Trauma Disorders (CTDs) is the latest four-letter word for employees and employers. The purpose of this pilot study was to test the efficacy and cost effectiveness of ASTM, previously executed with Division I college athletes, in a work-related population. ASTM uses specially designed instruments to assist clinicians in rapid localization and effective treatment of soft tissue fibrosis/scar tissue. The protocol includes a flexibility and functional program that helps the worker adapt to the demands of the job. Physical and occupational therapists in both an outpatient clinic, and an industrial on-site setting, utilized ASTM. ASTM was considered successful, with symptoms resolved in over 70 percent of the patients. ASTM demonstrated impressive results in both settings and decreased medical and non-medical expenditures.

Clinical trends on tendinitis.

Tendinitis has dramatically risen over the last few years. Some instances of tendinitis are resistant to traditional management aimed at decreasing the inflammatory process leaving clinicians to wonder whether or not they are truly dealing with an inflammatory condition. An understanding is essential for the appropriate clinical management of tendon disorders. The focus of this article will be to review tendon injuries, their healing, and to present an illustrative case treated successfully with an innovative form of treatment.