Time dependent neuroprotection of mycophenolate mofetil: effects on temporal dynamics in glial proliferation, apoptosis, and scar formation

BACKGROUND: Immunosuppressants such as mycophenolate mofetil (MMF) have the capacity to inhibit microglial and astrocytic activation and to reduce the extent of cell death after neuronal injury. This study was designed to determine the effective neuroprotective time frame in which MMF elicits its beneficial effects, by analyzing glial cell proliferation, migration, and apoptosis. METHODS: Using organotypic hippocampal slice cultures (OHSCs), temporal dynamics of proliferation and apoptosis after N-methyl-D-aspartate (NMDA)-mediated excitotoxicity were analyzed by quantitative morphometry of Ki-67 or cleaved caspase-3 immunoreactive glial cells. Treatment on NMDA-lesioned OHSCs with mycophenolate mofetil (MMF)100 μg/mL was started at different time points after injury or performed within specific time frames, and the numbers of propidium iodide (PI)(+) degenerating neurons and isolectin (I)B(4)(+) microglial cells were determined. Pre-treatment with guanosine 100 μmol/l was performed to counteract MMF-induced effects. The effects of MMF on reactive astrocytic scar formation were investigated in the scratch-wound model of astrocyte monolayers. RESULTS: Excitotoxic lesion induction led to significant increases in glial proliferation rates between 12 and 36 hours after injury and to increased levels of apoptotic cells between 24 and 72 hours after injury. MMF treatment significantly reduced glial proliferation rates without affecting apoptosis. Continuous MMF treatment potently reduced the extent of neuronal cell demise when started within the first 12 hours after injury. A crucial time-frame of significant neuroprotection was identified between 12 and 36 hours after injury. Pre-treatment with the neuroprotective nucleoside guanosine reversed MMF-induced antiproliferative effects on glial cells. In the scratch-wound model, gap closure was reached within 48 hours in controls, and was potently inhibited by MMF. CONCLUSIONS: Our data indicate that immunosuppression by MMF significantly attenuates the extent of neuronal cell death when administered within a crucial time frame after injury. Moreover, long-lasting immunosuppression, as required after solid-organ transplantation, does not seem to be necessary. Targeting inosine 5-monophosphate dehydrogenase, the rate-limiting enzyme of purine synthesis, is an effective strategy to modulate the temporal dynamics of proliferation and migration of microglia and astrocytes, and thus to reduce the extent of secondary neuronal damage and scar formation

Factors associated with return to work after open reinsertion of the triangular fibrocartilage

The aim of this study was to assess return to work (RTW) after open Triangular Fibrocartilage Complex (TFCC) reinsertion. RTW after open surgery for TFCC injury was assessed by questionnaires at 6 weeks, 3 months, 6 months, and 12 months post-operatively. Median RTW time was assessed on inverted Kaplan–Meier curves and hazard ratios were calculated with Cox regression models. 310 patients with a mean age of 38 years were included. By 1 year, 91% of the patients had returned to work, at a median 12 weeks (25%–75%: 6–20 weeks). Light physical labor (HR 3.74) was associated with RTW within the first 15 weeks; this association altered from 23 weeks onward: light (HR 0.59) or moderate physical labor (HR 0.25) was associated with lower RTW rates. Patients with poorer preoperative Patient-Rated Wrist Evaluation (PRWE) total score returned to work later (HR 0.91 per 10 points). Overall cost of loss of productivity per patient was €13,588. In the first year after open TFCC reinsertion, 91% of the patients returned to work, including 50% within 12 weeks. Factors associated with RTW were age, gender, work intensity, and PRWE score at baseline

Prognostic Factors in Open Triangular Fibrocartilage Complex (TFCC) Repair

Purpose: Patients with triangular fibrocartilage complex (TFCC) injury report ulnar-sided wrist pain and impaired function. Open TFCC repair aims to improve the condition of these patients. Patients have shown reduction in pain and improvement in function at 12 months after surgery; however, results are highly variable. The purpose of this study was to relate patient (eg, age and sex), disease (eg, trauma history and arthroscopic findings), and surgery factors (type of bone anchor) associated with pain and functional outcomes at 12 months after surgery. Methods: This study included patients who underwent an open TFCC repair between December 2011 and December 2018 in various Xpert Clinics in the Netherlands. All patients were asked to complete Patient-Rated Wrist Evaluation (PRWE) questionnaires at baseline as well as at 12 months after surgery. Patient, disease, and surgery factors were extracted from digital patient records. All factors were analyzed by performing a multivariable hierarchical linear regression. Results: We included 274 patients who had received open TFCC repair and completed PRWE questionnaires. Every extra month of symptoms before surgery was correlated with an increase of 0.14 points on the PRWE total score at 12 months after surgery. In addition, an increase of 0.28 points in the PRWE total score at 12 months was seen per extra point of PRWE total score at baseline. Conclusions: Increased preoperative pain, less preoperative function, and a longer duration of complaints are factors that were associated with more pain and less function at 12 months after open surgery for TFCC. This study arms surgeons with data to predict outcomes for patients undergoing open TFCC repair. Type of study/level of evidence: Prognostic II.</p