Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis

Parps: Rapidly Evolving Weapons in the War against Viral Infection

Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic 'arms races' with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in 'housekeeping' functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts

Clinical and functional outcomes after type B-C(AO/OTA) distal humeral fractures treated with locking compression plates: A retrospective study

BACKGROUND: B-C (AO/OTA) fractures of distal humerus are lesions difficult to treat with results that are not always satisfactory. The aim of this study was to evaluate the outcome of patients with this type of fractures treated at our institute. METHODS: A retrospective study considering 32 patients with mean age of 57.1 years (19-85) treated with open reduction and internal fixation (ORIF) for distal humerus articular fractures, 5 type B1, 1 type B2, 12 type C1, 4 type C2, 10 type C3 (AO/OTA), 29 closed fractures, 2 with grade I-II (Gustillo) of exposure, 1 with point exposure. Surgical exposures used are triceps-on and olecranon osteotomy, while the synthesis was performed with locking compression plates. The average follow-up was 42.7 months (79-9). The radiograms performed during the standard controls were evaluated and the Mayo Elbow Performance Score was used for functional evaluation. RESULTS: Average MEPS of 90.6 (55-100), excellent in 68.8%, good 18.7%, fair, 6.3% and poor 6.3%. Average flexion of 125.1 ° (40-140°) with an average deficiency of 11 ° (0-40°). All olecranial osteotomies healed, no pseudoarthrosis was found. Registered complications: 2 wound dehiscences, 7 cases with residual hypoesthesia in the territory of the ulnar nerve, 1 mobilization of a healed fracture screw, 3 cases with presence of joint ossifications and marked rigidity with subsequent surgical revision. CONCLUSIONS: ORIF with orthogonal construct and locking compression plates is an optimal technique for the treatment of distal humerus articular fractures. Associated with an early mobilization leads to an excellent functional result with a minimum rate of complications

Use of pulsed radiofrequency electromagnetic field (Prfe) therapy for pain management and wound healing in total knee and reverse shoulder prosthesis: Randomized and double-blind stud

Pulsed radiofrequency Electromagnetic field (PRFE) has a long history about treatment of various medical conditions. Several clinical studies have demonstrated its safety and efficacy as a treatment for pain, edema, and soft tissue injury. In this pilot, prospective, randomized and double-blind study, a wearable, energy-emitting PRFE therapy device (MetiMed, Performance Hospital Srl, Seriate, Italy) was used to control postoperative pain and to accelerate wound healing in patients who underwent total knee or reverse shoulder prosthesis. We enrolled in the study 50 consecutive patients who had a total knee arthroplasty or a reverse shoulder prosthesis. The subjects were randomly assigned to receive a placebo or active PRFE device for 20 postoperative days. Postoperative pain was assessed with a 0-to 10-point visual analog scale (VAS). The use of painkillers was also registered. The healing of surgical scars was assessed with Vancouver Scar Scale (VSS) (total score ranging from 0 to 13, with 0 representing normal skin). Consecutive VAS scores in the 20 days of the study showed no significant decrease in the control group with a day 1 to day 20 difference of 1.48 VAS points. On the other side, VAS score in the study group showed a steady decline (VAS score difference was 4.2 VAS points). The use of painkillers was lower in the group that received PRFE therapy.VSS score in the active group showed a steady decline (day 1 to day 20 difference was 3.92 VSS points) while the VSS scores showed no significant improvement in the placebo group (0.88 VSS points). According to these findings, PRFE therapy in this form is an excellent, safe, drug-free method of postoperative pain control and wound healing in patients who undergo total knee or reverse shoulder prosthesis. © EuroMediterranean Biomedical Journal 2018

Clinical and radiographical outcome after surgical treatment of periprosthetic type B proximal femur fractures: a retrospective study

Purpose Periprosthetic fractures after hip prosthesis represent a constantly increasing clinical problem and a challenging complication to treat surgically. Among these, type B proximal femur fractures should be diagnosed correctly to be treated surgically. The aim of this study was to re-evaluate the type of surgical treatment of periprosthetic fractures. Methods We examined the cases treated between January 2012 and February 2018, classifying them according to the U.C.S. AO/OTA. We evaluated the radiographic outcome according to the Beals and Tower criteria. Patients still alive were also re-evaluated according to the H.H.S. and the WOMAC score. Results We treated 48 patients (12 men, 35 women, average age 81 years), divided into 24 type B1, 14 type B2 and 10 type B3 fractures. The overall consolidation rate was 95.4%, while the major complication (implant dislocation, pseudoarthrosis and deep infection) rate was 12.5%. Clinically, it was possible to reassess 34 patients with a mean follow-up of 38.4 months, an average HHS of 75.89 and a mean WOMAC score of 79.93. Conclusions Periprosthetic type B fractures are difficult to manage and require careful preoperative planning and appropriate intraoperative management. However, the overall clinical and radiographic result was satisfactory, although patients should still be aware of the risk of complications associated with this type of fractur

Complex fibular head avulsion fracture: surgical management of a case

Fibular head avulsion fractures are rare injuries determined by traction of the fibular attachment of the lateral collateral ligament (LCL). Surgical treatment is often recommended with different techniques such as tension band fixation or lag screws stabilization. In this article, we describe a fixation technique of fibular head fractures obtained through the use of anchors. A 45-year-old athletic patient came to our attention in our traumatologic service after a motorcycle accident. He reported a complex injury of the posterolateral corner with an avulsion fracture of the left fibular head. We performed a clinical evaluation at the final follow-up visit (six months). We demonstrated that the use of suture anchors may be an effective technique of fixation in avulsion fracture of the fibular head associated with combined posterolateral corner injuries

The independent association between altered renal arterial resistance and loop diuretic dose in chronic heart failure outpatients

In chronic heart failure (CHF) patients there is a wide variability in the minimal effective diuretic dose. The aim of this study is to evaluate whether renal resistance index (RRI) is associated to baseline diuretic dose and the changes at one year. Methods and results: 250 outpatients in a stable condition and in conventional therapy were enrolled. Baseline RRI was calculated by renal arterial Doppler. The total daily dose of loop diuretics was assessed at baseline and after one year. High diuretic dose (HDD) was defined as a daily furosemide equivalent dose >. 100. mg. RRI was independently associated with baseline HDD at univariate (OR 1.39; 95% CI: 1.233-1.58; p. <. 0.001) and multivariate analysis (OR 1.27; 95% CI: 1.09-1.49; p: 0.002) after correction for other univariate predictors (age, NYHA class, left ventricular ejection fraction, tricuspid annulus peak of systolic excursion, NT-proBNP, glomerular filtration rate by EPI formula and central venous pressure). Moreover, baseline RRI was independently associated to one year stable increase in loop diuretic dose at univariate and multivariate regression analyses. Conclusions: RRI is independently associated with high dose loop diuretics and their increase during a mid-term follow-up thus suggesting its usefulness in detecting an altered diuretic response in CHF outpatients