Microbiology of Prosthetic Joint Infections: A Retrospective Study of an Italian Orthopaedic Hospital.

The most frequent cause of periprosthetic infections (PJIs) is intraoperative contamination; hence, antibiotic prophylaxis plays a crucial role in prevention. Modifications to standard prophylaxis can be considered if there is a high incidence of microorganisms resistant to current protocols. To date, very few studies regarding microbial etiology have been published in Italy. In this single-center, retrospective study conducted at IRCCS Ospedale Galeazzi-Sant'Ambrogio in Milan, we analyzed hip, knee, and shoulder PJIs in patients undergoing first implantation between 1 January 17 and 31 December 2021. The primary aim was to derive a local microbiological case history. The secondary aim was to evaluate the adequacy of preoperative antibiotic prophylaxis in relation to the identified bacteria. A total of 57 PJIs and 65 pathogens were identified: 16 S. aureus, 15 S. epidermidis, and 10 other coagulase-negative staphylococci (CoNS), which accounted for 63% of the isolations. A total of 86.7% of S. epidermidis were methicillin-resistant (MRSE). In line with other case reports, we found a predominance of staphylococcal infections, with a lower percentage of MRSA than the Italian average, while we found a high percentage of MRSE. We estimated that 44.6% of the bacteria isolated were resistant to cefazolin, our standard prophylaxis. These PJIs could be prevented by using glycopeptide alone or in combination with cefazolin, but the literature reports conflicting results regarding the adequacy of such prophylaxis. In conclusion, our study showed that in our local hospital, our standard antibiotic prophylaxis is ineffective for almost half of the cases, highlighting the importance of defining specific antibiotic guidelines based on the local bacterial prevalence of each institution.

Barbed sutures and skin adhesives improve wound closure in hip and knee arthroplasty.

PURPOSE: This study aimed to formulate evidence-based recommendations for optimising wound management in hip and knee arthroplasty by exploring alternative methods such as barbed sutures and skin adhesives. METHODS: A Delphi panel, comprising seven orthopaedic surgeons, one musculoskeletal infectious disease specialist, and one health economics expert, was convened to evaluate the use of barbed sutures and skin adhesives for wound closure in hip and knee arthroplasty. Two systematic reviews informed the development of questionnaires, with panelists ranking their agreement on statements using a 5-point Likert scale. Consensus was achieved if ≥75% agreement. Unresolved statements were revisited in a second round. RESULTS: Consensus was reached on 11 statements, providing evidence-based recommendations. The expert panel advocates for a multilayer watertight technique using barbed sutures to prevent surgical site infections (SSI), reduce complications, shorten surgical times, optimise resources and improve cosmetic appearance. For skin closure, the panel recommends topical adhesives to decrease wound dehiscence, enhance cosmetic appearance, promote patient compliance, prevent SSIs, and optimise resources. CONCLUSION: The Delphi consensus by Italian total joint arthroplasty experts underscores the pivotal role of barbed sutures and skin adhesives in optimising outcomes. While guiding clinical decision-making, these recommendations are not prescriptive and should be adapted to local practices. The study encourages further research to enhance current evidence. LEVEL OF EVIDENCE: Level III.

The Intraoperative Use of Defensive Antibacterial Coating (DAC®) in the Form of a Gel to Prevent Peri-Implant Infections in Orthopaedic Surgery: A Clinical Narrative Review.

Periprosthetic joint infections (PJIs) in arthroplasty and osteosynthesis-associated infections (OAIs) in reconstructive surgery still represent a challenging complication in orthopaedics and traumatology causing a burden worsening the patient's quality of life, for caregiver and treating physicians, and for healthcare systems. PJIs and OAIs are the result of bacterial adhesion over an implant surface with subsequent biofilm formation. Therefore, the clinical pathological outcome is a difficult-to-eradicate persistent infection. Strategies to treat PJIs and OAIs involve debridement, the replacement of internal fixators or articular prostheses, and intravenous antibiotics. However, long treatments and surgical revision cause discomfort for patients; hence, the prevention of PJIs and OAIs represents a higher priority than treatment. Local antibiotic treatments through coating-release systems are becoming a smart approach to prevent this complication. Hydrophilic coatings, loaded with antibiotics, simultaneously provide a barrier effect against bacterial adhesion and allow for the local delivery of an antibiotic. The intraoperative use of a hyaluronan (HY)-derivative coating in the form of a gel, loaded with antibiotics to prevent PJI, has recently raised interest in orthopaedics. Current evidence supports the use of this coating in the prophylaxis of PJI and IRIs in terms of clinical outcomes and infection reduction. Thus, the purpose of this narrative review is to assess the use of a commercially available HY derivative in the form of a gel, highlighting the characteristics of this biomaterial, which makes it attractive for the management of PJIs and IRIs in orthopaedics and traumatology.

Evaluation of Synovial Calprotectin by Using a Lateral Flow Test for the Diagnosis of Prosthetic Joint Infections.

The analysis of synovial fluid is a crucial step in the diagnosis of prosthetic joint infections (PJIs). Recently several studies illustrated the efficacy of synovial calprotectin in supporting the diagnosis of PJI. In this study, synovial calprotectin was analyzed by a commercial stool test to explore whether it might accurately predict PJIs. The synovial fluids of 55 patients were analyzed and calprotectin levels were compared to other synovial biomarkers of PJI. Of the 55 synovial flu-ids, 12 patients were diagnosed with PJI and 43 with an aseptic failure of the implant. Specificity, sensitivity, and AUC of calprotectin resulted in 0.944, 0.80, and 0.852 (95%CI: 0.971-1.00), respectively, with a set threshold of 529.5 µg/g. Calprotectin had a statistically relevant correlation with the synovial leucocyte counts (rs = 0.69, p < 0.001) and the percentage of synovial neutrophils (rs = 0.61, p < 0.001). From this analysis, it can be concluded that synovial calprotectin is a valuable biomarker that correlates with other established indicators of local infection, and the use of a commercial lateral flow stool test could be a cost-effective strategy delivering rapid and reliable results and supporting the diagnostic process of PJI.

The combined evaluation of fibrinogen and D-dimer levels are a helpful tool to exclude periprosthetic knee infection.

This retrospective study was undertaken to (i) define the most appropriate thresholds for serum d-dimer and fibrinogen for differentiating aseptic failure from periprosthetic joint infection (PJI) and (ii) evaluate the predictive value of our d-dimer and fibrinogen threshold compared to previously proposed thresholds. This observational cohort study included consecutive patients who had undergone total knee arthroplasty (TKA) revision between January 2019 and December 2020. International Consensus Meeting diagnostic criteria were used to identify patients affected by the prosthetic infection. Receiver operating characteristic curve analyses assessed the predictive value of the parameters, and the areas under the curves were evaluated. We included 125 patients with a median age of 69 years (53-82) affected by painful TKA. Fifty-seven patients (47%) had PJI. Patients with PJI had higher median d-dimer, fibrinogen, ESR, and CRP when compared to patients believed to be free of PJI. The best threshold values for d-dimer and fibrinogen were 1063 ng/ml (sensitivity 0.72, specificity 0.74) and 420 mg/dl (sensitivity 0.67 and specificity 0.82), respectively. A d-dimer level >1063 ng/ml combined with a fibrinogen level >420 mg/dl had a sensitivity of 0.52, and a specificity of 0.90. We found that an increased d-dimer beyond 1063 ng/ml showed a better predictive value than the previously proposed threshold. The combined determination of d-dimer and fibrinogen displayed high specificity and should be considered an excellent tool to rule out an infection. The accuracy of the proposed cutoffs is more effective than previously reported.

Reimplantation after Periprosthetic Joint Infection: The Role of Microbiology.

Periprosthetic joint infection (PJI) is among the most feared orthopedic complications. Critical questions are whether the infection is completely resolved before reimplantation and what the clinical significance of positive culture is at reimplantation. The aim of this study was to determine whether a correlation exits between culture results at reimplantation after spacer insertion for hip and knee PJI and treatment failure rate. The data of 84 patients who underwent two-stage exchange arthroplasty for hip or knee PJI were reviewed and the results of intraoperative culture at reimplantation were analyzed quantitatively and qualitatively. Correlations were sought between these patterns and treatment outcome. Our data indicate no evidence for a correlation between positive culture at reimplantation and greater risk of treatment failure. Nonetheless, we noted a higher, albeit statistically not significant rate of treatment failure in patients with at least two samples testing positive. The role of microbiology at reimplantation remains unclear, but a positive culture might signal increased risk for subsequent implant failure. Further studies are needed to elucidate the implications of this finding.

Osteomyelitis, Oxidative Stress and Related Biomarkers.

Bone is a very dynamic tissue, subject to continuous renewal to maintain homeostasis through bone remodeling, a process promoted by two cell types: osteoblasts, of mesenchymal derivation, are responsible for the deposition of new material, and osteoclasts, which are hematopoietic cells, responsible for bone resorption. Osteomyelitis (OM) is an invasive infectious process, with several etiological agents, the most common being Staphylococcus aureus, affecting bone or bone marrow, and severely impairing bone homeostasis, resulting in osteolysis. One of the characteristic features of OM is a strong state of oxidative stress (OS) with severe consequences on the delicate balance between osteoblastogenesis and osteoclastogenesis. Here we describe this, analyzing the effects of OS in bone remodeling and discussing the need for new, easy-to-measure and widely available OS biomarkers that will provide valid support in the management of the disease.

Megaprostheses for the revision of infected hip arthroplasties with severe bone loss.

BACKGROUND: Periprosthetic hip infections with severe proximal femoral bone loss may require the use of limb salvage techniques, but no agreement exists in literature regarding the most effective treatment. Aim of this study is to analyze the infection eradication rate and implant survival at medium-term follow-up in patients treated with megaprostheses for periprosthetic hip infections with severe bone loss. METHODS: Twenty-one consecutive patients were retrospectively reviewed at a mean 64-month follow-up (24-120). Functional and pain scores, microbiological, radiological and intraoperative findings were registered. Kaplan Meier survival analysis and log rank test were used for infection free survival and implant survival analyses. RESULTS: The infection eradication rate was 90.5%, with an infection free survival of 95.2% at 2 years (95%CI 70.7-99.3) and 89.6%(95%CI 64.3-97.3) at 5 years. Only two patients required major implant revisions for aseptic implant loosening. The most frequent complication was dislocation (38.1%). The major revision-free survival of implants was 95.2% (95%CI 70.7-99.3) at 2 years and 89.6% (95%CI 64.3-97.3) at 5 years. The overall implant survival was 83.35% (CI95% 50.7-93.94) at 2 and 5 years. Subgroup analyses (cemented versus cementless MPs, coated versus uncoated MPs) revealed no significant differences at log rank test, but its reliability was limited by the small number of patients included. CONCLUSIONS: Proximal femoral arthroplasty is useful to treat periprosthetic hip infections with severe bone loss, providing good functional results with high infection eradication rates and rare major revisions at medium-term follow-up. No conclusions can be drawn on the role of cement and coatings.

High rate of infection eradication following cementless one-stage revision hip arthroplasty with an antibacterial hydrogel coating.

PURPOSE: We conducted a retrospective study to evaluate the outcomes of one-stage revision total hip arthroplasty (THA) following periprosthetic joint infection (PJI) in terms of eradication of the infection, improvement of pain and joint function. We hypothesized that this treatment strategy could lead to satisfying results in selected patients after preoperative microorganism isolation. METHODS: Ten patients underwent cementless one-stage revision hip arthroplasty with antibacterial hydrogel coating for the treatment of an infected THA. Inclusion criteria were: the presence of a known organism with known sensitivity, patients non-immunocompromised with healthy soft tissues with minimal or moderate bone loss. Mean age at surgery was 69.4 years. Assessment included objective examination, Harris hip score, visual analog scale pain score, standard X-rays. RESULTS: At a mean follow-up of 3.1 years (range, 2-5 years), none of the patients had clinical or radiographic signs suggesting recurrent infection. Follow-up examination showed significant improvement of all variables compared to pre-operative values (p < 0.05). Radiographs did not show progressive radiolucent lines or change in the position of the implant. CONCLUSIONS: One-stage revision THA with antibacterial hydrogel coated implants represents a safe and effective procedure providing infection eradication and satisfying subjective functional outcomes in selected patients.

Is debridement really the best we can do for periprosthetic joint infections following total ankle replacements? A systematic review and meta-analysis.

BACKGROUND: Ankle periprosthetic joint infections are rising in number, but an evidence-based gold standard treatment has not been defined yet. METHODS: We made a systematic review about the operative treatment of infections following total ankle arthroplasty. Proportional meta-analysis was used to summarize effects of the surgical techniques included. Primary outcome of this study was infection eradication, followed by complications, re-interventions, amputation rates and functions. RESULTS: We included six studies(113 patients) reporting 6 types of surgical interventions, mostly irrigation and debridement (35.4%) and two-stage revisions (24.8%). No differences among all analyzed techniques were found in the infection eradication outcome as well as in the secondary outcomes. Patients receiving a permanent spacer are most likely to end up with amputation. CONCLUSIONS: Literature dealing with infections after total ankle replacement is currently composed by few low-quality articles. The overlapping of confidence intervals related to all analyzed interventions showed no superiority of either technique. LEVEL OF EVIDENCE: III.

Can the Leukocyte Esterase Strip Test Predict Persistence of Periprosthetic Joint Infection at Second-Stage Reimplantation?

BACKGROUND: We evaluated the reliability of intraoperative assessment of leukocyte esterase (LE) in synovial fluid samples from patients undergoing reimplantation following implant removal and spacer insertion for periprosthetic joint infection (PJI). Our hypothesis was that a positive intraoperative LE test would be a better predictor of persistent infection than either serum C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) or the combination of serum CRP and ESR. METHODS: The records of 76 patients who received a 2-stage exchange for PJI were retrospectively reviewed. Synovial fluid was collected for LE measurement during surgery before arthrotomy in 79 procedures. Receiver operating characteristic curves were generated. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and area under the curve (AUC) of LE, CRP, ESR, and CRP + ESR were calculated. RESULTS: Sensitivity, specificity, positive predictive value, and negative predictive value of the LE assay were 82%, 99%, 90%, and 97%, respectively. Receiver operating characteristic analysis revealed an LE threshold of 1.5 between the first (negative) and the second (positive) level of the ordinal variable, so that a grade starting from 1+ was accurate for a diagnosis of persistent infection (AUC 0.9044). The best thresholds for the CRP and the ESR assay were 8.25 mg/L (82% sensitivity, 84% specificity, AUC 0.8416) and 45 mm/h (55% sensitivity, 87% specificity, AUC 0.7493), respectively. CONCLUSION: The LE strip test proved a reliable tool to diagnose persistence of infection and outperformed the serum CRP and ESR assays. The strip test provides a valuable intraoperative diagnostic during second-stage revision for PJI.

Classification and management options for prosthetic joint infection.

Periprosthetic joint infection (PJI) is one of the major complications following arthroplasty implantation. Management of PJIs is a challenge for surgeons and various classification systems have been introduced, which consider variables such as onset of symptoms, pathogenesis and clinical manifestation. In an attempt to overcome the shortcomings which may limit their usefulness in borderline cases, a new classification system focusing on the topography of the infectious process has been proposed. This theory relies on the identification of the exact location of the bacterial colonization thus allowing to decide between a conservative or a more radical intervention irrespectively of the timing. The use of nuclear medicine device like radiolabelled white blood cells (WBC) scan could lead the path in identifying pathogenetic processes and their exact location thus guiding orthopaedic surgeons to the most appropriate diagnosis and treatment options. Currently management relies on debridement, antibiotics and implant retention (DAIR), which is traditionally performed at early stages, 1- or 2-stage revision arthroplasty which is commonly limited to chronic cases. Reports have demonstrated similar rates of infection recurrence following one and two-stage revisions, and the use of one-stage revision surgery is gaining popularity. More recently, satisfying results following partial implant retention during revision total arthroplasty for septic failures have been reported. In addition, in severe cases, definitive articulating antibiotic spacer, excision arthroplasty, arthrodesis or amputation can be performed.

A spacer infection by Candida albicans secondary to a Staphylococcus capitis prosthetic joint infection: a case report.

BACKGROUND: Prosthetic joint infection (PJI) is one of the most feared complications following total arthroplasty surgeries. Gram-positive bacteria are the most common microorganisms implicated in PJIs, while infections mediated by fungi only account for 1% of cases. When dealing with PJIs, a two-stage revision arthroplasty is widely used. Briefly, a spacer is introduced until re-implantation of the definitive prosthesis to provide skeleton stabilization while delivering antibiotics in the site of the infection. Sometimes, antimicrobial therapy may fail, but the isolation of a second microorganism from the spacer is uncommon and even less frequent that of a yeast. CASE PRESENTATION: Here is described a case of a 75-year-old woman who underwent two-stage revision surgery of the left hip prosthesis secondary to a Staphylococcus capitis infection, whose spacer was found to be infected by Candida albicans at a later time. Briefly, the patient underwent revision surgery of the hip prosthesis for a suspected PJI. After the debridement of the infected tissue, an antibiotic-loaded spacer was implanted. The microbiological analysis of the periprosthetic tissues and the implant depicted a S. capitis infection that was treated according to the antimicrobial susceptibility profile of the clinical isolate. Three months later, the patient was admitted to the emergency room due to local inflammatory signs. Synovial fluid was sent to the laboratory for culture. No evidence of S. capitis was detected, however, a yeast was identified as Candida albicans. Fifteen days later, the patient was hospitalized for the removal of the infected spacer. Microbiological cultures confirmed the results of the synovial fluid analysis. According to the susceptibility profile, the patient was treated with fluconazole (400 mg/day) for 6 months. Seven months later, the patient underwent second-stage surgery. The microbiological tests on the spacer were all negative. After 12 months of follow-up, the patient has fully recovered and no radiological signs of infection have been detected. CONCLUSIONS: Given the exceptionality of this complication, it is important to report these events to better understand the clinical outcomes after the selected therapeutic options to prevent and forestall the development of either bacterial or fungal spacer infections.

One-stage revision surgery provides infection eradication and satisfying outcomes for infected knee arthroplasty in selected patients.

OBJECTIVES: We conducted a retrospective study to evaluate the outcomes of one-stage revision total knee arthroplasty (TKA) in terms of eradication of the infection, improvement of pain, and knee function. METHODS: Between 2009 and 2016, 20 patients underwent one-stage revision TKA for the treatment of a prosthetic joint infection (PJI). Inclusion criteria were: patients nonimmunocompromised with minimal or moderate bone loss, known organisms with known sensitivity. Assessment included clinical signs of infection eradication, range of motion, Knee Society clinical rating score, visual analog scale pain score, and radiographic assessment. RESULTS: After a mean follow-up of 6.2 years (range, 2-10 years), none of the patients had signs suggesting recurrent infection. Follow-up examination showed significant improvement of all variables compared to preoperative values (p < 0.001). CONCLUSIONS: One-stage revision surgery provides infection eradication and satisfying subjective functional outcomes for infected knee arthroplasty in selected patients. EXPERT OPINION: One-stage revision knee arthroplasty is a valuable resource to approach PJIs in selected patients whose infecting micro-organism and sensitivity are determined before surgery. In order to succeed strict inclusion criteria should be applied, as only non-immunocompromised patients with healthy soft tissues with minimal or moderate bone loss are eligible for this procedure.

Antibiotics and cement: what I need to know?

We conducted a systematic review about antibiotic-loaded bone cement (ALBC) with a focus on clinical evidence about ALBC in general, concerns about ALBC and ALBC cost.

Two-stage revision shoulder prosthesis vs. permanent articulating antibiotic spacer in the treatment of periprosthetic shoulder infections.

INTRODUCTION: Periprosthetic shoulder infections (PSIs) represent a serious complication following shoulder arthroplasty. No consensus exists regarding the optimal option. We conducted a retrospective case-control study to compare the outcomes of 2-stage revision shoulder arthroplasty and those of definitive articulating antibiotic spacer implantation with regards to eradication of the infection, improvement of pain and shoulder function. MATERIALS AND METHODS: Thirty patients treated for an infected shoulder arthroplasty were retrospectively reviewed after a mean follow-up of 8 years (range, 2-10 years). Nineteen underwent definitive articulating antibiotic spacer implantation and 11 underwent 2-stage revision arthroplasty. Mean age at surgery was 68.8 years. Assessment included Constant-Murley score, visual analog scale pain score, objective examination, patient subjective satisfaction score as well as standard radiographs. RESULTS: At the most recent follow-up, none of the patients had clinical or radiographic signs suggesting recurrent infection. Most patients reported satisfying subjective and objective outcomes. Follow-up examination showed significant improvement of all variables compared to preoperative values (p<0.001). Radiographs did not show progressive radiolucent lines or change in the position of the functional spacer. No statistically significant differences were reported between the two groups concerning Constant-Murley and VAS scores, while average forward flexion and abduction were significantly higher in patients undergoing 2-stage revision surgery. CONCLUSIONS: Both surgical procedures provided infection eradication and satisfying subjective functional outcomes. Functional results were superior in patients treated with revision shoulder prosthesis, although a higher rate of complication was reported in this cohort of patients, thus suggesting the use of permanent spacer in high-risk or low-demanding elderly patients. LEVEL OF EVIDENCE: III, Retrospective case-control study.

A new perspective on current prosthetic joint infection classifications: introducing topography as a key factor affecting treatment strategy.

Periprosthetic joint infection (PJI) is a relatively frequent and devastating complication following prosthetic joint implantation. Several classification systems have been presented by various authors and are routinely used in clinical practice to help in early diagnosis and treatment. The most widely accepted classifications of periprosthetic infections rely on the timing of clinical presentation. Unfortunately, these schemes possess important shortcomings which limit their usefulness in clinical practice, as data reported in literature are contrasting, with success rate ranging from 60 to 80%, irrespectively of prosthetic infection timing. An attempt is made by us to update the current knowledge on PJIs by looking them from a different perspective, introducing a topographic principle in their classification. Our approach is based on the theory that identifying the exact location of the bacterial colonization may allow to decide whether to conservatively treat the patient or to perform a more radical intervention. The aim is to improve the understanding of the aetiology of this serious complication, lead to the appropriate treatment strategy according to the stage of the disease thus enhancing the outcomes of surgical management. Such a strategy, if widely accepted, could guide research studies on the management of PJIs. The availability of investigations like scintigraphy could aid in identifying pathogenetic processes and their exact location, which may be missed on conventional radiographs, and could enable orthopaedic surgeons to have a better understanding of PJI patterns.

Management of periprosthetic shoulder infections with the use of a permanent articulating antibiotic spacer.

INTRODUCTION: Management of periprosthetic shoulder infections (PSIs) still remains challenging. We conducted a retrospective case study to assess the outcomes of definitive articulating antibiotic spacer implantation in a cohort of elderly, low-demanding patients. We hypothesized that in patients with low functional demands seeking pain relief with chronic PSIs, treatment with a definitive articulating antibiotic spacer would lead to satisfying results concerning eradication of the infection, improvement of pain, and improving shoulder function. MATERIALS AND METHODS: 19 patients underwent definitive articulating antibiotic spacer implantation for the treatment of an infected shoulder arthroplasty. Mean age at surgery was 70.2 years. Patients were assessed pre-operatively with functional assessment including Constant-Murley score, and objective examination comprehending ROM, visual analog scale pain score, and patient subjective satisfaction (excellent, good, satisfied, or unsatisfied) score. Radiographs were taken to examine signs of loosening, and change in implant positioning. RESULTS: At the most recent follow-up, none of the patients had clinical or radiographic signs suggesting recurrent infection. Most patients reported satisfying subjective and objective outcomes. Follow-up examination showed significant improvement of all variables compared to pre-operative values (p < 0.001). Radiographs did not show progressive radiolucent lines or change in the position of the functional spacer. In one case, glenoid osteolysis was reported, which did not affect the clinical outcome. CONCLUSIONS: In selected elderly patients with low functional demands seeking pain relief with infected shoulder arthroplasty, definitive management with a cement spacer is a viable treatment option that helps in eradicating shoulder infection and brings satisfying subjective and objective outcomes. LEVEL OF EVIDENCE: Case series, Level IV.

Tuberculosis of the Knee: A Case Report and Literature Review.

Tuberculosis (TB) is currently in resurgence due to immigration from endemic areas. Skeletal TB frequently mimics more common etiologies and can be difficult to diagnose. A case of TB knee arthritis in a young woman with painful and swelling knee is reported here. Arthrotomy was performed and inflamed synovial tissue was found, with multiple rice bodies in the eroded lateral femoral condyle. The patient was treated with an antituberculosis polytherapy and at 1-year follow-up, she reported relief from pain and swelling. We believe that all surgeons assessing patients from TB endemic regions have to adopt an updated approach to TB treatment. Thus, a literature review is also reported here on the current strategies used in different knee TB cases.

Noradrenaline in Parkinson's disease: from disease progression to current therapeutics.

The loss of the neurotransmitter noradrenaline occurs constantly in Parkinson's disease. This is supposed to worsen disease progression, either by increasing the vulnerability of dopamine-containing neurons or by reducing the recovery once they are damaged. Novel data also show that the loss of noradrenergic innervation facilitates the onset of dyskinesia occurring in Parkinsonian patients during dopamine replacement therapy. In the first part of the manuscript we review the evidence showing the loss of the noradrenergic system as an early event in the natural history of Parkinsonism. This evidence is discussed in light of novel reports showing the deleterious effects produced by the noradrenergic deficit on the survival of nigral dopamine neurons. In particular, we analyze the biochemical and morphological changes produced in the nigrostriatal system by the loss of endogenous noradrenaline. In a dedicated paragraph we specifically evaluate the cross affinity between dopamine and noradrenaline systems. In fact, this is critical during dopamine/noradrenaline replacement therapy in Parkinson's disease. In the last part, we overview novel therapeutic approaches aimed at restoring the activation of noradrenaline receptors to reduce the dyskinesia occurring in the treatment of Parkinson's disease.