How to manage a native stiff knee.

Knee stiffness is a widely known and worrying condition in several postoperative knees. Less is known about native stiff knee. The aim of this manuscript is to summarize the available literature on native stiff knee epidemiology, classification and treatment. In 1989 stiff knee was defined as a knee with less than 50° of total range of motion. If range of motion is <30°, it is defined as an ankylosed knee. Knee stiffness can be divided into three main types: flexion contractures, extension contractures, and combined contractures. Different risk factors have been associated to native stiff knee and grouped into modifiable or not modifiable. Furthermore, risk factors can be divided into patients' related no patients'-related. Different treatment modalities can be indicated to treat knee stiffness, including manipulation under anesthesia (MUA), arthroscopic and open surgical release. When stiffness is associated with articular disruption TKA represent an option. TKA in native stiff knee can be challenging for the surgeon. Implant's choice and knee exposure are the first steps. In some cases, additional release and extensive can be considered. A stepwise approach and careful preoperative planning are mandatory to obtain long-term satisfactory outcomes. Native stiff knee is a rare but invalidating condition. Different treatment modalities have been proposed as treatment. However, considering that it is frequently associated to sever arthritis, TKA can be an option in painful stiff knees. Nature of knee stiffness necessitates a customized approach to ensure successful management and achieve satisfying outcomes.

Mucopolysaccharidosis type II zebrafish model exhibits early impaired proteasomal-mediated degradation of the axon guidance receptor Dcc.

Most of the patients affected by neuronopathic forms of Mucopolysaccharidosis type II (MPS II), a rare lysosomal storage disorder caused by defects in iduronate-2-sulfatase (IDS) activity, exhibit early neurological defects associated with white matter lesions and progressive behavioural abnormalities. While neuronal degeneration has been largely described in experimental models and human patients, more subtle neuronal pathogenic defects remain still underexplored. In this work, we discovered that the axon guidance receptor Deleted in Colorectal Cancer (Dcc) is significantly dysregulated in the brain of ids mutant zebrafish since embryonic stages. In addition, thanks to the establishment of neuronal-enriched primary cell cultures, we identified defective proteasomal degradation as one of the main pathways underlying Dcc upregulation in ids mutant conditions. Furthermore, ids mutant fish-derived primary neurons displayed higher levels of polyubiquitinated proteins and P62, suggesting a wider defect in protein degradation. Finally, we show that ids mutant larvae display an atypical response to anxiety-inducing stimuli, hence mimicking one of the characteristic features of MPS II patients. Our study provides an additional relevant frame to MPS II pathogenesis, supporting the concept that multiple developmental defects concur with early childhood behavioural abnormalities.

Exploring the Importance of Environmental Complexity for Newly Hatched Zebrafish.

The effects of an early impoverished social or physical environment on vertebrate neural development and cognition has been known for decades. While existing studies have focused on the long-term effects, measuring adult cognitive phenotypes, studies on the effects of environmental complexity on the early stages of development are lacking. Zebrafish (Danio rerio) hatchlings are assumed to have minimal interaction with their environment and are routinely reared in small, bare containers. To investigate the effects of being raised under such conditions on development of behaviour and cognition, hatchlings housed for 10 days in either an enriched or a standard environment underwent two cognitive tasks. The results were mixed. Subjects of the two treatments did not differ in performance when required to discriminate two areas. Conversely, we found a significant effect in a number discrimination task, with subjects from impoverished condition performing significantly worse. In both experiments, larvae reared in impoverished environment showed a reduced locomotor activity. Given the effects that enrichment appears to exert on larvae, a third experiment explored whether hatchlings exhibit a spontaneous preference for more complex environments. When offered a choice between a bare setting and one with objects of different shapes and colors, larvae spent over 70% of time in the enriched sector. Deepening these effects of an early impoverished environment on cognitive development is crucial for the welfare of captive zebrafish populations and for enhancing the quality and reliability of studies on larval zebrafish.

Optogenetic Methods to Investigate Brain Alterations in Preclinical Models.

Investigating the neuronal dynamics supporting brain functions and understanding how the alterations in these mechanisms result in pathological conditions represents a fundamental challenge. Preclinical research on model organisms allows for a multiscale and multiparametric analysis in vivo of the neuronal mechanisms and holds the potential for better linking the symptoms of a neurological disorder to the underlying cellular and circuit alterations, eventually leading to the identification of therapeutic/rescue strategies. In recent years, brain research in model organisms has taken advantage, along with other techniques, of the development and continuous refinement of methods that use light and optical approaches to reconstruct the activity of brain circuits at the cellular and system levels, and to probe the impact of the different neuronal components in the observed dynamics. These tools, combining low-invasiveness of optical approaches with the power of genetic engineering, are currently revolutionizing the way, the scale and the perspective of investigating brain diseases. The aim of this review is to describe how brain functions can be investigated with optical approaches currently available and to illustrate how these techniques have been adopted to study pathological alterations of brain physiology.

Environmental enrichment decreases anxiety-like behavior in zebrafish larvae.

The development of anxiety disorders is often linked to individuals' negative experience. In many animals, development of anxiety-like behavior is modeled by manipulating individuals' exposure to environmental enrichment. We investigated whether environmental enrichment during early ontogenesis affects anxiety-like behavior in larval zebrafish. Larvae were exposed from hatching to either an environment enriched with 3D-objects of different color and shape or to a barren environment. Behavioral testing was conducted at different intervals during development (7, 14, and 21 days post-fertilization, dpf). In a novel object exploration test, 7 dpf larvae of the two treatments displayed similar avoidance of the visual stimulus. However, at 14 and 21 dpf, larvae of the enriched environment showed less avoidance, indicating lower anxiety response. Likewise, larvae of the two treatments demonstrated comparable avoidance of a novel odor stimulus at 7 dpf, with a progressive reduction of anxiety behavior in the enriched treatment with development. In a control experiment, larvae treated before 7 dpf but tested at 14 dpf showed the effect of enrichment on anxiety, suggesting an early determination of the anxiety phenotype. This study confirms a general alteration of zebrafish anxiety-like behavior due to a short enrichment period in first days of life.

Hypothalamic Galanin-producing neurons regulate stress in zebrafish through a peptidergic, self-inhibitory loop.

Animals possess neuronal circuits inducing stress to avoid or cope with threats present in their surroundings, for instance, by promoting behaviors, such as avoidance and escape. However, mechanisms must exist to tightly control responses to stressors, since overactivation of stress circuits is deleterious for the wellbeing of an organism. The underlying neuronal dynamics responsible for controlling behavioral responses to stress have remained unclear. Here, we describe a neuronal circuit in the hypothalamus of zebrafish larvae that inhibits stress-related behaviors and prevents excessive activation of the neuroendocrine pathway hypothalamic-pituitary-interrenal axis. Central components of this circuit are neurons secreting the neuropeptide Galanin, as ablation of these neurons led to abnormally high levels of stress. Surprisingly, we found that Galanin has a self-inhibitory action on Galanin-producing neurons. Our results suggest that hypothalamic Galanin-producing neurons play an important role in fine-tuning stress responses by preventing potentially harmful overactivation of stress-regulating circuits.

Innate visual discrimination abilities of zebrafish larvae.

The ability to discriminate between objects visually plays a key role in animals' interactions with their environment because it enables them to recognise companions, prey, and predators. In the zebrafish, Danio rerio, hatching occurs early on during development (48-72 h post fertilisation), and the larvae must forage and evade predators despite their immature sensory and cognitive systems. Using a preference paradigm, we investigated whether larval zebrafish are nonetheless capable of discriminating between visual stimuli. We found that larvae discriminated not only between figures with different colours or different shapes, but also between two identical figures with different orientations and between sets of figures with different numerosities. By manipulating larvae's exposure to objects before the test, we demonstrated that their discrimination abilities are innate and do not depend upon experience. This study highlighted that zebrafish possess relatively sophisticated visual discrimination abilities even at the larval stage. These abilities likely improve larval survival via the recognition of biologically relevant stimuli.

Whole brain functional recordings at cellular resolution in zebrafish larvae with 3D scanning multiphoton microscopy.

Optical recordings of neuronal activity at cellular resolution represent an invaluable tool to investigate brain mechanisms. Zebrafish larvae is one of the few model organisms where, using fluorescence-based reporters of the cell activity, it is possible to optically reconstruct the neuronal dynamics across the whole brain. Typically, leveraging the reduced light scattering, methods like lightsheet, structured illumination, and light-field microscopy use spatially extended excitation profiles to detect in parallel activity signals from multiple cells. Here, we present an alternative design for whole brain imaging based on sequential 3D point-scanning excitation. Our approach relies on a multiphoton microscope integrating an electrically tunable lens. We first apply our approach, adopting the GCaMP6s activity reporter, to detect functional responses from retinal ganglion cells (RGC) arborization fields at different depths within the zebrafish larva midbrain. Then, in larvae expressing a nuclear localized GCaMP6s, we recorded whole brain activity with cellular resolution. Adopting a semi-automatic cell segmentation, this allowed reconstructing the activity from up to 52,000 individual neurons across the brain. In conclusion, this design can easily retrofit existing imaging systems and represents a compact, versatile and reliable tool to investigate neuronal activity across the larva brain at high resolution.

Measuring recognition memory in zebrafish larvae: issues and limitations.

Recognition memory is the capacity to recognize previously encountered objects, events or places. This ability is crucial for many fitness-related activities, and it appears very early in the development of several species. In the laboratory, recognition memory is most often investigated using the novel object recognition test (NORt), which exploits the tendency of most vertebrates to explore novel objects over familiar ones. Despite that the use of larval zebrafish is rapidly increasing in research on brain, cognition and neuropathologies, it is unknown whether larvae possess recognition memory and whether the NORt can be used to assess it. Here, we tested a NOR procedure in zebrafish larvae of 7-, 14- and 21-days post-fertilization (dpf) to investigate when recognition memory first appears during ontogeny. Overall, we found that larvae explored a novel stimulus longer than a familiar one. This response was fully significant only for 14-dpf larvae. A control experiment evidenced that larvae become neophobic at 21-dpf, which may explain the poor performance at this age. The preference for the novel stimulus was also affected by the type of stimulus, being significant with tri-dimensional objects varying in shape and bi-dimensional geometrical figures but not with objects differing in colour. Further analyses suggest that lack of effect for objects with different colours was due to spontaneous preference for one colour. This study highlights the presence of recognition memory in zebrafish larvae but also revealed non-cognitive factors that may hinder the application of NORt paradigms in the early developmental stages of zebrafish.

Hip Spacers in Two-Stage Revision for Periprosthetic Joint Infection: A Review of Literature.

Infection after total hip arthroplasty (THA) is a devastating complication with significant consequences for patients. In literature, single and two-stage revision, irrigation and debridement, Girdlestone resection arthroplasty, and arthrodesis and amputation are reported as possible treatments. Recently, two-stage revision has become popular as the gold standard treatment for chronic hip joint infections after THA. In this review, we evaluate the current literature about microbiology of periprosthetic joint infections and the use of antibiotic-loaded cement spacers. We aim to give an overview about indications, clinical results, and mechanical complications for spacers implantation, evaluating also selection criteria, pharmacokinetic properties, and systemic safety of the most frequently used antibiotics.

Revision total knee arthroplasty (TKA): mid-term outcomes and bone loss/quality evaluation and treatment.

BACKGROUND: Revision total knee arthroplasty (rTKA) is a demanding procedure, with a high complication and failure rate and a high rate of bone losses and poor bone quality. Different classifications for bone losses have been proposed, but they do not consider bone quality, which may affect implant fixation. The aim of this study is to describe the outcomes of a consecutive series of rTKA. Furthermore, a modified bone loss classification will be proposed based also on bone quality. Finally, the association between radiolucent line (RLL) development and different risk factors will be evaluated. METHODS: All the patients who underwent rTKA between 2008 and 2016 in the same institution were included. rTKAs were performed by the same surgeon according to the three-step technique. Bone losses were classified according to the proposed classification, including bone quality evaluation. The Knee Scoring System (KSS), the Hospital for Special Surgery Knee Score (HSS), and the SF-12 were used for the clinical evaluation. Radiological evaluation was performed according to the Knee Society Roentgenographic Evaluation System. Different possible risk factors (i.e., gender, age, amount of bone losses) associated to RLL development were identified, and this association was evaluated using logistic regression. RESULTS: Fifty-one patients (53 knees) were included (60.8% female, average age 71.5 years). The average follow-up was 56.6 months (range 24-182). The most frequent cause of failure was aseptic loosening (41.5%). 18.9% of the cases demonstrated poor bone quality. Bone losses were treated according to the proposed algorithm. In all the cases, there was a significant improvement in all the scores (P < 0.05). The average post-operative range of motion was 110.5° (SD 10.7). At the radiological evaluation, all the implants resulted well aligned, with 15.1% of non-progressive RLL. There were 2 failures, with a cumulative survivorship of 92.1% at the last follow-up (SD 5.3%). At the logistic regression, none of the evaluated variables resulted associated to RLL development. CONCLUSION: rTKA is a demanding procedure, and adequate treatment of bone losses is mandatory to achieve good results. However, also bone quality should be taken into consideration when approaching bone losses, and the proposed classification may need surgeons after an adequate validation. LEVEL OF EVIDENCE: Level IV.

Total knee arthroplasty in the varus knee: tips and tricks.

Varus knee deformity is very common, and it can be classified according to the severity and reducibility of the deformity. Pre-operative planning is mandatory to obtain a good result. Both clinical and radiological planning should be carefully performed, particularly focused on collateral ligament deficiency. In most of the cases, a postero-stabilized implant is necessary, but in the presence of a varus thrust, a midlevel constrained (MLC) implant may be necessary. Rarely, if a severe extra-articular deformity is present, a femoral osteotomy and a high constrain implant may be necessary. In most of the cases, a standard midline approach can be performed. Soft tissue balancing is crucial, avoiding excessive releases of the medial collateral ligament (MCL). In the presence of severe deformity, more aggressive procedure such as tibial reduction osteotomy or sliding medial epicondyle osteotomy can be performed. In literature, good outcomes are reported for total knee arthroplasty (TKA) in varus deformity. In this manuscript, the available literature on TKA in varus deformity is analyzed, and the preferred surgical techniques of the authors are described.

Medium-term follow-up of 149 mobile-bearing total knee arthroplasties and evaluation of prognostic factors influencing outcomes.

OBJECTIVE: To evaluate the medium-term outcomes of a posterior-stabilized mobile-bearing total knee arthroplasty (PS-MB-TKA) and the role of different prognostic factors. METHODS: Patients indicated for a primary cemented PS-MB-TKA between 2002 and 2010 were included and prospectively evaluated using the Knee Society Scoring System (KSS) and the Hospital for Special Surgery (HSS) knee scores. The Knee Society Roentgenographic Evaluation form was used for the radiological evaluation. Different variables were collected and divided into patient- and surgery-related. Logistic regression was used to analyze the correlation between these variables and implants outcomes and survivorship. RESULTS: In total, 149 cases were included (67.8% female, average age 70.4 years, SD ±9.4). The patella was resurfaced in 12.1% of the cases. All the implants were cemented. The average follow-up was 87.3 months (SD ±21.2). Postoperatively, there was a statistically significant improvement in all the scores. The cumulative survival was 96.2% (SD ±0.02%). At the regression analysis, female gender was associated to worse satisfaction KSS (OR = 0.26), functional KSS (OR = 0.22), and HSS (OR = 0.37) scores. Patellar resurfacing and subsequent contralateral procedures were associated to better functional KSS score (OR = 4.13, OR = 2.21), as well as varus preoperative alignment (OR = 2.12). On contrary, valgus preoperative alignment was associated to worse objective KSS score (OR = 0.23). No variables were correlated to failure or presence of radiolucent lines. CONCLUSION: Good medium-term outcomes were obtained using PS-MB-TKA, with a cumulative survivorship of 96.5%. Female gender and valgus preoperative alignment were associated to worse objective and subjective outcomes. Conversely, patellar replacement, subsequent contralateral TKA, and varus preoperative alignment were associated to better functional outcomes.

High tibial osteotomy in varus knees: indications and limits.

Opening wedge high tibial osteotomy (OWHTO) is a surgical procedure that aims to correct the weight-bearing axis of the knee, moving the loads laterally from the medial compartment. Conventional indications for OWHTO are medial compartment osteoarthritis and varus malalignment of the knee; recently OWHTO has been used successfully in the treatment of double and triple varus. OWHTO, in contrast to closing wedge high tibial osteotomy, does not require fibular osteotomy or peroneal nerve dissection, or lead to disruption of the proximal tibiofibular joint and bone stock loss. For these reasons, interest in this procedure has grown in recent years. The aim of this study is to review the literature on OWHTO, considering indications and prognostic factors (body mass index, grade of osteoarthritis, instability, range of movement and age), outcomes at mid-term follow-up, and limits of the procedure (slope modifications, patellar height changes and difficulties in conversion to a total knee arthroplasty).

Prognostic factors for mortality after hip fracture: Operation within 48 hours is mandatory.

The aim of this study was to assess whether surgery delay and other variables are associated with an increased mortality rate after surgical treatment of hip fractures in the elderly. Patients treated for a proximal femoral fracture at our Orthopaedic Department between 2005 and 2012 were included in this study. A logistic regression was performed to evaluate the relationship between mortality rate at different follow-up times (30 days, six months and one year) and different patient or treatment variables. A total of 1448 consecutive patients with 1558 proximal femoral fractures (55 bilateral) were enrolled in this study (mean age 80.3 years, 75.8% female). The postoperative mortality rate was 4% at 30 days, 14.1% at six months, and 18.8% at one year after surgery. Logistic regression revealed an increased mortality at all the endpoints in patients affected by more than two co-morbidities (respectively OR30-day=2.003, OR6-month=1.8654 and OR1-year=1.5965). Male sex was associated with an increased six-month (OR=1.7158) and one-year (OR=1.9362) mortality. Patients aged under 74 years had a decreased mortality at all endpoints (OR30-day=0.0703, OR6-month=0.2191 and OR1-year=0.2486). In this study, the surgery delay influenced mortality at one-year follow-up: operating within 48hours was associated with a decreased mortality rate (OR=0.7341; p=0.0392). Additionally, the patients who were operated on within 72hours were specifically analysed to understand if the option of 'operating within day 3' was acceptable. In the logistic regression, operating between 48 and 72hours was not reported as a risk factor for mortality, both compared to early surgery (within 48 hours) and to late surgery (after 72hours). This study showed that age, sex and number of co-morbidities influenced both early and late mortality in patients affected by proximal hip fractures. Early surgery influenced late mortality, with a decreased risk in patients operated on within 48hours. The option of operating within day 3 is not a valid alternative.

Cruciate retaining and cruciate substituting ultra-congruent insert.

The posterior cruciate ligament (PCL) conservation and the polyethylene insert constraint in total knee arthroplasty (TKA) are still debated. The PCL is one of the primary stabilizers of the joint, but cruciate retaining (CR) implants have the disadvantage of a difficult balancing of the PCL. Postero-stabilized (PS) implants were introduced to reduce this problem. However, also the PS implants have some disadvantages, due to the cam-mechanism, such as high risk of cam-mechanism polyethylene wear. To minimize the polyethylene wear of the cam-mechanism and the bone sacrifice due to the intercondylar box, different types of inserts were developed, trying to increase the implant conformity and to reduce stresses on the bone-implant interface. In this scenario ultra-congruent (UC) inserts were developed. Those inserts are characterized by a high anterior wall and a deep-dished plate. This conformation should guarantee a good stability without the posterior cam. Few studies on both kinematic and clinical outcomes of UC inserts are available. Clinical and radiological outcomes, as well as kinematic data are similar between UC mobile bearing (MB) and standard PS MB inserts at short to mid-term follow-up. In this manuscript biomechanics and clinical outcomes of UC inserts will be described, and they will be compared to standard PS or CR inserts.

Total knee arthroplasty and infection: how surgeons can reduce the risks.

Total joint arthroplasty (TJA) is one of the most common orthopaedic procedures. Nevertheless, several complications can lead to implant failure.Peri-prosthetic joint infections (PJI) certainly represent a significant challenge in TJA, constituting a major cause of prosthetic revision. The surgeon may have an important role in reducing the PJI rate by limiting the impact of significant risk factors associated to either the patient, the operative environment or the post-operative care.In the pre-operative period, several preventive measures may be adopted to manage reversible medical comorbidities. Other recognised pre-operative risk factors are urinary tract infections, intra-articular corticosteroid injections and nasal colonisation with Staphylococcus (S.) aureus, particularly the methicillin-resistant strain (MRSA).In the intra-operative setting, protective measures for PJI include antibiotic prophylaxis, surgical-site antisepsis and use of pre-admission chlorhexidine washing and pulsed lavage during surgery. In this setting, the use of plastic adhesive drapes and sterile stockinette, as well as using personal protection systems, do not clearly reduce the risk of infection. On the contrary, using sterile theatre light handles and splash basins as well as an increased traffic in the operating room are all associated with an increased risk for PJI.In the post-operative period, other infections causing transient bacteraemia, blood transfusion and poor wound care are considered as risk factors for PJI. Cite this article: Ratto N, Arrigoni C, Rosso F, Bruzzone M, Dettoni F, Bonasia DE, Rossi R. Total knee arthroplasty and infection: how surgeons can reduce the risks. EFORT Open Rev 2016;1: 339-344 DOI: 10.1302/2058-5241.1.000032.

Use of tranexamic acid in total knee arthroplasty.

PURPOSE: different strategies have been developed to reduce blood loss in total knee arthroplasty (TKA). The efficacy of both systemic and local tranexamic acid (TXA) administration is demonstrated in the literature. The aim of the present study was to compare the efficacy of systemic, local and combined (systemic + local) administration of TXA in reducing blood loss after TKA. METHODS: we enrolled all patients submitted to a primary TKA in our department between November 2014 and August 2015. They were divided into three groups corresponding to the method of TXA administration used: intravenous (IV), intra-articular (IA), and a combination of the two. Demographic data, as well as preoperative hemoglobin and platelet levels, were collected. The primary outcome was the maximum hemoglobin loss, while the secondary outcomes were the amount of blood in the drain (cc/hour) and the rate of transfusions; postoperative pain was also assessed. Student's t-test or a χ2 test was used to evaluate between-group differences, using p<0.05 as the cut-off for statistically significant differences. RESULTS: the sample comprised 34 patients: IV, 10 cases; IA, 15 cases, and combined (IV + IA), 9 cases. The average age of the patients was 71.1±6.4 years. No significant differences in the outcome measures were found between the groups, with the exception of a significantly lower maximum hemoglobin loss in the combined versus the IV group (p=0.02). There were no differences between the groups in the amount of blood in the drain or the rate of transfusions. CONCLUSIONS: the data from this preliminary study, as well as data from the literature, confirm that TXA administration is safe and effective in reducing total blood loss in TKA, and no administration protocol seems to be superior to the others. LEVEL OF EVIDENCE: Level II, prospective comparative study.

The use of spacers (static and mobile) in infection knee arthroplasty.

Revision total knee arthroplasty (TKA) is the treatment of choice in patients with periprosthetic joint infection. It may be performed in either a single stage or two stages. In the latter option, between stages, an antibiotic-loaded spacer may be used to maintain a certain amount of joint stability and mobility after the infected implant is removed, adding an intra-articular concentration of antibiotics. There are two types of antibiotic-loaded cement spacers: static and dynamic. Static spacers basically create a temporary arthrodesis with antibiotic-loaded cement and usually are handmade within the surgical field. Dynamic spacers can be created intraoperatively by using different tools or may be prepackaged by the manufacturer; they allow range of motion between stages. In this article, the authors review the indications, surgical techniques, and results for static and dynamic spacers in two-stage revision TKA.

Painful knee arthroplasty: current practice.

Primary total knee arthroplasty is the treatment for end-stage arthritis of the knee; in the last years, it is becoming more common and reliable, due to technical and implant improvement. With larger implant rates, the overall complications will increase and pain is the most common sign of implant failure. Pain can be related to a lot of different clinical findings, and the surgeon has to be aware of the various etiologies that can lead to failure. Pain does not always mean revision, and the patient has to be fully evaluated to have a correct diagnosis; if surgery is performed for the wrong reason, this will surely lead to a failure. In this paper, the authors revised the more common causes of failure that can have a painful onset proposing an approach for diagnosis and treatment.