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Secretome Analysis of Vibrio cholerae Type VI Secretion System Reveals a New Effector Immunity Pair

Secretome Analysis of Vibrio cholerae Type VI Secretion System Reveals a New Effector Immunity Pair

IMPORTANCE The Gram-negative bacterium Vibrio cholerae causes cholera, a severe and often lethal diarrheal disease. The 2010-2012 epidemic in Haiti and new explosive epidemics in Africa show that cholera remains a significant global public health problem. The type VI secretion system (T6SS) is a dynamic organelle expressed by many Gram-negative bacteria, which use it to inject toxic effector proteins into eukaryotic and bacterial prey cells. In this study, we applied a comparative proteomics ap- proach to the V. cholerae T6SS secretome to identify new substrates of this secretion apparatus. We show that the product of the gene VCA0285 is likely a new peptidoglycan hydrolase that is secreted by T6SS and that its cognate immunity protein is encoded by the gene that is immediately downstream (VCA0286). Bioinformatics analysis shows that VCA0285 carries four conserved motifs that likely define a large family of hydrolases with antibacterial activity. The identification of new antibacterial T6SS effec- tors provides useful information for the development of novel antibiotics and therapeutic agents.
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Clinical impact of the type VI secretion system on virulence of Campylobacter species during infection

Clinical impact of the type VI secretion system on virulence of Campylobacter species during infection

The clinical manifestation of infection with Campylo- bacter spp. is determined by host factors such as immune-competency, age, genetic background, and bac- terial factors such as virulence of the pathogen, initial in- fectious dose, and initiated therapy [6, 7]. Current research has identified novel mechanisms that may con- tribute to virulence and survival of Campylobacter spp. in humans, such as the Type VI Secretion System (T6SS) [8], one of several bacterial systems for protein secretion [9]. With a structure similar to the tail of the contractile bac- teriophages [10], the T6SS allows the contact-dependent secretion of effectors into other bacterial or host cells [11, 12]. The T6SS is encoded by a gene cluster of approx.17kb comprising 13 genes [13]. One of the hallmark genes of the T6SS gene cluster is hcp (encoding the secreted com- ponent hemolysin co-regulated protein) [14], which has been defined as a marker of a complete T6SS [15].
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Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase

Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase

Background: Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; MPS VI) is an autosomal recessive lysosomal storage disorder in which deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) leads to the storage of glycosaminoglycans (GAGs) in connective tissue. The genotype-phenotype correlation has been addressed in several publications but the picture is not complete. Since 2007, enzyme-replacement therapy (ERT) has been available for patients with MPS VI in the Netherlands. The purpose of our study was to learn more about the genotype-phenotype correlations in MPS VI and the antibody response to ERT with galsulfase (recombinant human arylsulfatase B). Methods: We identified ARSB mutations in 12 patients and used site-directed mutagenesis to study their effect. Antibody levels to galsulfase were measured using ELISA and a semi-quantitative immunoprecipitation method. We assessed the in vitro inhibitory effect of antibodies on galsulfase uptake and their effect on clinical outcome. Results: Five patients had a rapidly progressive phenotype and seven a slowly progressive phenotype. In total 9
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Enzyme replacement therapy from birth in a feline model of mucopolysaccharidosis type VI

Enzyme replacement therapy from birth in a feline model of mucopolysaccharidosis type VI

We report evidence of a dose responsive effect of enzyme re- placement therapy in mucopolysaccharidosis type VI cats from birth, at the clinical, biochemical, and histopathologi- cal level. Cats treated with weekly, intravenous recombi- nant human N -acetylgalactosamine-4-sulfatase at 1 and 5 mg/kg, were heavier, more flexible, had greatly reduced or no spinal cord compression, and had almost normal urinary glycosaminoglycan levels. There was near normalization or complete reversal of lysosomal storage in heart valve, aorta, skin, dura, liver, and brain perivascular cells. No reduction in lysosomal vacuolation was observed in cartilage or cor- nea; however, articular cartilage was thinner and external ear pinnae were larger in some treated cats. Degenerative joint changes were not obviously delayed in treated cats. Skeletal pathology was reduced, with more normalized bone dimensions and with more uniform bone density and trabe- cular pattern clearly visible on radiographs by 5 to 6 mo; however, differences between 1 and 5 mg/kg dose rates were not clearly distinguishable. At a dose of 0.2 mg/kg, disease was not significantly altered in the majority of parameters examined. Lysosomal storage was present in all tissues ex- amined in the midterm mucopolysaccharidosis type VI fe- tus and increased rapidly in extent and severity from birth. (J. Clin. Invest. 1997. 99:651–662.) Key words: muco- polysaccharidosis VI • lysosomal storage diseases • genetics, medical • disease models, animal • dysostoses
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Two years’ experience with denosumab for children with Osteogenesis imperfecta type VI

Two years’ experience with denosumab for children with Osteogenesis imperfecta type VI

Osteogenesis imperfecta type VI (OI VI) is autosomal- recessively inherited and displays an increased amount of non-mineralized osteoid and a poor response to bisphos- phonate treatment [4,5]. Additional signs are the only discrete findings at birth and the late onset of fractures and deformities. OI VI is caused by mutations in SERPINF1, a gene which is coding for the pigment epithelium-derived factor (PEDF) [6,7]. In patients with bi-allelic truncating mutations in SERPINF1, PEDF is not detectable in the serum [8]. In-vitro and in-vivo models provided evidence that PEDF inhibits osteoclast differentiation and hence bone resorption via osteoprotegerin (OPG) and RANKL [9]. Receptor activator of NF-kB (RANK), the ligand RANKL, and the decoy receptor OPG are pivotal regulators of osteoclast differentiation and function. Denosumab is a monoclonal RANKL-blocking antibody which inhibits
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Understanding the sequential activation of Type III and Type VI Secretion Systems in Salmonella typhimurium using Boolean modeling

Understanding the sequential activation of Type III and Type VI Secretion Systems in Salmonella typhimurium using Boolean modeling

In addition to T3SS, the Type VI Secretion System (T6SS) has also been reported to be functionally active in S. typhimurium [7]. T6SS has been suggested to play a sig- nificant role in later phases of infection. Although the genes constituting T6SS do not participate directly in pathogenesis, they apparently enhance the efficiency of colonization/infection [8]. It has been proposed that, T6SS genes in S. typhimurium get expressed in the host macro- phage at a late stage of infection when the levels of SPI-2 proteins are reduced [9]. Intriguingly, this inverse regula- tion between SPI-2 and T6SS has been implicated in help- ing the pathogen’ s persistence inside macrophage by preventing its over-growth and subsequent rapid death of the host cell [9]. In summary, a wide range of experimen- tal evidences suggest that a sequential activation of SPI-1, SPI-2 and T6SS are required during the progression of the chronic infection. A schematic representation of different stages of infection mediated by these secretion systems of the pathogen is depicted in Figure 1. The different envi- ronments experienced by the pathogen in course of infec- tion have also been included in the figure.
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Horizontal Gene Transfer of Functional Type VI Killing Genes by Natural Transformation

Horizontal Gene Transfer of Functional Type VI Killing Genes by Natural Transformation

IMPORTANCE The contact-dependent type VI secretion system (T6SS) is frequently used by Proteobacteria to kill adjacent competitors. While DNA released by T6 killing can be horizontally acquired, it remains untested whether T6 genes themselves can be horizontally acquired and then utilized to compete with neighboring cells. Using naturally transformable Vibrio cholerae, we provide the first direct empirical support for the hypothesis that T6 genes are exchanged horizontally (e.g., from dead com- petitors) and functionally deployed to compete with neighboring cells. Using com- putational simulations, we also demonstrate that high rates of HGT can be adaptive, allowing V. cholerae to improve upon existing T6 weaponry and survive direct en- counters with otherwise superior competitors. We anticipate that our evolutionary results are of broad microbiological relevance, applying to many bacteria capable of HGT that utilize the T6SS or similar antagonistic systems, and highlight the profound impact of HGT in shaping microbial community structure.
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A Transcriptional Regulatory Mechanism Finely Tunes the Firing of Type VI Secretion System in Response to Bacterial Enemies

A Transcriptional Regulatory Mechanism Finely Tunes the Firing of Type VI Secretion System in Response to Bacterial Enemies

IMPORTANCE Serratia marcescens is among the health-threatening pathogens categorized by the WHO as research priorities to develop alternative antimicro- bial strategies, and it was also recently identified as one major component of the gut microbiome in familial Crohn disease dysbiosis. Type VI secretion systems (T6SSs) stand among the array of survival strategies that Serratia displays. They are contractile multiprotein complexes able to deliver toxic effectors directed to kill bac- terial species sharing the same niche and, thus, competing for vital resources. Here, we show that Serratia is able to detect and measure the extent of damage gener- ated through T6SS-delivered toxins from neighboring bacteria and responds by tran- scriptionally adjusting the expression level of its own T6SS machinery to counterat- tack the rival. This strategy allows Serratia to finely tune the production of costly T6SS devices to maximize the chances of successfully fighting against enemies and minimize energy investment. The knowledge of this novel mechanism provides in- sight to better understand bacterial interactions and design alternative treatments for polymicrobial infections.
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Functional and radiological outcome of Proximal tibial fractures type V and Type VI treated by modified hybrid external fixator

Functional and radiological outcome of Proximal tibial fractures type V and Type VI treated by modified hybrid external fixator

In our study,a total of 19 patients regained functional use of the knee joint, good axis without pain or instability. Patient’s knee ROM was gradually increasing at consecutive clinical evaluations. After one year follow up the knee ROM ranged from 30º to 130º with an average knee ROM of 102.5º.in similar studies conducted by Babis et al and Ariffin et al,the average ROM was reported as 115º.reduced functional outcome in our study was acceptable and attributed tothe more compound fractures, more type VI fractures and poor compliance of two patients to the rehabilitation exercises. Moreover two patients had associated injuries like patella fracture and shaft of femur fracture and two patients.
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The Tip of the VgrG Spike Is Essential to Functional Type VI Secretion System Assembly in Acinetobacter baumannii

The Tip of the VgrG Spike Is Essential to Functional Type VI Secretion System Assembly in Acinetobacter baumannii

ABSTRACT The type VI secretion system (T6SS) is a critical weapon in bacterial war- fare between Gram-negative bacteria. Although invaluable for niche establishment, this machine represents an energetic burden to its host bacterium. Acinetobacter baumannii is an opportunistic pathogen that poses a serious threat to public health due to its high rates of multidrug resistance. In some A. baumannii strains, the T6SS is transcriptionally downregulated by large multidrug resistance plasmids. Other strains, such as the clinical isolate AbCAN2, express T6SS-related genes but lack T6SS activity under laboratory conditions, despite not harboring these plasmids. This sug- gests that alternative mechanisms exist to repress the T6SS. Here, we used a trans- poson mutagenesis approach in AbCAN2 to identify novel T6SS repressors. Our screen revealed that the T6SS of this strain is inhibited by a homolog of VgrG, an es- sential structural component of all T6SSs reported to date. We named this protein inhibitory VgrG (VgrGi). Biochemical and in silico analyses demonstrated that the un- precedented inhibitory capability of VgrGi is due to a single amino acid mutation in a widely conserved C-terminal domain of unknown function, DUF2345. We also show that unlike in other bacteria, the C terminus of VgrG is essential for functional T6SS assembly in A. baumannii. Our study provides insight into the architectural re- quirements underlying functional assembly of the T6SS of A. baumannii. We propose that T6SS-inactivating point mutations are beneficial to the host bacterium, since they eliminate the energy cost associated with maintaining a functional T6SS, which appears to be unnecessary for A. baumannii virulence.
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Genetic Dissection of the Type VI Secretion System in Acinetobacter and Identification of a Novel Peptidoglycan Hydrolase, TagX, Required for Its Biogenesis

Genetic Dissection of the Type VI Secretion System in Acinetobacter and Identification of a Novel Peptidoglycan Hydrolase, TagX, Required for Its Biogenesis

ABSTRACT The type VI secretion system (T6SS) is a widespread secretory apparatus produced by Gram-negative bacteria that has emerged as a potent mediator of antibacterial activity during interbacterial interactions. Most Acinetobacter species produce a genetically conserved T6SS, although the expression and functionality of this system vary among different strains. Some patho- genic Acinetobacter baumannii strains activate this secretion system via the spontaneous loss of a plasmid carrying T6SS repres- sors. In this work, we compared the expression of T6SS-related genes via transcriptome sequencing and differential proteomics in cells with and without the plasmid. This approach, together with the mutational analysis of the T6SS clusters, led to the deter- mination of the genetic components required to elaborate a functional T6SS in the nosocomial pathogen A. baumannii and the nonpathogen A. baylyi. By constructing a comprehensive combination of mutants with changes in the T6SS-associated vgrG genes, we delineated their relative contributions to T6SS function. We further determined the importance of two effectors, in- cluding an effector-immunity pair, for antibacterial activity. Our genetic analysis led to the identification of an essential membrane-associated structural component named TagX, which we have characterized as a peptidoglycan hydrolase possessing
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Structural insights into the function of type VI secretion system TssA subunits.

Structural insights into the function of type VI secretion system TssA subunits.

The type VI secretion system (T6SS) is a multi-protein complex that injects bacterial effector proteins into target cells. It is composed of a cell membrane complex anchored to a con- tractile bacteriophage tail-like apparatus consisting of a sharpened tube that is ejected by the contraction of a sheath against a baseplate. We present structural and biochemical studies on TssA subunits from two different T6SSs that reveal radically different quaternary structures in comparison to the dodecameric E. coli TssA that arise from differences in their C-terminal sequences. Despite this, the different TssAs retain equivalent interactions with other com- ponents of the complex and position their highly conserved N-terminal ImpA_N domain at the same radius from the centre of the sheath as a result of their distinct domain archi- tectures, which includes additional spacer domains and highly mobile interdomain linkers. Together, these variations allow these distinct TssAs to perform a similar function in the complex.
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Functional Outcome of Locking Compression Plating for Closed Schatzker Type V and Type VI Tibial Plateau Fractures: A Prospective study

Functional Outcome of Locking Compression Plating for Closed Schatzker Type V and Type VI Tibial Plateau Fractures: A Prospective study

Forty year old agricultural labourer presented to our casualty with polytrauma following a road traffic accident. Following initial resuscitation radiographs showed that he had a fracture neck of femur, fracture shaft of femur and schatzker type 6 tibial plateau fracture all on the right side. He was immobilized in a bohler braun splint with a calcaneal pin traction. Patient was taken up for surgery only after 3 weeks due to delay in getting anesthetic assessment. We performed an Open Reduction Internal Fixation with cannulated cancelous screws for neck of femur, Open Reduction Internal Fixation with Broad DCP for shaft of femur, Open Reduction Internal Fixation with single lateral locking compression plate for tibial plateau fracture. All were performed in single stage.
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Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Neither MTS, the oral findings, mesoaxial polydactyly, nor hypothalamic hamartoma are pathognomonic as each can occur in other entities as well. However, the present study shows that the combination of MTS with one (or more) of the three other signs is pathognomonic for the diagnosis of OFD VI. Therefore we suggest that these form the diagnostic criteria for OFD VI (Table 4). We realize that no patient with MTS and hypothalamic hamartoma but without oral or limb defects has been described to date, but in theory can occur and then our criteria would be sufficient for the diagnosis of OFD VI. We are aware that the suggested diagnostic criteria do not match the inclusion criteria for this study. We derived the inclusion criteria from the literature while the diagnostic criteria are based on the literature and the present study. Indeed both patient 4 and the siblings patients 12 and 13 do not fulfill the diagnostic criteria suggested here (although the siblings fulfill the criteria together).
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Segmentation of Natural Images and Retrievals Based On the Mixture of Pearson Type III Distributions

Segmentation of Natural Images and Retrievals Based On the Mixture of Pearson Type III Distributions

One can identify distant characters in different regions of the image. The lot of work is done in image segmentation, literature review also reported regarding the segmentation and its applications by the [1], [2], [3], [4], [5], [6] and [7] are presented different techniques of image segmentation. Segmentation of the image contains two types of methods, 1) model based image segmentation method and 2) heuristic methods. Segmentation methods of the image based on model methods are additional proficient than the heuristic methods of segmentation given by [8], [9]. The segmentation based on model & the segmentation of the image is done based on finite GMM. Much work is reported on Gaussian mixture model [10] and [11]. And it becomes a popular because of its simplicity. In GMM, the regions of image are tacit to be meso- kurtic & symmetric in nature. But [12],[13], [14] and many others developed a different segmentation techniques depending on truncated GMM & new symmetric distribution . The above authors tacit that feature of the regions of the image are symmetric but may not meso-kurtic. In numerous images, feature vector of image regions are associated with skewed distribution. Basing on the skewed distribution, extremely less exertion is done in the literature concerning the model based segmentation. Hence [15] developed and analyzed segmentation of the image based on Pearson Type I Mixture Distribution. In a few images, the intensities (pixels) of the each part represents the left skewed and asymmetric in nature. Image segmentation methods are empowered and investigated depend on the mixture Pearson Type I and Pearson Type VI [16] distributions through K-means & Hierarchical algorithms, when the pixels of image are left skewed in image regions. But in few images, the pixels of the image parts might not be left skewed. But in few images, might have lengthy higher tail by means of a right slanted curve. To segment such images, one has use right skewed distribution. Therefore, segmentation methods of image are implemented and analyzed with long upper tail and right skewed distributions is capable by the (PTIIID) Pearson Type III distribution. Hence, the pixels of each region and complete image is represented by a finite mixture of PTIIID. Under Bayes framework, the segmentation of the image algorithm is empowered from beginning to end by maximizing component likelihood. By calculating, segmentation recital procedures (PRI, GCE, VOI) by carrying out tests with three images from Berkeley dataset namely BOAT, SEA, WATER & performance is evaluated. The utility of proposed method through image segmentation is match up to with segmentation algorithm based on finite GMM through
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Comparison of extended anterolateral approach in treatment of simple/complex tibial plateau fracture with posterolateral tibial plateau fracture

Comparison of extended anterolateral approach in treatment of simple/complex tibial plateau fracture with posterolateral tibial plateau fracture

A total of 46 patients were included in the study and were followed up for 23–45 months (mean, 31.9 months). Twenty patients were male, and 26 were female, aged 29–77 years, with an average of 53.9 years. According to Schatzker classification, 24 patients of Schatzker type II fracture were divided into group A, and 18 patients of type V fracture and 4 patients of type VI fracture were divided into group B. According to the three-column classification, 6 cases involved the posterior column, 18 cases involved the lateral and posterior columns, 6 cases involved the medial and posterior columns, and 16 cases involved three columns. The causes of injury were tum- bles in 28 cases (60.7%), traffic accidents in 14 cases (30.4%), falls in 2 cases (4.3%), and direct impact in 2 cases (4.3%). The injury mechanism was flexion valgus injury in 30 cases (65.2%), flexion varus injury in 4 cases (8.7%), ex- tension injury in 6 cases (13%), and flexion injury in 6 cases (13%). Twenty-two patients had a fibular fracture, and 6 had associated injuries (3 vertebral fractures, 1 skull fracture and pelvic fracture, 1 pelvic fracture, and 1 ankle fracture) (Table 1).
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Functional outcome of communited intra articular distal radius fractures managed by fragment specific fracture fixation: A Prospective study.

Functional outcome of communited intra articular distal radius fractures managed by fragment specific fracture fixation: A Prospective study.

Type IV: radiocarpal joint involved with ulnar styloid fracture Type V: distal radioulnar joint involved Type VI: distal radioulnar joint involved with ulnar styloid fracture Type VII: b[r]

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Comparison of outcome of unilateral locking plate and dual plating in the treatment of bicondylar tibial plateau fractures

Comparison of outcome of unilateral locking plate and dual plating in the treatment of bicondylar tibial plateau fractures

Forty-five patients with complex tibial plateau frac- tures were enrolled, and the study group consisted of 21 males (47%) and 24 females (53%) with an average age of 51.68 years (range 18 ~ 83 years). The mechanism of in- jury was a motor vehicle accident in 38 patients, and the others were falls from height. All patients had antero- posterior and lateral view radiographs at our emergency department initially, and a CT scan was performed if the fracture pattern was difficult to classify. There were 25 Schatzker type V (55.5%) and 20 Schatzker type VI (44.4%) fractures. The soft tissue condition was the most crucial item on our preoperative planning for the timing of the operation and the choice of surgical equipment. Twelve patients (26.7%) received staged therapy, with an average of a 5.4-day delay (range 3 ~ 9 days) due to open fracture or extreme swelling of soft tissue (external skeletal fixation first, then shifted to an internal fixator). Prophylactic antibiotics with first-generation cephalo- sporin, cefazolin, were administered intravenously in all patients and were prescribed as necessary for at least the
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Sleep-Enabled Roadside Units for Motorway Vehicular Networks

Sleep-Enabled Roadside Units for Motorway Vehicular Networks

Average energy savings of and were achieved in sleep cycles type-III and type-IV, respectively. Although the improvement in energy savings of type IV compared to type I is only , the improvement in average packet delay is substantial (i.e. ). Due to the very high switching overhead (at peak hour) associated with sleep cycles type-V, the energy savings become negative even though only average packet delay was achieved throughout the day. Sleep cycles type-VI alleviated the negative energy savings while marginally improving the average packet delay. For example, the average energy savings achieved through sleep cycles type-VI is compared to in the case of sleep cycles type-V. These improvements are achieved under a very stringent QoS bound, which indicates the suitability and generality of our proposed sleep mechanisms. Based on our findings in this paper, it can be concluded that each type of sleep cycles exhibits a few advantages and disadvantages. If the aim is to achieve the best QoS regardless of maximising energy savings, sleep cycles type-VI is ideal. On the other hand, if the aim is to maximise energy savings while maintaining the required QoS, sleep cycles type-IV should be adopted. Thus, it is inferred that the time based burst accumulation (type-III and IV) overall performs better in terms of energy savings. On the other hand, the length based burst accumulation (type-V and VI) overall outperforms the time based burst accumulation, in terms of QoS.
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Functional and radiological evaluations of high-energy tibial plateau fractures treated with double-buttress plate fixation

Functional and radiological evaluations of high-energy tibial plateau fractures treated with double-buttress plate fixation

High-energy tibial plateau fractures remain a challenge to orthopaedic surgeons, with the bicondylar type (Schatzker type V) and the comminuted type (Schatzker type VI) fractures being the most difficult to treat [1]. The severity of the tibial plateau fracture depends on the energy applied to the limb. The higher the energy to the limb, the more severe and complex the fracture is. Compared to their low-energy counterparts, high-ener- gy fractures have unique patterns of fractures. The bi- condylar type fracture involves both the lateral and me- dial tibial plateaus, usually with lateral depression, meniscal detachment, and anterior cruciate ligament (ACL) avulsions [2]. The comminuted type fracture is characterized by the dissociation of the diaphysis from the metaphysis, often associated with severe soft tissue injuries around the knee that require special clinical consideration [3].
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