Digital game-based interventions for cognitive training in healthy adults and adults with cognitive impairment: protocol for a two-part systematic review and meta-analysis.

INTRODUCTION: Digital game-based training interventions are scalable solutions that may improve cognitive function for many populations. This protocol for a two-part review aims to synthesise the effectiveness and key features of digital game-based interventions for cognitive training in healthy adults across the life span and adults with cognitive impairment, to update current knowledge and impact the development of future interventions for different adult subpopulations. METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. A systematic search was performed in PubMed, Embase, CINAHL, Cochrane Library, Web of Science, PsycINFO and IEEE Explore on 31 July 2022 for relevant literature published in English from the previous 5 years. Experimental, observational, exploratory, correlational, qualitative and mixed methods studies will be eligible if they report at least one cognitive function outcome and include a digital game-based intervention intended to improve cognitive function. Reviews will be excluded but retained to search their reference lists for other relevant studies. All screening will be done by at least two independent reviewers. The appropriate Joanna Briggs Institute Critical Appraisal Tool, according to the study design, will be applied to perform the risk of bias assessment. Outcomes related to cognitive function and digital game-based intervention features will be extracted. Results will be categorised by adult life span stages in the healthy adult population for part 1 and by neurological disorder in part 2. Extracted data will be analysed quantitatively and qualitatively, according to study type. If a group of sufficiently comparable studies is identified, we will perform a meta-analysis applying the random effects model with consideration of the I2 statistic. ETHICS AND DISSEMINATION: Ethics approval is not applicable for this study since no original data will be collected. The results will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42022351265.

A Phase I, First-in-Human Study of PRL3-zumab in Advanced, Refractory Solid Tumors and Hematological Malignancies.

BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is involved in cellular processes driving metastasis, cell proliferation, invasion, motility and survival. It has been shown to be upregulated and overexpressed in cancer tissue, in contrast to low or no expression in most normal tissue. PRL3-zumab is a first-in-class humanized antibody that specifically binds to PRL-3 oncotarget with high affinity and has been shown to reduce tumor growth and increase survival. OBJECTIVE: In the study, we aimed to determine the safety and efficacy of PRL3-zumab in patients with advanced solid tumors and hematological malignancies. METHODS: We conducted a phase I, first-in-human study in advanced solid tumors and hematological malignancies to investigate the safety, tolerability and efficacy of PRL3-zumab. Response rates were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) for solid tumors. For acute myeloid leukemia (AML) patients, bone marrow response criteria based on the European Leukaemia Network (ELN) 2017 guidelines for AML were used. We also explored the pharmacokinetics and pharmacodynamic relationships of PRL3-zumab in patients. This study was registered with ClinicalTrials.gov: NCT03191682. RESULTS: In the dose-escalation cohort, 11 patients with advanced solid tumors were enrolled into the study. An additional 12 patients with solid tumors and four patients with AML were enrolled in the dose-expansion cohort. Maximum tolerability was not achieved in this study, as there were no dose-limiting toxicities. Potential treatment-emergent adverse events were grade 1 increased stoma output and fatigue and grade 2 vomiting. Best response observed was stable disease in three solid-tumor patients (11.1%). The pharmacokinetics of PRL3-zumab were dose proportional, consistent with an IgG type monoclonal antibody. CONCLUSIONS: PRL3-zumab, a first-in-class humanized antibody, was safe and tolerable in solid tumors and hematological malignancies.

Searching for common ground.

The conserved coronavirus fusion peptide is a target of broadly neutralizing antibodies.

Broadly neutralizing antibodies target the coronavirus fusion peptide.

The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We used an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha- and betacoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than receptor binding domain-specific antibodies. In crystal structures of COV44-62 and COV44-79 antigen-binding fragments with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine residue at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.

Does Cigarette Smoking Affect Cervical Laminoplasty Clinical and Radiologic Outcomes?

STUDY DESIGN: Retrospective review. OBJECTIVE: This study aimed to investigate if smokers have both poorer early clinical and radiologic outcomes in cervical laminoplasty when compared with nonsmokers. SUMMARY OF BACKGROUND DATA: Cigarette smoking had been reported to increase rates of pseudoarthrosis following spinal instrumentation with fusion. METHODOLOGY: A retrospective review of all patients who underwent open-door cervical laminoplasty was performed. Nurick, neck pain visual analog scale, and neck disability index scores were reviewed. Cervical lordosis, range of motion (ROM), and intervertebral disc height were measured. The rates and reasons for revision surgery were recorded and classified according to the etiology of laminoplasty revision surgery. RESULTS: Sixty patients were recruited, of which 20 patients (18 males, 2 females) were smokers and 40 patients (27 males, 13 females) were nonsmokers. There was no statistically significant difference between smokers and nonsmokers in preoperative and postoperative visual analog scale, neck disability index, and Nurick scores. A trend was noted toward a greater postoperative reduction in cervical lordosis (13±8 vs. 11±11 degrees). Furthermore, 41% of smokers versus 30% in nonsmokers had >10% loss of postoperative ROM, and 59% smokers versus 50% nonsmokers had >5% loss of postoperative ROM.Postoperative complications and intervertebral disc deterioration were similar in both groups. A higher reoperation rate was noted in smokers with 6 smokers (30%) as compared with 4 nonsmokers (10%), although this did not reach statistical significance. Among the smokers, 4 (20%) were because of cervical disease progression while 2 were technique related. In nonsmokers, all 4 (10%) were because of cervical disease progression. CONCLUSION: This study showed that while there was a nonstatistically significant trend noted toward higher rates of revision surgery in smokers, the laminoplasty outcomes were not significantly poorer in smokers. In heavy smokers with multilevel cervical myelopathy, laminoplasty may be the treatment of choice over anterior spinal decompression and fusion where a high risk of pseudoarthrosis is anticipated.

Protective effects of combining monoclonal antibodies and vaccines against the Plasmodium falciparum circumsporozoite protein.

Combinations of monoclonal antibodies (mAbs) against different epitopes on the same antigen synergistically neutralize many viruses. However, there are limited studies assessing whether combining human mAbs against distinct regions of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) enhances in vivo protection against malaria compared to each mAb alone or whether passive transfer of PfCSP mAbs would improve protection following vaccination against PfCSP. Here, we isolated a panel of human mAbs against the subdominant C-terminal domain of PfCSP (C-CSP) from a volunteer immunized with radiation-attenuated Pf sporozoites. These C-CSP-specific mAbs had limited binding to sporozoites in vitro that was increased by combination with neutralizing human "repeat" mAbs against the NPDP/NVDP/NANP tetrapeptides in the central repeat region of PfCSP. Nevertheless, passive transfer of repeat- and C-CSP-specific mAb combinations did not provide enhanced protection against in vivo sporozoite challenge compared to repeat mAbs alone. Furthermore, combining potent repeat-specific mAbs (CIS43, L9, and 317) that respectively target the three tetrapeptides (NPDP/NVDP/NANP) did not provide additional protection against in vivo sporozoite challenge. However, administration of either CIS43, L9, or 317 (but not C-CSP-specific mAbs) to mice that had been immunized with R21, a PfCSP-based virus-like particle vaccine that induces polyclonal antibodies against the repeat region and C-CSP, provided enhanced protection against sporozoite challenge when compared to vaccine or mAbs alone. Collectively, this study shows that while combining mAbs against the repeat and C-terminal regions of PfCSP provide no additional protection in vivo, repeat mAbs do provide increased protection when combined with vaccine-induced polyclonal antibodies. These data should inform the implementation of PfCSP human mAbs alone or following vaccination to prevent malaria infection.

Structural basis of malaria RIFIN binding by LILRB1-containing antibodies.

Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)-variant surface antigens that are expressed on infected erythrocytes1-bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies2,3. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to ß2 microglobulin and RIFINs through their apical domains4,5. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable-constant (VH-CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN-LILRB1 D3 interaction that is similar to that of RIFIN-LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH-CH1 elbow without affecting VH-VL or CH1-CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH-CH1 elbow.

A Feasibility Study of a New Muscle Sparing "C3 Dome-Hybrid Open-Door Laminoplasty": A Surgical Technique, Clinical Outcome, and Learning Curve Description.

STUDY DESIGN: Retrospective case series to investigate the result of a new C3 dome-hybrid open-door laminoplasty technique. OBJECTIVE: This study reports the design and feasibility of a new hybrid laminoplasty technique aimed to reduce the complications of the conventional laminoplasty, with the incorporation of C3 dome-osteotomy, an open-door C4-6 instrumented laminoplasty and C7 cephalad dome-osteotomy. SUMMARY OF BACKGROUND DATA: Recent findings showed that the preservation of the dorsal muscles attached at either C2 or C7 cervical spine reduced the complications of C3-C7 open-door laminoplasty. METHODS: A retrospective review of consecutive patients who underwent the C3 dome-hybrid laminoplasty technique by a single surgeon with at least 2 years follow-up was performed. The surgical technique was described in detail. Clinical and radiological outcome data were analyzed. RESULTS: Twenty six patients with cervical cord compression who underwent C3 dome-hybrid laminoplasty were recruited. The mean postoperative follow-up was 45.6 ±â€Š24.7 (24-101) months. Significant improvements were observed in the preoperative to postoperative mean Japanese Orthopaedic Association (JOA) score (13→15, P < 0.001), Nurick grade (2.3→1.2, P < 0.001), neck disability index (NDI) (23→11, P = 0.011), 36-item short form survey (SF-36) physical component score (40→46, P = 0.027), and neck visual analogue scale (VAS) (3.1→0.3, P < 0.001). There was no significant loss in cervical lordosis from 12° preoperatively to 8° at final follow-up. Postoperative cervical range of motion (ROM) was preserved at 85% and 78% of the preoperative ROM at 2 years and at final follow-up, respectively. When comparing the first 10 patients with the next 16 patients, there was a reduction in mean operation time from 252 ±â€Š75 to 208 ±â€Š7 minutes, mean blood loss from 359 ±â€Š326 to 211 ±â€Š177 mL, and median hospital stay from 7 days (interquartile range [IQR]: 34) to 5 days (IQR: 6).At final follow-up, no patients had revision surgery, spinal infection, C5 palsy, symptomatic cervical kyphosis, or axial neck pain. CONCLUSION: The new C3 dome-hybrid laminoplasty technique is safe, feasible, and reproducible with good clinical outcomes. This technique may be considered as an alternative to traditional laminoplasty for patients with C3-C7 multi-level myelopathic disease. LEVEL OF EVIDENCE: 3.

Caspase-1-dependent inflammasomes mediate photoreceptor cell death in photo-oxidative damage-induced retinal degeneration.

Activation of the inflammasome is involved in the progression of retinal degenerative diseases, in particular, in the pathogenesis of Age-Related Macular Degeneration (AMD), with NLRP3 activation the focus of many investigations. In this study, we used genetic and pharmacological approaches to explore the role of the inflammasome in a mouse model of retinal degeneration. We identify that Casp1/11-/- mice have better-preserved retinal function, reduced inflammation and increased photoreceptor survivability. While Nlrp3-/- mice display some level of preservation of retinal function compared to controls, pharmacological inhibition of NLRP3 did not protect against photoreceptor cell death. Further, Aim2-/-, Nlrc4-/-, Asc-/-, and Casp11-/- mice show no substantial retinal protection. We propose that CASP-1-associated photoreceptor cell death occurs largely independently of NLRP3 and other established inflammasome sensor proteins, or that inhibition of a single sensor is not sufficient to repress the inflammatory cascade. Therapeutic targeting of CASP-1 may offer a more promising avenue to delay the progression of retinal degenerations.

Catheter-directed foam sclerotherapy, an alternative to ultrasound-guided foam sclerotherapy for varicose vein treatment: A systematic review and meta-analysis.

PURPOSE: Catheter-directed foam sclerotherapy is a new addition to the treatment modalities available for varicose veins. As a modification of ultrasound-guided foam sclerotherapy, catheter-directed foam sclerotherapy has been purported to offer higher complete ablation rates and an improved safety profile. The aim of this study is to appraise the current literature on the outcomes of catheter-directed foam sclerotherapy compared to ultrasound-guided foam sclerotherapy in chronic venous insufficiency. METHODS: The review of the literature was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data from studies that reported the outcomes of catheter-directed foam sclerotherapy and ultrasound-guided foam sclerotherapy were extracted, to determine the pooled proportion of complete ablation rates, using a random effect meta-analysis model. RESULTS: A total of 62 studies, involving 3689 patients, were included in the systematic review. Higher rates of complete ablation were reported in catheter-directed foam sclerotherapy compared to ultrasound-guided foam sclerotherapy during the short- and medium-term follow-ups (Relative Risk = 1.06, Relative Risk = 1.15, Relative Risk = 1.19, p < 0.05). Fewer major and minor complications were also reported in patients who underwent catheter-directed foam sclerotherapy (Relative Risk = 0.23, Relative Risk= 0.43-0.76, p < 0.05). CONCLUSION: Catheter-directed foam sclerotherapy has been demonstrated to have many advantages over ultrasound-guided foam sclerotherapy, offering superior complete ablation rates in the short-, medium- and long-term follow-ups. It also has a better safety profile, conferring a lower risk of major and minor complications. The conclusions should however be viewed in the context of significant limitations imposed by limited study data.

Is Spinal Surgery Safe for Elderly Patients Aged 80 and Above? Predictors of Mortality and Morbidity in an Asian Population.

OBJECTIVE: We aimed to determine the 2-year mortality and morbidity rates following spine surgery in elderly patients (age ≥80 years) and to study the associated risk factors. METHODS: The records of patients ≥80 years of age who underwent spine surgery during the years 2003-2015 at Tan Tock Seng Hospital, Singapore were retrospectively reviewed. Information was collected on their demographic characteristics, comorbidities, diagnosis, general and neurological status, type of surgery, and outcomes. The mortality and morbidity rates over a 2-year period were analyzed. Bivariate analyses were carried out to identify factors associated with mortality. RESULTS: We selected 47 patients (mean age, 83.3 years; range, 80-91 years) who were followed up for a mean duration of 27.7 months. The mortality rates at 30 days, 6 months, 1 year, and 2 years following surgery were 2.1%, 8.5%, 10.6%, and 12.8%, respectively. The factors significantly associated with mortality included multiple comorbidities, nondegenerative aetiology, and vertebral fractures. The overall morbidity rate was 48.9%, and 17% of this cohort had major complications. CONCLUSION: Surgeons should strategize management protocols with due consideration of the mortality and morbidity rates, and be wary of operating on patients with multiple comorbidities, nondegenerative conditions, and vertebral fractures.

Transcriptomic Abnormalities in Epstein Barr Virus Associated T/NK Lymphoproliferative Disorders.

Epstein Barr virus positive T/NK lymphoproliferative disorders (EBV-TNKLPD) comprise a spectrum of neoplasms ranging from cutaneous lymphoid proliferations to aggressive lymphomas. The spectrum includes extranodal NK/T-cell lymphoma (ENKTL), aggressive NK-cell leukemia, and a group of EBV-TNKLPDs affecting children which are poorly characterized in terms of their molecular biology. Gene and miRNA expression profiling has elucidated RNA abnormalities which impact on disease biology, classification, and treatment of EBV-TNKLPD. Pathways promoting proliferation, such as Janus associated kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) and nuclear factor kB, are upregulated in ENKTL while upregulation of survivin and deregulation of p53 inhibit apoptosis in both ENKTL and chronic active EBV infection (CAEBV). Importantly, immune evasion via the programmed cell death-1 and its ligand, PD-1/PD-L1 checkpoint pathway, has been demonstrated to play an important role in ENKTL. Other pathogenic mechanisms involve EBV genes, microRNA deregulation, and a variety of other oncogenic signaling pathways. The identification of EBV-positive Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) as a tumor with a distinct molecular signature and clinical characteristics highlights the important contribution of the knowledge derived from gene and miRNA expression profiling in disease classification. Novel therapeutic targets identified through the study of RNA abnormalities provide hope for patients with EBV-TNKLPD, which often has a poor prognosis. Immune checkpoint inhibition and JAK inhibition in particular have shown promise and are being evaluated in clinical trials. In this review, we provide an overview of the key transcriptomic aberrancies in EBV-TNKLPD and discuss their translational potential.

Retinal Macrophages Synthesize C3 and Activate Complement in AMD and in Models of Focal Retinal Degeneration.

Purpose: Complement system dysregulation is strongly linked to the progression of age-related macular degeneration (AMD). Deposition of complement including C3 within the lesions in atrophic AMD is thought to contribute to lesion growth, although the contribution of local cellular sources remains unclear. We investigated the role of retinal microglia and macrophages in complement activation within atrophic lesions, in AMD and in models of focal retinal degeneration. Methods: Human AMD donor retinas were labeled for C3 expression via in situ hybridization. Rats were subject to photo-oxidative damage, and lesion expansion was tracked over a 2-month period using optical coherence tomography (OCT). Three strategies were used to determine the contribution of local and systemic C3 in mice: total C3 genetic ablation, local C3 inhibition using intravitreally injected small interfering RNA (siRNA), and depletion of serum C3 using cobra venom factor. Results: Retinal C3 was expressed by microglia/macrophages located in the outer retina in AMD eyes. In rodent photo-oxidative damage, C3-expressing microglia/macrophages and complement activation were located in regions of lesion expansion in the outer retina over 2 months. Total genetic ablation of C3 ameliorated degeneration and complement activation in retinas following damage, although systemic depletion of serum complement had no effect. In contrast, local suppression of C3 expression using siRNA inhibited complement activation and deposition, and reduced cell death. Conclusions: These findings implicate C3, produced locally by retinal microglia/macrophages, as contributing causally to retinal degeneration. Consequently, this suggests that C3-targeted gene therapy may prove valuable in slowing the progression of AMD.

Microglia-derived IL-1ß promotes chemokine expression by Müller cells and RPE in focal retinal degeneration.

BACKGROUND: Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1ß (IL-1ß) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors. METHODS: Inhibition of retinal IL-1ß expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1ß, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL. RESULTS: Photo-oxidative damage elevated the expression of Il-1ß and inflammasome-related genes, and IL-1ß protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1ß inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1ß, with increased macrophage accumulation detected in vivo. CONCLUSIONS: IL-1ß is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1ß may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD.

Intraoperative Measurements of Joint Line Changes Using Computer Navigation Do Not Correlate With Postoperative Radiographic Measurements in Total Knee Arthroplasty.

BACKGROUND: The adverse effects of joint line (JL) changes on kinematics and outcomes of total knee arthroplasty (TKA) have been studied. Some authors have quantified JL changes using intraoperative data from computer navigation, despite no studies validating these measurements to date. We designed a prospective study to determine whether intraoperative measurements of JL changes using computer navigation correlate with measurements obtained on weight-bearing radiographs postoperatively. METHODS: A total of 195 consecutive patients (195 knees) underwent computer-navigated cruciate-retaining TKA by the senior author. Twenty-four patients had missing radiographic data and were excluded from the study. The final JL change was calculated intraoperatively from the verified bony cuts and planned JL change as determined by the computer. JL position was also measured on preoperative and postoperative radiographs using an anteroposterior method. RESULTS: One hundred seventy-one knees were evaluated. Using computer-navigated and radiographic measurements, the mean JL change was 1.95 ± 1.5 mm (0-8.0 mm) and 4.05 ± 2.9 mm (0-17.3 mm), respectively. One hundred fourteen (67%) vs 129 (75%) had JL elevation, 44 (26%) vs 30 (18%) had JL depression, and 13 (7%) vs 12 (7%) had no JL change, respectively. Inter-rater and intrarater reliability of radiographic measurements was excellent. We found a poor correlation between computer-navigated and radiographic measurements (r = 0.303). CONCLUSION: There is a poor correlation between computer-aided and radiographic measurements of JL changes post-TKA. Elevation/depression of the JL needs to be considered in patients who remain symptomatic despite TKA, although the optimal method of assessment remains uncertain.

The Role of Pyruvate in Protecting 661W Photoreceptor-Like Cells Against Light-Induced Cell Death.

PURPOSE: Light is a requirement for the function of photoreceptors in visual processing. However, prolonged light exposure can be toxic to photoreceptors, leading to increased reactive oxygen species (ROS), lipid peroxidation, and photoreceptor cell death. We used the 661W mouse cone photoreceptor-like cell line to study the effects of pyruvate in protecting these cells from light-induced toxicity. METHODS: 661W cells were exposed to 15,000 lux continuous bright light for 5 hours and incubated in Dulbecco's modified eagle medium (DMEM) with various concentrations of pyruvate. Following light damage, cells were assessed for changes in morphology, cell toxicity, viability, and ROS production. Mitochondrial respiration and anaerobic glycolysis were also assessed using a Seahorse Xfe96 extracellular flux analyzer. RESULTS: We found that cell death caused by light damage in 661W cells was dramatically reduced in the presence of pyruvate. Cells with pyruvate-supplemented media also showed attenuation of oxidative stress and maintained normal levels of ATP. We also found that alterations in the concentrations of pyruvate had no effect on mitochondrial respiration or glycolysis in light-damaged cells. CONCLUSIONS: Taken together, the results show that pyruvate is protective against light damage but does not alter the metabolic output of the cells, indicating an alternative role for pyruvate in reducing oxidative stress. Thus, sodium pyruvate is a possible candidate for the treatment against the oxidative stress component of retinal degenerations.

An Algorithm for the Management of Concomitant Maxillofacial, Laryngeal, and Cervical Spine Trauma.

Concomitant maxillofacial, laryngeal and cervical spine injuries may occur after high-energy accidents. Although this presentation is uncommon, the multiple injuries may compromise airway, breathing, circulation, and neurologic function. We identified 8 adult trauma patients admitted to the National University Hospital with the concomitant injuries. We reviewed the patient data and existing literature to identify the important factors that must be considered for management. Seven resulted from high velocity accidents, whereas 1 was assaulted. An algorithm that prioritizes in-tandem diagnosis and acute management of the adult trauma patient with maxillofacial, laryngeal, and cervical spine trauma was developed. The first priority is to assess airway, breathing, and circulation with cervical spine immobilization. Early diagnosis of patients with severe laryngeal injury, confirmation by video endoscopy, and establishing a surgical airway prevents airway obstruction or even a laryngotracheal dissociation. Urgent computed tomography scans of the head and neck are essential for definitive diagnosis and surgical planning for the 3 injuries. Prudent sequencing of surgery is important to avoid complications and to achieve better functional outcomes.

The HIV-1-containing macrophage compartment: a perfect cellular niche?

Macrophages are a major target of HIV-1 infection and are believed to act as viral reservoirs and mediators of HIV-1-associated neurological damage. These pathological roles may be associated with the ability of the virus to assemble and accumulate in apparently intracellular compartments in macrophages. These so-called virus-containing compartments were initially thought to be late endosomes or multivesicular bodies, but it has since been shown that they are distinct structures that have complex three-dimensional morphology, a unique set of protein markers, and features such as a near-neutral pH and frequent connections to the extracellular milieu. These features appear to protect HIV-1 from hostile elements both within and outside the cell. This review discusses the cellular and molecular characteristics of HIV-1-containing compartments in macrophages and how they offer a safe haven for the virus, with important consequences for pathogenesis.

Tyrosine sulfation of chemokine receptor CCR2 enhances interactions with both monomeric and dimeric forms of the chemokine monocyte chemoattractant protein-1 (MCP-1).

Chemokine receptors are commonly post-translationally sulfated on tyrosine residues in their N-terminal regions, the initial site of binding to chemokine ligands. We have investigated the effect of tyrosine sulfation of the chemokine receptor CCR2 on its interactions with the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Inhibition of CCR2 sulfation, by growth of expressing cells in the presence of sodium chlorate, significantly reduced the potency for MCP-1 activation of CCR2. MCP-1 exists in equilibrium between monomeric and dimeric forms. The obligate monomeric mutant MCP-1(P8A) was similar to wild type MCP-1 in its ability to induce leukocyte recruitment in vivo, whereas the obligate dimeric mutant MCP-1(T10C) was less effective at inducing leukocyte recruitment in vivo. In two-dimensional NMR experiments, sulfated peptides derived from the N-terminal region of CCR2 bound to both the monomeric and dimeric forms of wild type MCP-1 and shifted the equilibrium to favor the monomeric form. Similarly, MCP-1(P8A) bound more tightly than MCP-1(T10C) to the CCR2-derived sulfopeptides. NMR chemical shift mapping using the MCP-1 mutants showed that the sulfated N-terminal region of CCR2 binds to the same region (N-loop and ß3-strand) of both monomeric and dimeric MCP-1 but that binding to the dimeric form also influences the environment of chemokine N-terminal residues, which are involved in dimer formation. We conclude that interaction with the sulfated N terminus of CCR2 destabilizes the dimerization interface of inactive dimeric MCP-1, thus inducing dissociation to the active monomeric state.