Evaluation of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies: Lessons learned from a 14-year retrospective study.

INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is a clinical thrombotic microangiopathy (TMA) syndrome defined by the pentad of symptoms. Therapeutic plasma exchange with plasma replacement is an ASFA Category I modality that can reduce morbidity and mortality if initiated early. We describe a 14-year review of patients referred for plasma exchange with a suspected diagnosis of TTP. METHODS: For 70 patients referred for urgent plasma exchange, clinical, therapeutic, and laboratory data were retrospectively analyzed, and the diagnosis was determined. RESULTS: Fifteen of the patients were diagnosed with TTP based upon ADAMTS-13 activity with the other 51 patients having other non-TTP TMA diagnoses. The mortality rate was significant for both TTP and non-TTP TMAs. PLASMIC scores were also calculated retrospectively and were noted to have limited value. TMA is a diagnostic challenge and encompasses different syndromes with similar presentations. CONCLUSION: Determining an accurate diagnosis, including prompt ADAMTS-13 testing, makes it possible to initiate appropriate therapy for the multiple different TMAs that can be seen in clinical practice.

Type I Arnold Chiari Malformation with Syringomyelia and Scoliosis: Radiological Correlations between Tonsillar Descent, Syrinx Morphology and Curve Characteristics: A Retrospective Study

Methods@#Data regarding patients, who underwent PFD for ACM-I presenting with SM and scoliosis between January 2009 and December 2018, were retrospectively collected. Only patients with 2-year follow-up were included. Sagittal/coronal deformity and sagittal spinopelvic parameters were examined. Symmetry and extent of tonsillar descent, as well as morphology (configuration/variation) and extent of syrinx were determined. @*Results@#A total of 42 patients (20 females; age: 14.2±5.8 years) were included; 35 patients (83.3%) had atypical curves. Mean preoperative coronal Cobb was 57.7°±20.9°; and 12 (28.6%) had significant coronal imbalance. Tonsillar descent was classified as grade 1, 2, and 3 in 16 (38.1%), 11 (26.2%), and 15 (35.7%) patients; 35 patients (83.3%) had asymmetric tonsillar descent; 17 (40.4%), 3 (7.1%), 16 (38.1%), and 6 (14.4%) had circumscribed, moniliform, dilated, and slender syrinx patterns; and 9 (21.4%), 12 (28.6%), and 21 (50%) of syrinx were right-sided, left-sided, and centric. There was no significant relationship between side of tonsillar dominance (p =0.31), grade of descent (p =0.30), and convexity of deformity. There was significant association between side of syrinx and convexity of scoliosis (p =0.01). PFD was performed in all, and deformity correction was performed in 23 patients. In curves ≤40°, PFD alone could stabilize scoliosis progression (p =0.02). There was significant reduction in syrinx/cord ratio following PFD (p 40°.

NMR spectroscopy analysis reveals differential metabolic responses in arabidopsis roots and leaves treated with a cytokinesis inhibitor.

In plant cytokinesis, de novo formation of a cell plate evolving into the new cell wall partitions the cytoplasm of the dividing cell. In our earlier chemical genomics studies, we identified and characterized the small molecule endosidin-7, that specifically inhibits callose deposition at the cell plate, arresting late-stage cytokinesis in arabidopsis. Endosidin-7 has emerged as a very valuable tool for dissecting this essential plant process. To gain insights regarding its mode of action and the effects of cytokinesis inhibition on the overall plant response, we investigated the effect of endosidin-7 through a nuclear magnetic resonance spectroscopy (NMR) metabolomics approach. In this case study, metabolomics profiles of arabidopsis leaf and root tissues were analyzed at different growth stages and endosidin-7 exposure levels. The results show leaf and root-specific metabolic profile changes and the effects of endosidin-7 treatment on these metabolomes. Statistical analyses indicated that the effect of endosidin-7 treatment was more significant than the developmental impact. The endosidin-7 induced metabolic profiles suggest compensations for cytokinesis inhibition in central metabolism pathways. This study further shows that long-term treatment of endosidin-7 profoundly changes, likely via alteration of hormonal regulation, the primary metabolism of arabidopsis seedlings. Hormonal pathway-changes are likely reflecting the plant's responses, compensating for the arrested cell division, which in turn are leading to global metabolite modulation. The presented NMR spectral data are made available through the Metabolomics Workbench, providing a reference resource for the scientific community.

Validation of Enthalpy-Entropy Compensation Mechanism in Partial Amide Bond Rotation.

The concept of enthalpy-entropy compensation (EEC) is one of the highly debated areas of thermodynamics. The conformational change due to restricted double-bond rotation shows a classic two-site chemical exchange phenomenon and has been extensively studied. Fifty-four analogs of N,N-diethyl-m-toluamide (DEET) as a model system were synthesized to study the thermodynamics of the partial amide bond character using nuclear magnetic resonance (NMR) spectroscopy. Line-shape analysis as a function of temperature is used to estimate the chemical exchange. Eyring analysis was then used to convert the chemical exchange rates to determine the transition state enthalpy and entropy of the molecules. The experimental design follows selective variations that perturb one aspect of the molecular system and its influence on the observed thermodynamic effect. The results of the study demonstrate that amide bond resonance in analogs of DEET follows an EEC mechanism. Simple modifications made to DEET's structural motif alter both the enthalpy and entropy of the system and were limited overall to a temperature compensation factor, T ß = 292.20 K, 95% CI [290.66, 293.73]. We suggest EEC as a model to describe the kinetic compensation seen in chemical exchange phenomena in analogs of DEET.

Role of glycosylation on the ensemble of conformations in the MUC1 immunodominant epitope.

MUC1 is a membrane glycoprotein, which in adenocarninomas is overexpressed and exhibits truncated O-glycosylation. Overexpression and altered glycosylation make MUC1 into a candidate for immunotherapy. Monoclonal antibodies directed against MUC1 frequently bind an immunodominant epitope that contains a single site for O-glycosylation. Glycosylation with tumor carbohydrate antigens such as the Tn-antigen (GalNAc-O-Ser/Thr) results in antibodies binding with higher affinity. One proposed model to explain the enhanced affinity of antibodies for the glycosylated antigen is that the addition of a carbohydrate alters the conformational properties, favoring a binding-competent state. The conformational effects associated with Tn glycosylation of the MUC1 antigen was investigated using solution-state NMR and molecular dynamics. NMR experiments revealed distinct substructures of the glycosylated MUC1 peptides compared with the unglycosylated peptide. Molecular dynamics simulations of the MUC1 glycopeptide and peptide revealed distinguishing differences in their conformational preferences. Furthermore, the glycopeptide displayed a smaller conformational sampling compared with the peptide, suggesting that the glycopeptide sampled a narrower conformational space and is less dynamic. A comparison of the computed ensemble of conformations assuming random distribution, NMR models, and molecular dynamics simulations indicated that the MUC1 glycopeptide and aglycosylated peptide sampled structurally distinctly ensembles and that these ensembles were different from that of the random coil. Together, these data support the hypothesis that that conformational pre-selection could be an essential feature of these peptides that dictates the binding affinities to MUC1 specific antibodies.

Principles for Managing Patients with Spinal Ailments in the Coronavirus Disease 2019 Era: What Do We Know So Far? An Evidence-Based, Narrative Review

The coronavirus disease 2019 (COVID-19) pandemic has significantly affected all specialty practices in medicine, including the field of spinal surgery. Spinal surgery is unique in that the procedures include not only fully elective and fully emergent interventions, but also involve a separate group of semi-emergent surgeries, where delayed intervention may lead to permanent neurological deficits. Here, we present an evidence-based review on the impact of the COVID-19 pandemic on spinal surgery and our current knowledge about this issue. We conducted a thorough search of the PubMed, Medline, and Google Scholar databases using the keywords, “COVID-19,” “COVID-19 impact on spine surgery,” “coronavirus impact on spine surgery,” “COVID-19 impact on neurosurgery,” “coronavirus impact on neurosurgery,” “COVID-19 impact on spine surgeons,” and “coronavirus impact on spine surgeons” on May 6, 2020. A total of 8,322 articles were identified in the initial search. Articles that were duplicated, those that did not pertain to COVID-19 or spine surgeries, those with details not pertaining to the current topic of interest, and those published in languages other than English were excluded from our analyses. After complete screening, six articles were included in this review. During the previous few weeks, the COVID pandemic has significantly influenced all major aspects of spine surgery across the world. Outpatient care has been gradually shifted from physical visits to tele-health and online consultations. General recommendations have favored the conservative approach over surgeries, although no patient should be deprived of standard care owing to concerns about COVID. The general principles followed by spine surgeons should include early detection of COVID symptomatology; triaging of patients based on underlying spinal pathology; prescription of appropriate investigations to confirm the COVID status; isolation, as needed; selection of optimal management method as per the guidelines; adherence to best intraoperative practices; and ensuring protective measures for non-infected patients, family members, fellow heath care providers, and themselves against the disease.

The Ensemble of Conformations of Antifreeze Glycoproteins (AFGP8): A Study Using Nuclear Magnetic Resonance Spectroscopy.

The primary sequence of antifreeze glycoproteins (AFGPs) is highly degenerate, consisting of multiple repeats of the same tripeptide, Ala-Ala-Thr*, in which Thr* is a glycosylated threonine with the disaccharide beta-d-galactosyl-(1,3)-alpha-N-acetyl-d-galactosamine. AFGPs seem to function as intrinsically disordered proteins, presenting challenges in determining their native structure. In this work, a different approach was used to elucidate the three-dimensional structure of AFGP8 from the Arctic cod Boreogadussaida and the Antarctic notothenioid Trematomusborchgrevinki. Dimethyl sulfoxide (DMSO), a non-native solvent, was used to make AFGP8 less dynamic in solution. Interestingly, DMSO induced a non-native structure, which could be determined via nuclear magnetic resonance (NMR) spectroscopy. The overall three-dimensional structures of the two AFGP8s from two different natural sources were different from a random coil ensemble, but their "compactness" was very similar, as deduced from NMR measurements. In addition to their similar compactness, the conserved motifs, Ala-Thr*-Pro-Ala and Ala-Thr*-Ala-Ala, present in both AFGP8s, seemed to have very similar three-dimensional structures, leading to a refined definition of local structural motifs. These local structural motifs allowed AFGPs to be considered functioning as effectors, making a transition from disordered to ordered upon binding to the ice surface. In addition, AFGPs could act as dynamic linkers, whereby a short segment folds into a structural motif, while the rest of the AFGPs could still be disordered, thus simultaneously interacting with bulk water molecules and the ice surface, preventing ice crystal growth.

Molecular Thermodynamics Using Nuclear Magnetic Resonance (NMR) Spectroscopy.

Nuclear magnetic resonance (NMR) spectroscopy is perhaps the most widely used technology from the undergraduate teaching labs in organic chemistry to advanced research for the determination of three-dimensional structure as well as dynamics of biomolecular systems... The NMR spectrum of a molecule under a given experimental condition is unique, providing both quantitative and structural information. In particular, the quantitative nature of NMR spectroscopy offers the ability to follow a reaction pathway of the given molecule in a dynamic process under well-defined experimental conditions. To highlight the use of NMR when determining the molecular thermodynamic parameters, a review of three distinct applications developed from our laboratory is presented. These applications include the thermodynamic parameters of (a) molecular oxidation from time-dependent kinetics, (b) intramolecular rotation, and (c) intermolecular exchange. An experimental overview and the method of data analysis are provided so that these applications can be adopted in a range of molecular systems.

Factors Affecting Early and 1-Year Motor Recovery Following Lumbar Microdiscectomy in Patients with Lumbar Disc Herniation: A Prospective Cohort Review

STUDY DESIGN: Prospective cohort study. PURPOSE: The study was aimed at evaluating clinicoradiological factors affecting recovery of neurological deficits in cases of lumbar disc herniation (LDH) treated by lumbar microdiscectomy. OVERVIEW OF LITERATURE: The majority of the available literature on neurological recovery following neurodeficit is limited to retrospective series. The literature is currently limited regarding variables that can help predict the recovery of neurodeficits following LDH. METHODS: A prospective analysis was performed on 70 consecutive patients who underwent lumbar microdiscectomy (L1–2 to L5–S1) owing to neurological deficits due to LDH. Patients with motor power ≤3/5 in L2–S1 myotomes were considered for analysis. Follow-up was performed at 2, 6, and 12 months to note recovery of motor deficits. Clinicoradiological parameters were compared between the recovered and nonrecovered groups. RESULTS: A total of 65 patients were available at the final follow-up: 41 (63%) had completely recovered by 2 months; four showed delayed recovery at the 6-month follow-up; and 20 (30.7%) showed no recovery at 1 year. Clinicoradiological factors, including diabetes, complete initial deficit, areflexia, multilevel disc prolapse, longer duration since initial symptoms, and ≥2 previous symptomatic episodes were associated with a significant risk of poorer recovery (p 0.05 for all). Diabetes mellitus (p=0.033) and complete initial motor deficit (p=0.028) were significantly associated with delayed recovery in the multivariate analysis. CONCLUSIONS: The overall neurological recovery rate in our study was 69%. Diabetes mellitus (p=0.033) and complete initial motor deficit were associated with delayed motor recovery.

Proteomic profiles by multiplex microsphere suspension array.

Advances in high-throughput proteomic approaches have provided substantial momentum to novel disease-biomarker discovery research and have augmented the quality of clinical studies. Applications based on multiplexed microsphere suspension array technology are making strong in-roads into the clinical diagnostic/prognostic practice. Conventional proteomic approaches are designed to discover a broad set of proteins that are associated with a specific medical condition. In comparison, multiplex microsphere immunoassays use quantitative measurements of selected set(s) of specific/particular molecular markers such as cytokines, chemokines, pathway signaling or disease-specific markers for detection, metabolic disorders, cancer, and infectious agents causing human, plant and animal diseases. This article provides a foundation to the multiplexed microsphere suspension array technology, with an emphasis on the improvements in the technology, data analysis approaches, and applications to translational and clinical research with implications for personalized and precision medicine.

Comparison of Three Different Options for C7 Posterior Vertebral Anchor in the Indian Population—Lateral Mass, Pedicle, and Lamina: A Computed Tomography-Based Morphometric Analysis

STUDY DESIGN: Radiological cohort study. PURPOSE: The options of posteriorly stabilizing C7 vertebra include using lateral mass, pedicle or lamina, as bony anchors. The current study is a computed tomography (CT)-based morphometric analysis of C7 vertebra of 100 Indian patients and discusses the feasibility of these different techniques. OVERVIEW OF LITERATURE: C7 is a peculiar vertebra with unique anatomy, which poses challenges for each of these fixation modalities. There are no reports available in the literature, which discuss and compare the feasibility of diverse posterior C7 fixation techniques in Indian population. METHODS: We included 100 consecutive cervical spine CT scans of Indian patients performed between July 2016 and September 2016. We excluded CT scans with any significant congenital anomaly or other pathological lesions of C7 and patients with non-Indian ethnicity. Regarding screw placement, we assessed and studied various dimensions of the C7 lateral mass, pedicles, and laminae in relevant sections. RESULTS: The mean age of our patients was 49.5±16.1 years. We included 56 male and 44 female patients. The mean anteroposterior and mediolateral dimensions of the lateral mass were 11.38±1.76 and 12.91±1.82 mm, respectively. The mean length of the lateral mass screw (Magerl technique) was 12.17±1.9 mm; 92% of patients could accommodate a lateral mass screw at least 10-mm long (unicortical), whereas 48% could accommodate a screw (unicortical) longer than 12 mm. Foramen transversarium was found in 30.5% of lateral masses. The mean outer and inner cortical widths of the pedicles were 6.5±0.71 mm and 3.72±0.61 mm, respectively. Approximately 58% of pedicles could accommodate 3.5-mm screws (based on the inner cortical pedicle width). The outer cortical and inner cortical widths of the laminae were 6.21±1.2 mm and 3.23±0.9 mm, respectively. Subsequently, 37% of the laminae could accommodate 3.5-mm screws. The mean angle of intralaminar screw trajectory was 50.7°±5.1°, and the mean length of the intralaminar screw was 32.6±3.05 mm. In addition, 96.4% and 60.7% of male patients could accommodate lateral mass screws longer than 10 mm and 12 mm, respectively. However, only 86.4% and 31.8% of female patients could accommodate 10- and 12-mm long lateral mass screws, respectively. Furthermore, 75% of male patients and 36% of female patients had pedicles that could accommodate 3.5-mm diameter screws, and 48.2% of male patients had laminae that could accommodate 3.5-mm screws; however, only 22.7% of female patients could accommodate 3.5-mm laminar screws. CONCLUSIONS: Based on our CT-guided morphometric analysis, 92% and 48% of Indian patients could accommodate at least 10- and 12-mm long lateral mass screws, and 58% of pedicles and 37% of laminae could accommodate 3.5-mm screws. Thus, lateral mass screws (between 10- and 12-mm long) seem to be the safest feasible option for C7 fixation. In case of the need for an alternative mode of stabilization (pedicle or intralaminar screw), particularly in female patients, careful preoperative planning with a CT scan is of utmost importance.

Western Diet-Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment.

Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin). Mice were subjected to morphological analysis as well as gut microbiota and bile acid profiling. Male WD-fed FXR KO mice had the most severe steatohepatitis. FXR KO also had reduced Firmicutes and increased Proteobacteria, which could be reversed by Abx. In addition, Abx eliminated hepatic neutrophils and lymphocytes in CD-fed, but not WD-fed, FXR KO mice. Proteobacteria and Bacteroidetes persisted in WD-fed FXR KO mice even after Abx treatment. Only polymyxin B could reduce hepatic lymphocytes in WD-fed FXR KO mice. The reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids as well as changes in gut microbiota. Our data revealed that Lactococcus, Lactobacillus, and Coprococcus protect the liver from inflammation.

Gender Differences in Bile Acids and Microbiota in Relationship with Gender Dissimilarity in Steatosis Induced by Diet and FXR Inactivation.

This study aims to uncover how specific bacteria and bile acids (BAs) contribute to steatosis induced by diet and farnesoid X receptor (FXR) deficiency in both genders. A control diet (CD) and Western diet (WD), which contains high fat and carbohydrate, were used to feed wild type (WT) and FXR knockout (KO) mice followed by phenotyping characterization as well as BA and microbiota profiling. Our data revealed that male WD-fed FXR KO mice had the most severe steatosis and highest hepatic and serum lipids as well as insulin resistance among the eight studied groups. Gender differences in WD-induced steatosis, insulin sensitivity, and predicted microbiota functions were all FXR-dependent. FXR deficiency enriched Desulfovibrionaceae, Deferribacteraceae, and Helicobacteraceae, which were accompanied by increased hepatic taurine-conjugated cholic acid and ß-muricholic acid as well as hepatic and serum lipids. Additionally, distinct microbiota profiles were found in WD-fed WT mice harboring simple steatosis and CD-fed FXR KO mice, in which the steatosis had a potential to develop into liver cancer. Together, the presented data revealed FXR-dependent concomitant relationships between gut microbiota, BAs, and metabolic diseases in both genders. Gender differences in BAs and microbiota may account for gender dissimilarity in metabolism and metabolic diseases.

Upregulation of cystathionine ß-synthase and p70S6K/S6 in neonatal hypoxic ischemic brain injury.

Encephalopathy of prematurity (EOP) is a complex form of cerebral injury that occurs in the setting of hypoxia-ischemia (HI) in premature infants. Using a rat model of EOP, we investigated whether neonatal HI of the brain may alter the expression of cystathionine ß-synthase (CBS) and the components of the mammalian target of rapamycin (mTOR) signaling. We performed unilateral carotid ligation and induced HI (UCL/HI) in Long-Evans rats at P6 and found increased CBS expression in white matter (i.e. corpus callosum, cingulum bundle and external capsule) as early as 24 h (P7) postprocedure. CBS remained elevated through P21, and, to a lesser extent, at P40. The mTOR downstream target 70 kDa ribosomal protein S6 kinase (p70S6K and phospho-p70S6K) and 40S ribosomal protein S6 (S6 and phospho-S6) were also overexpressed at the same time points in the UCL/HI rats compared to healthy controls. Overexpression of mTOR components was not observed in rats treated with the mTOR inhibitor everolimus. Behavioral assays performed on young rats (postnatal day 35-37) following UCL/HI at P6 indicated impaired preference for social novelty, a behavior relevant to autism spectrum disorder, and hyperactivity. Everolimus restored behavioral patterns to those observed in healthy controls. A gait analysis has shown that motor deficits in the hind paws of UCL/HI rats were also significantly reduced by everolimus. Our results suggest that neonatal HI brain injury may inflict long-term damage by upregulation of CBS and mTOR signaling. We propose this cascade as a possible new molecular target for EOP-a still untreatable cause of autism, hyperactivity and cerebral palsy.

Letter to the Editor: Long-term Outcomes of In Situ Fusion for Treating Dysplastic Spondylolisthesis

No abstract available.

Letter to the Editor: Role of Transpedicular Percutaneous Vertebral Biopsy for Diagnosis of Pathology in Vertebral Compression Fractures

No abstract available.

Letter to the editor: Does Segmental Kyphosis Affect Surgical Outcome after a Posterior Decompressive Laminectomy in Multisegmental Cervical Spondylotic Myelopathy?

No abstract available.

Comprehensive Laboratory Evaluation of a Highly Specific Lateral Flow Assay for the Presumptive Identification of Bacillus anthracis Spores in Suspicious White Powders and Environmental Samples.

We conducted a comprehensive, multiphase laboratory evaluation of the Anthrax BioThreat Alert(®) test strip, a lateral flow immunoassay (LFA) for the rapid detection of Bacillus anthracis spores. The study, conducted at 2 sites, evaluated this assay for the detection of spores from the Ames and Sterne strains of B. anthracis, as well as those from an additional 22 strains. Phylogenetic near neighbors, environmental background organisms, white powders, and environmental samples were also tested. The Anthrax LFA demonstrated a limit of detection of about 10(6) spores/mL (ca. 1.5 × 10(5) spores/assay). In this study, overall sensitivity of the LFA was 99.3%, and the specificity was 98.6%. The results indicated that the specificity, sensitivity, limit of detection, dynamic range, and repeatability of the assay support its use in the field for the purpose of qualitatively evaluating suspicious white powders and environmental samples for the presumptive presence of B. anthracis spores.

Equilibrium Dynamics of ß-N-Methylamino-L-Alanine (BMAA) and Its Carbamate Adducts at Physiological Conditions.

Elevated incidences of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia complex (ALS/PDC) is associated with ß-methylamino-L-alanine (BMAA), a non-protein amino acid. In particular, the native Chamorro people living in the island of Guam were exposed to BMAA by consuming a diet based on the cycad seeds. Carbamylated forms of BMAA are glutamate analogues. The mechanism of neurotoxicity of the BMAA is not completely understood, and BMAA acting as a glutamate receptor agonist may lead to excitotoxicity that interferes with glutamate transport systems. Though the interaction of BMAA with bicarbonate is known to produce carbamate adducts, here we demonstrate that BMAA and its primary and secondary adducts coexist in solution and undergoes a chemical exchange among them. Furthermore, we determined the rates of formation/cleavage of the carbamate adducts under equilibrium conditions using two-dimensional proton exchange NMR spectroscopy (EXSY). The coexistence of the multiple forms of BMAA at physiological conditions adds to the complexity of the mechanisms by which BMAA functions as a neurotoxin.

Letter: Comparison of Posterior Lumbar Interbody Fusion and Posterolateral Lumbar Fusion in Monosegmental Vacuum Phenomenon within an Intervertebral Disc

No abstract available.