Anthrax toxin

Anthrax is primarily a disease of herbivores caused by gram-positive, aerobic, spore-forming Bacillus anthracis. Humans are accidental hosts through the food of animal origin and animal products. Anthrax is prevelant in most parts of the globe, and cases of anthrax have been reported from almost every country. Three forms of the disease have been recognized: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). The major virulence factors of Bacillus anthracis are a poly-D glutamic acid capsule and a three-component protein exotoxin. The genes coding for the toxin and the enzymes responsible for capsule production are carried on plasmid pXO1 and pXO2, respectively. The three proteins of the exotoxin are protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa), and edema factor (EF, 89 kDa). The toxins follow the A-B model with PA being the B moeity and LF/EF, the alternative A moeities. LF and EF are individually nontoxic, but in combination with PA form two toxins causing different pathogenic responses in animals and cultured cells. PA + LF forms the lethal toxin and PA + EF forms the edema toxin. During the process of intoxication, PA binds to the cell surface receptor and is cleaved at the sequence RKKR (167) by cell surface proteases such as furin generating a cell-bound, C-terminal 63 kDa protein (PA63). PA63 possesses a binding site to which LF or EF bind with high affinity. The complex is then internalized by receptor-mediated endocytosis. Acidification of the vesicle leads to instertion of PA63 into the endosomal membrane and translocation of LF/EF across the bilayer into the cytosol where they exert their toxic effects. EF has a calcium- and calmodulin-dependent adenylate cyclase activity. Recent reports indicate that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and 2), and this cleavage inactivates MAPKK1 and thus inhibits the mitogen-activated protein kinase signal transduction pathway. We describe in detail the studies so far done on unraveling the molecular mechanisms of pathogenesis of Bacillus anthracis.     

Interaural phase-sensitive units in the inferior colliculus of the unanesthetized rabbit: effects of changing frequency

We studied the interaural phase sensitivity of 85 units in the inferior colliculus (IC) of the unanesthetized rabbit. We assessed this sensitivity at several frequencies within each unit's responsive range. The interaural phase disparity was varied by delivering tones that differed by 1 Hz to the two ears, resulting in a 1-Hz binaural beat. We analyzed each unit's response to different frequencies by calculating four measures: characteristic delay (CD), characteristic phase (CP), composite peak delay, and mean peak delay. We estimated the CD and CP from the slope and phase intercept, respectively, of the regression line fitted to a plot of the mean interaural phase against stimulating frequency. The composite peak delay was estimated from the peak of a composite delay curve. This was generated by replotting the response to changes in interaural phase, as a function of the equivalent interaural delay and averaging the resultant interaural delay curves. The composite delay curve reflects the unit's average response to interaural delays across frequencies. Last, we calculated a mean peak delay, derived by converting the mean interaural phase of the response at each frequency to an equivalent delay and then averaging these delays. Interaural phase sensitivity was observed to frequencies as high as 2,150 Hz. However, the majority of units showed such sensitivity below 1,500 Hz. For most units, the interaural delay curves measured at several frequencies coincided near the peak discharge. This result is consistent with a neural model, where excitatory inputs from each ear converge upon a binaural cell, evoking maximum discharge only when the two inputs arrive simultaneously. As a first approximation, our data fit this model, indicating that IC neurons can act like coincidence detectors or cross-correlators. The distributions of CD, composite peak delay, and mean peak delay showed that most units preferred ipsilateral stimulus delays, which in the natural situation corresponds to sounds emanating from the contralateral field. Moreover, most units preferred delays that were within the estimated physiological range of the rabbit. These results support the viewpoint that neurons in the IC participate in sound localization. The distributions of CP and CD differ substantially from those found in the IC of the anesthetized cat. These differences may reflect species differences, the effects of anesthesia, or a difference in the population of units sampled. For each unit, we assessed the linearity of the plot of mean interaural phase against frequency of stimulation using a chi 2 method. For most units the plots were significantly nonlinear.(ABSTRACT TRUNCATED AT 400 WORDS)     

Significance and clinical impact of routinely tested urinary ethyl glucuronide after liver transplantation – development of a risk score

Alcohol abuse after liver transplantation can seriously impact graft and patient survival. However, to date, there is no defined standard procedure to identify patients consuming alcohol after liver transplantation. The aim of this study was to analyze the diagnostic value and clinical impact of routinely measured urinary ethyl glucuronide (uEtG) – a metabolite of ethanol – in patients after liver transplantation. Data of 362 consecutive patients after liver transplantation who visited the University Hospital of Tuebingen for outpatient follow-up were analyzed. Forty-eight patients (13%) displayed positive uEtG results. The uEtG positive group contained significantly more patients with pretransplant alcoholic liver disease. However, two thirds of the uEtG positive patients had no history of pretransplant alcoholic liver disease. Several clinical parameters were significantly associated with positive uEtG. In order to enable a more cost-effective application of uEtG in the future, a clinical risk score was developed (specificity 0.95). In conclusion, routine testing for uEtG reveals a considerable percentage of patients practicing alcohol intake after liver transplantation. Application of our proposed risk score could help focusing uEtG testing on patients at risk.     

Perioperative Blood Transfusions Are Associated with a Higher Incidence of Thromboembolic Events After TKA: An Analysis of 333,463 TKAs

BackgroundGiven the morbidity, mortality, and financial burden associated with venous thromboembolism (VTE) after TKA, orthopaedic providers continually seek to identify risk factors associated with this devastating complication. The association between perioperative transfusion status and VTE risk has not been thoroughly explored, with previous studies evaluating this relationship being limited in both generalizability and power.Questions/purposesTherefore, we sought to determine whether perioperative transfusions were associated with an increased risk of (1) pulmonary embolism (PE) or (2) deep vein thrombosis (DVT) after primary TKA in a large, multi-institutional sample.MethodsThe American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was implemented for our analysis. The definitions of complications, such as DVT and PE, and risk adjustment validation is monitored by the central ACS NSQIP office to ensure participating hospitals are adhering to the same guidelines to log patients. Additionally, both preoperative and intraoperative/72 hour postoperative transfusion status is included for all patients. Therefore, ACS NSQIP was determined to be the most appropriate database for our analysis. All patients who underwent primary TKA between 2011 and 2018 were identified using Current Procedural Terminology code 27447. Primary TKAs designated as “non-elective” were excluded, thereby providing a cohort composed solely of patients undergoing unilateral primary elective TKA for further analysis. The final analysis included 333,463 patients undergoing TKA (mean age 67 ± 9 years, 62% female). Preoperative transfusions were received by < 0.01% (48 of 333,463) of the patients, while 4% (14,590 of 333,463) received a transfusion within the interim between the start of surgery up to 72 hours postoperatively. All missing values were imputed through multiple imputation by chained equation to avoid variable availability-based selection and the subsequent listwise deletion-associated bias in the estimate of parameters. A multivariable logistic regression analysis was conducted using variables identified in a univariate model to calculate adjusted odds ratios and 95% confidence intervals for risk factors associated with symptomatic DVT and/or PE. For variables that maintained significance in the multivariable model, an additional model without confounders was used to generate fully adjusted ORs and 95% CIs. A propensity score matched comparison between recipients versus nonrecipients (1:1) of transfusion (preoperative and intraoperative/72 hours postoperative) was then conducted to evaluate the independent association between DVT/PE development and patients’ transfusion status. Significance was determined at a p value < 0.05.ResultsAdjusted multivariable regression analysis accounting for patient age, sex, race, BMI, American Society of Anesthesiologists (ASA) class and baseline comorbidities demonstrated the absence of an association between preoperative (OR 1.75 [95% CI 0.24 to 12.7]; p = 0.58) or intraoperative/72 hours postoperative (OR 1.12 [95% CI 0.93 to 1.35]; p = 0.23) transfusions and higher odds of developing PE. Similar findings were demonstrated after propensity score matching. Although multivariable regression demonstrated the absence of an association between preoperative transfusion and the odds of developing DVT within the 30-day postoperative period (OR 1.85 [95% CI 0.43 to 8.05]; p = 0.41), intraoperative/postoperative transfusion was associated with higher odds of DVT development (OR 3.68 [95% CI 1.14 to 1.53]; p < 0.001) relative to transfusion naïve patients. However, this significance was lost after propensity score matching.ConclusionAfter controlling for various potential confounding variables such as ASA Class, age, anesthesia type, and BMI, the receipt of an intra- or postoperative transfusion was found to be associated with an increased risk of DVT. Our findings should encourage orthopaedic providers to strictly adhere to blood management protocols, further tighten transfusion eligibility, and adjust surgical approach and implant type to reduce the incidence of transfusion among patients with other DVT risk factors. Additionally, our findings should encourage a multidisciplinary approach to VTE prophylaxis and prevention, as well as to blood transfusion guideline adherence, among all providers of the care team.Level of EvidenceLevel III, therapeutic study.     

Clinico-Radio-Histopathological Correlation by C-Arm Image-Guided Biopsy in Spinal Tuberculosis

Background/Purpose of the StudyC-arm-guided biopsy is a safe and effective technique for evaluating TB spine and is useful in planning therapy. The purpose of this study was to find a correlation between clinically and radiologically suspected TB spine and C-arm image-guided biopsy-proven cases and to study the complications encountered.MethodsAfter evaluating the clinical, laboratory, X-ray and MRI findings, 92 patients with provisionally diagnosed tubercular spine were subjected to C-arm image-guided biopsy.ResultsAmong our 92 cases, histopathology was positive in 55 cases (59.78%). Out of these 55 histologically positive cases, CBNAAT was positive in 42 cases and negative in the rest 13 cases. Overall, among the 92 cases, CBNAAT was positive in 51(55.43%) of cases, and out of these, histopathology turned out to be positive in 42 of cases. Out of 41 cases with negative CBNAAT, histopathology was suggestive of tuberculosis in 13. The strength of agreement between CBNAAT and histopathology was statistically significant (p < 0.0001; kappa = 0.511). No complication such as bleeding, nerve/cord injury, infection, injury to aorta or pneumothorax was encountered during and after the C-arm biopsy in any case.ConclusionC-arm image-guided biopsy is reasonably accurate and should be used as a tool for diagnosis of TB spine. We recommend histopathological examination as a key component for the diagnosis of TB spine, as it is precise and consumes relatively shorter time. CBNAAT is more rapid but is not a substitute for histopathology for spine TB diagnosis.     

Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66–0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66–0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = −0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.     

Safety and immunogenicity of adjuvanted recombinant subunit herpes zoster vaccine in lung transplant recipients

Lung transplant recipients are at high risk for herpes zoster and preventive measures are a significant unmet need. We investigated the safety and immunogenicity of two doses of a recombinant zoster vaccine (RZV) in lung transplant recipients (≥50 years). We enrolled 50 patients of which 49 received at least one vaccine dose. Anti-glycoprotein E (gE) antibody levels (n = 43) increased significantly compared to baseline (median optical density [OD] 1.96; interquartile range [IQR]: 1.17–2.89) after the first (median OD 3.41, IQR 2.54–3.81, p < .0001) and second vaccine dose (median OD 3.63, IQR 3.39–3.86, p < .0001). gE-specific polyfunctional CD4+ T cell frequencies (n = 38) also increased from baseline (median 85 per 10⁶ CD4+ T cells; IQR: 46–180) to the first (median 128 per 10⁶ CD4+ T cells; IQR: 82–353; p = .023) and after the second dose (median 361 per 10⁶ CD4+ T cells; IQR: 146–848; p < .0001). Tenderness (83.0%; 95%CI: 69.2–92.4%) and redness (31.9%; 95%CI: 19.1–47.1%) at injection site were common. One rejection episode within 3 weeks of vaccination was observed. This is the first study demonstrating that RZV was safe and elicited significant humoral and cell-mediated immunity in lung transplant recipients. RZV is a new option for the prevention of shingles in this population.     

Full and Abbreviated Courses of Maintenance Electroconvulsive Therapy

The authors describe their experience with maintenance electroconvulsive therapy administered to 10 patients, using an abbreviated or a full maintenance schedule. Recommendation for either form of treatment was made on clinical grounds. Patients with major depressive episodes with delusional features appear to respond best to maintenance ECT.