TCRs with high affinity for foreign pMHC show self-reactivity

T cells with high-affinity T cell receptors (TCRs) for a foreign peptide-major histocompatibility complex (pMHC) appear to be negatively selected, even though they have never seen the foreign antigen. To examine how this process operates, we used in vitro yeast display to isolate high-affinity TCRs from the T cell clone 2C. The TCRs showed fast on-rates, which were consistent with reduced CDR (complementarity determining region) flexibility, and cross-reactivity with other cognate pMHCs. T cell hybridomas transfected with a high-affinity TCR were stimulated by endogenous self-pMHC, which suggested that T cells bearing the TCR would be negatively selected. The immune system appears to maintain a repertoire of flexible, low-affinity TCRs at the expense of more effective high-affinity TCRs.     

Effects of tryptophan depletion on central and peripheral chemoreflexes in man

Klein (Arch. Gen. Psychiatry 50, 306-317, 1993) suggests that panic attacks are the result of a defective 'suffocation alarm' threshold that presents with carbon dioxide (CO(2)) hypersensitivity, exaggerated ventilatory response and panic in panic disorder (PD) patients. Serotonergic deficiencies enhance this ventilatory response in PD patients, as per 'suffocation alarm' theory predictions, suggesting that serotonin (5-HT) normalizes the ventilatory response. Other research supports a serotonin system-mediated stimulation of ventilation. Knowledge of 5-HT's role on ventilatory output and its neurophysiological sources impacts on the 'suffocation alarm' theory validity and predictive value. We used tryptophan depletion (TRP-) in concert with a modified Read rebreathing test to determine the effect of deficient serotonergic modulation on the central and peripheral chemoreflex threshold and sensitivity of response to CO(2) in 11 healthy men. TRP- did not affect central or peripheral chemoreflex threshold or sensitivity of response to CO(2). However, basal ventilation was significantly elevated during TRP-. In contrast to 'suffocation alarm' theory predictions, decreased 5-HT neurotransmission does not significantly affect the respiratory chemoreflex response to CO(2), impacting on non-chemoreflex drives to breathe. Panic associated respiratory abnormalities may be related to defective 5-HT modulation of non-chemoreflex drives to breathe, unrelated to any respiratory chemoreflex abnormality.     

Variable MHC class I engagement by Ly49 natural killer cell receptors demonstrated by the crystal structure of Ly49C bound to H-2K(b)

The Ly49 family of natural killer (NK) receptors regulates NK cell function by sensing major histocompatibility complex (MHC) class I. Ly49 receptors show complex patterns of MHC class I cross-reactivity and, in certain cases, peptide selectivity. To investigate whether specificity differences result from topological differences in MHC class I engagement, we determined the structure of the peptide-selective receptor Ly49C in complex with H-2K(b). The Ly49C homodimer binds two MHC class I molecules in symmetrical way, a mode distinct from that of Ly49A, which binds MHC class I asymmetrically. Ly49C does not directly contact the MHC-bound peptide. In addition, MHC crosslinking by Ly49C was demonstrated in solution. We propose a dynamic model for Ly49-MHC class I interactions involving conformational changes in the receptor, whereby variations in Ly49 dimerization mediate different MHC-binding modes.     

The Accuracy of Incident Vertebral Fracture Detection in Children Using Targeted Case-Finding Approaches

Vertebral fractures are clinically important sequelae of a wide array of pediatric diseases. In this study, we examined the accuracy of case-finding strategies for detecting incident vertebral fractures (IVF) over 2 years in glucocorticoid-treated children (n = 343) with leukemia, rheumatic disorders, or nephrotic syndrome. Two clinical situations were addressed: the prevalent vertebral fracture (PVF) scenario (when baseline PVF status was known), which assessed the utility of PVF and low lumbar spine bone mineral density (LS BMD; Z-score <−1.4), and the non-PVF scenario (when PVF status was unknown), which evaluated low LS BMD and back pain. LS BMD was measured by dual-energy X-ray absorptiometry, vertebral fractures were quantified on spine radiographs using the modified Genant semiquantitative method, and back pain was assessed by patient report. Forty-four patients (12.8%) had IVF. In the PVF scenario, both low LS BMD and PVF were significant predictors of IVF. Using PVF to determine which patients should have radiographs, 11% would undergo radiography (95% confidence interval [CI] 8–15) with 46% of IVF (95% CI 30–61) detected. Sensitivity would be higher with a strategy of PVF or low LS BMD at baseline (73%; 95% CI 57–85) but would require radiographs in 37% of children (95% CI 32–42). In the non-PVF scenario, the strategy of low LS BMD and back pain produced the highest specificity of any non-PVF model at 87% (95% CI 83–91), the greatest overall accuracy at 82% (95% CI 78–86), and the lowest radiography rate at 17% (95% CI 14–22). Low LS BMD or back pain in the non-PVF scenario produced the highest sensitivity at 82% (95% CI 67–92), but required radiographs in 65% (95% CI 60–70). These results provide guidance for targeting spine radiography in children at risk for IVF. © 2021 American Society for Bone and Mineral Research (ASBMR).     

The length of menstrual bleeding and the risk of urogenital infections in the context of the activity of hemoglobin-derived microbicidal peptides

OBJECTIVE: Well-known natural unspecific antimicrobial factors acting in the vagina are additionally reinforced during menstrual bleeding by hemocidins--a recently discovered novel class of microbicidal peptides generated proteolytically from hemoglobin. The aim of the presented research was to investigate the relation between the average length of menstrual bleeding and the frequency of urogenital infections. We expected that the shorter menstrual bleeding might increase the risk of urogenital infections because is synonymous with the shorter period of exposition on bactericidal action of hemocidins. STUDY DESIGN: The study contains statistical analysis of an average declared length of menstrual bleeding in the group of 267 young, sexually active women with the symptoms of urogenital infections. The control group consisted of 300 young healthy women. RESULTS: The length of menstrual bleeding in the group of patients with urogenital infections (average 4.35 days) was statistically significantly shorter than in the control group (average 4.95 days). The average length of the menstrual cycle was equal and counted ca. 28 days in both groups. CONCLUSION: The length of menstrual bleeding seems to be a significant factor in the vaginal ecology maintenance.     

Share control of surgery robot master manipulator guiding tool along the standard path

Recently, minimally invasive surgery (MIS) robotics enters the phase of autonomous operation. However, because of the high variability of the environment, conducting a fully autonomous surgery is still extremely difficult. This paper presents a share control system, the objective of which is to suggest the optimum path of tool guidance through the use of force on the master manipulator (hereinafter as master), meaning the surgeon's hand. Owing to this type of control, the surgeon has full control over the position of the tool the entire time and is supported by the system to better and faster guide the tool during surgery. The force should be felt by the surgeon but, simultaneously, must not hinder or impact the surgical process. Furthermore, the share control system presented in the paper can be turned on or off at any moment during surgery.     

Carcinoma, a fibrolamellar variant--immunohistochemical analysis of 4 cases

BACKGROUND/AIMS: To analyze, by means of immunocytochemistry, the cases of fibrolamellar variant of hepatocellular carcinoma (FLC), diagnosed in our Department. METHODOLOGY: The material comprised 4 FLC cases of tumors resected surgically. Besides the routine morphological assessment, we used a panel of immunohistochemical stainings including: hepatocellular cytokeratin, CK7, CK19, Ki67, PCNA, chromogranin A, synaptophysin, NSE, insulin, calcitonin, parathormon, CD34, EBV (LMP), Bcl2, cyclin D1. RESULTS: In 3 out of 4 cases, we observed co-expression of CK7 with hepatocellular CK. In addition, there was positive staining with some endocrine markers in the majority of patients. In one case, we found strong cyclin D1 immunoreactivity which correlated with EBV (LMP) immunoreactivity, in the same patient. The score of PCNA positivity varied between 15 and 90%. In all cases Ki67 was negative. CONCLUSIONS: The incidence of FLC, among all hepatocellular carcinomas diagnosed in our Department was 5.1%. In accordance with other reports, all our FLC cases were young patients without underlying liver disease. We were unable to find a correlation between FLC cellular immunophenotype, and histological and clinical markers of malignancy. In addition, it appears that PCNA is a better marker of cell-proliferation in FLC than Ki67. The significance of EBV infection in FLC requires further study.     

RF ablation in a patient with recurrent post-infarction ventricular tachycardia requiring multiple cardioverter-defibrillator interventions

A case of a 51 year old patient with a history of myocardial infarction (MI) and recurrent ventricular tachycardia (VT) is presented. Three months after MI the patient underwent coronary angioplasty and one year later received prophylactic implantable cardioverter-defibrillator (ICD) due to complex ventricular arrhythmias, detected on Holter ECG monitoring, and depressed left ventricular ejection fraction. Later on the patient started to experience palpitations and ICD shocks during physical activity (cycling). Interrogation of the ICD memory showed appropriate shocks due to slow (160 betas/min) VT. The device was reprogrammed and new antitachycardia pacing (ATP) algorithms were enabled, however, it occurred proarrhythmic due to the ATP-induced acceleration of VT rate. Finally, in April 2005 he received 37 appropriate ICD shocks during a few hours. The patient was selected for RF ablation and underwent successful procedure with the use of the electro-anatomical CARTO mapping system.     

Mapping and ablation of polymorphic ventricular tachycardia after myocardial infarction

OBJECTIVES: The goal of this study was to describe the mapping and ablation of polymorphic ventricular tachycardia (VT) after myocardial infarction (MI). BACKGROUND: The initiating mechanisms of polymorphic VT after MI have not been reported. METHODS: Five patients (four males; age 61 +/- 7 years) with recurrent episodes of polymorphic VT after anterior MI (left ventricular ejection fraction 32 +/- 7%) despite revascularization and antiarrhythmic drugs were studied. All patients demonstrated frequent ventricular premature beats (PBs) initiating polymorphic VT. Pace mapping and activation mapping were used to identify the earliest site of PB activity. The presence of a Purkinje potential preceding PB defined its origin from the Purkinje network. Electroanatomic voltage mapping was performed to delineate the extent of MI. RESULTS: The PBs were observed in all cases to arise from the Purkinje arborization in the MI border zone. These PBs were right bundle-branch block in all five patients, with morphologic variations in the limb leads in four; one also had a left bundle-branch block morphology. The coupling interval of the PB to the preceding QRS complex demonstrated significant variations (320 to 600 ms). During PB, the Purkinje potential at the same site preceded the QRS complex by 20 to 160 ms and was associated with different morphologies. Repetitive Purkinje activity was documented during polymorphic VT. Splitting of Purkinje activity and Purkinje to muscle conduction block were also observed. Ablation at these sites eliminated all PBs. At 16 +/- 5 months follow-up using defibrillator memory interrogation, no patient has had recurrence of arrhythmia. CONCLUSIONS: The Purkinje arborization along the border-zone of scar has an important role in the mechanism of polymorphic VT in patients after MI. Ablation of the local Purkinje network allows suppression of polymorphic VT.