Phenotypic Heterogeneity Enables Uropathogenic Escherichia coli To Evade Killing by Antibiotics and Serum Complement

Uropathogenic strains of Escherichia coli (UPEC) are the major cause of bacteremic urinary tract infections. Survival in the bloodstream is associated with different mechanisms that help to resist serum complement-mediated killing. While the phenotypic heterogeneity of bacteria has been shown to influence antibiotic tolerance, the possibility that it makes cells refractory to killing by the immune system has not been experimentally tested. In the present study we sought to determine whether the heterogeneity of bacterial cultures is relevant to bacterial targeting by the serum complement system. We monitored cell divisions in the UPEC strain CFT073 with fluorescent reporter protein. Stationary-phase cells were incubated in active or heat-inactivated human serum in the presence or absence of different antibiotics (ampicillin, norfloxacin, and amikacin), and cell division and complement protein C3 binding were measured by flow cytometry and immunofluorescence microscopy. Heterogeneity in the doubling times of CFT073 cells in serum enabled three phenotypically different subpopulations to be distinguished, all of them being recognized by the C3 component of the complement system. The population of rapidly growing cells resists serum complement-mediated lysis. The dominant subpopulation of cells with intermediate growth rate is susceptible to serum. The third population, which does not resume growth upon dilution from stationary phase, is simultaneously protected from serum complement and antibiotics.     

Intranasal Low-Dose Dexmedetomidine Reduces Postoperative Opioid Requirement in Patients Undergoing Hip Arthroplasty Under General Anesthesia

Background

Patients undergoing total hip arthroplasty (THA) need substantial amount of opioids for postoperative pain management, which necessitates opioid-sparing modalities. Dexmedetomidine is a novel alpha-2-adrenoceptor–activating drug for procedural sedation. In addition to its sedative effect, dexmedetomidine has analgesic and antiemetic effects. We evaluated retrospectively the effect of intraoperatively administered intranasal low-dose dexmedetomidine on postoperative opioid requirement in patients undergoing THA.

Composition and functionality of the intrahepatic innate lymphoid cell‐compartment in human nonfibrotic and fibrotic livers

Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue‐residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue‐resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44^? ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL‐13 when exposed to IL‐33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR‐3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment.     

Crown heights in the permanent teeth of 45,X and 45,X/46,XX females

Objective. Previous results regarding human sex chromosome aneuploidies have shown that the X and Y chromosomes affect tooth size and morphology. This study looked for the effect of sex chromosome deficiency on permanent tooth crown heights. Materials and methods. The material, from the Finnish KVANTTI Research Project, consisted of 97 45,X females and 15 45,X/46,XX females. The controls were 32 sisters and 28 mothers of the 45,X females, eight sisters and two mothers of the 45,X/46,XX females and 35 female population controls. Crown heights of all the available teeth except third molars on both sides of the jaws were measured from panoramic radiographs with a digital calliper according to the defined procedure. Results. The tooth crown heights were significantly smaller in the 45,X females than in the female population controls, except for the incisors and one canine in the maxilla, whereas the tooth crown heights of the 45,X/46,XX females were close to those of the normal control females. The differences between the 45,X and 45,X/46,XX females were statistically significant, excluding the upper incisor area and a few teeth in the mandible. Conclusions. The effect of the sex chromosome deficiency on permanent tooth crown height is due to the magnitude of lacking sex chromosome material. The present results regarding the 45,X females are parallel to previous findings in Turner patients regarding reduced mesiodistal and labiolingual dimensions and tooth crown heights in the permanent dentition.     

Repeatability of tumour hypoxia imaging using [<Superscript>18</Superscript>F]EF5 PET/CT in head and neck cancer

Purpose

Hypoxia contributes to radiotherapy resistance and more aggressive behaviour of several types of cancer. This study was designed to evaluate the repeatability of intratumour uptake of the hypoxia tracer [¹⁸F]EF5 in paired PET/CT scans.

Methods

Ten patients with newly diagnosed head and neck cancer (HNC) received three static PET/CT scans before chemoradiotherapy: two with [¹⁸F]EF5 a median of 7 days apart and one with [¹⁸F]FDG. Metabolically active primary tumour volumes were defined in [¹⁸F]FDG images and transferred to co-registered [¹⁸F]EF5 images for repeatability analysis. A tumour-to-muscle uptake ratio (TMR) of 1.5 at 3 h from injection of [¹⁸F]EF5 was used as a threshold representing hypoxic tissue.

Results

In 10 paired [¹⁸F]EF5 PET/CT image sets, SUVmean, SUVmax, and TMR showed a good correlation with the intraclass correlation coefficients of 0.81, 0.85, and 0.87, respectively. The relative coefficients of repeatability for these parameters were 15%, 17%, and 10%, respectively. Fractional hypoxic volumes of the tumours in the repeated scans had a high correlation using the Spearman rank correlation test (r = 0.94). In a voxel-by-voxel TMR analysis between the repeated scans, the mean of Pearson correlation coefficients of individual patients was 0.65. The mean (± SD) difference of TMR in the pooled data set was 0.03 ± 0.20.

Conclusion

Pretreatment [¹⁸F]EF5 PET/CT within one week shows high repeatability and is feasible for the guiding of hypoxia-targeted treatment interventions in HNC.

     

Risk factors for reduced areal bone mineral density in young adults with stem cell transplantation in childhood

Slightly, but significantly, reduced bone mineral density (BMD) has been detected as a late effect after stem cell transplantation (SCT) performed in childhood. The aim of the study was to evaluate the risk factors of reduced BMD after SCT in childhood. We evaluated areal BMD of 16 young adults (six males, 10 females), aged 21 yr (range 15-34) by dual-energy X-ray absorptiometry at the lumbar spine, at the femoral neck, in the total hip, and in the total body. Bone turnover rate was evaluated by markers of bone formation and resorption. Six of the 16 patients had reduced BMD with a Z-score of < or = -1 at least at one measurement site. Factors associated with reduced BMD were prepubertal status at transplant (p = 0.03), delayed pubertal growth (p = 0.03), pubertal onset gonadal hormone insufficiency (p = 0.02), and female sex (p = 0.02). Surprisingly, height in SDs and lumbar spine BMD correlated negatively (p = 0.008) in those with reduced bone mass, indicating that low areal density could not be due the small size of the vertebrae. Bone turnover markers were similar for those with normal and reduced BMD. In conclusion, 38% of the SCT long-term survivors had reduced areal BMD. Prepubertal status at transplant with pubertal onset gonadal hormone insufficiency and female sex predisposed to reduced bone mass after SCT performed in childhood.     

Electric field-navigated transcranial magnetic stimulation for chronic tinnitus: a randomized,placebo-controlled study

Objective: Repetitive transcranial magnetic stimulation (rTMS) may alleviate tinnitus. We evaluated effects of electric field (E-field) navigated rTMS targeted according to tinnitus pitch. No controlled studies have investigated anatomically accurate E-field-rTMS for tinnitus. Design: Effects of E-field-rTMS were evaluated in a prospective randomised placebo-controlled 6-month follow-up study on parallel groups. Patients received 10 sessions of 1?Hz rTMS or placebo targeted to the left auditory cortex corresponding to tonotopic representation of tinnitus pitch. Effects were evaluated immediately after treatment and at 1, 3 and 6 months. Primary outcome measures were visual analogue scores (VAS 0–100) for tinnitus intensity, annoyance and distress, and the Tinnitus Handicap Inventory (THI). Study sample: Thirty-nine patients (mean age 50.3 years). Results: The mean tinnitus intensity (F₃?=?15.7, p?F₃?=?8.8, p?=?0.0002), distress (F₃?=?9.1, p?=?0.0002) and THI scores (F₄?=?13.8, p?p?=?0.082 and p?=?0.065). Conclusions: Despite the significant effects of rTMS on tinnitus, differences between active and placebo groups remained non-significant, due to large placebo-effect and wide inter-individual variation.