TAM receptors attenuate murine NK-cell responses via E3 ubiquitin ligase Cbl-b

TAM receptors (Tyro3, Axl, and Mer) are receptor tyrosine kinases (RTKs) that are expressed by multiple immune cells including NK cells. Although RTKs typically enhance cellular functions, TAM receptor ligation blocks NK-cell activation. The mechanisms by which RTKs block NK-cell signaling downstream of activating receptors are unknown. In this report, we demonstrate that TAM receptors attenuate NK cell responses via the activity of E3 ubiquitin ligase Casitas B lineage lymphoma b (Cbl-b). Specifically, we show that Tyro3, Axl, and Mer phosphorylate Cbl-b, and Tyro3 ligation activates Cbl-b by phosphorylating tyrosine residues 133 and 363. Ligation of TAM receptors by their ligand Gas6 suppresses activating receptor-stimulated NK-cell functions such as IFN-γ production and degranulation, in a TAM receptor kinase- and Cbl-b-dependent manner. Moreover, Gas6 ligation induces the degradation of LAT1, a transmembrane adaptor protein required for NK cell activating receptor signaling, in WT but not in Cbl-b knock-out NK cells. Together, these results suggest that TAM receptors may attenuate NK-cell function by phosphorylating Cbl-b, which in turn dampens NK-cell activation signaling by promoting the degradation of LAT1. Our data therefore support a mechanism by which RTKs attenuate, rather than stimulate, signaling pathways via the activation of ubiquitin ligases.     

Test–retest repeatability of [18F]Flortaucipir PET in Alzheimer’s disease and cognitively normal individuals

The aim of this study was to investigate the test–retest (TRT) repeatability of various parametric quantification methods for [¹⁸F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer’s disease and six cognitively normal subjects. All underwent two 130-min dynamic [¹⁸F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40–60, 80–100 and 110–130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest–test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68–2.15) to 6.84% (2.99–11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78–3.58) vs. SUVr_80–100: 3.05% (1.28–5.52), p < 0.001. Furthermore, for SUVr_80–100 and SUVr_110–130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.     

High‐frequency ventilation with the Dräger Babylog 8000plus: measuring the delivered frequency

Background: Ventilator frequency is one of the determinants of tidal volume delivery during high‐frequency ventilation. Clinicians increasingly use data on ventilator displays to inform their decisions. Aim: To measure the frequencies delivered by the Dräger Babylog 8000plus ventilator when used in high‐frequency mode. Methods: Ventilator waveforms using a test lung were recorded at the full range of settings 5–20 Hz using Spectra software at 1000 Hz. The changes in frequency produced by a 1‐ Hz change in set frequency were calculated. Actual and displayed frequencies were compared. Results: For settings up to 12 Hz, median (range) difference between set and delivered frequencies was 0 (?0.4 to +0.1) Hz. Above 12 Hz, delivered frequency varied by ?0.3 (?1.9 to +0.3) Hz. For 1‐ Hz changes in frequency settings, in the range 5–12 Hz, 1‐ Hz changes produced a change in delivered frequency of 1.0 (0.6–1.4) Hz. Above 12 Hz, the corresponding changes were 0.7 (0–2.9) Hz. The ventilator displays the set frequency during operation rather than the delivered frequency. Conclusion: At 12 Hz and below, the differences between set and delivered frequencies were relatively small compared with those at 13 Hz and higher. Above 13 Hz, the difference between set and delivered frequencies was up to 2.9 Hz. Some frequency setting changes did not result in a change in delivered frequency.     

Infestation of Tunga penetrans in villages near Zomba Central Hospital

An outbreak of Tunga Penetrans (Jigger Flea) infestation affecting a number of villages near to a Central Hospital in Malawi is described. Due to the large number of affected individuals, high parasitic load, and extended duration of infection an alternative to the recommended approach of surgical removal of the flea was required. Benzyl benzoate paint and liquid paraffin had been used in local Primary Healthcare settings previously and topical treatment with antiparasitic agents has been advocated in the literature, particularly for severe infestation. Benzyl benzoate and liquid paraffin were applied topically to four adults with numerous jigger flea burrows, and their progress assessed regularly. After completion of 7 days of treatment patients noted that fleas were dislodging spontaneously, and that embedded parasites had not increased in size to the same extent that untreated fleas had in previous infestations. Following confirmation of the viability of its implementation in a resource-poor setting, this treatment regimen has subsequently been adopted by the local branch of the District Health Office for distribution to infected communities.     

The biography of Mary E. O'Sullivan: an early American headache specialist

The aim of this study was to review the life of Mary E. O'Sullivan and to summarize her important contributions to the study of migraine. Mary E. O'Sullivan underwent extensive training to become a neurologist at a time when only 5% of women in America were physicians. She published five papers on migraine. In a 1936 Journal of the American Medical Association article, she described a patient with ergotamine overuse headache and recommended that daily doses of oral ergotamine should be avoided. Three years later she described migraine as a 'complex' syndrome with multiple causes and multiple cures. Mary E. O'Sullivan, an ambitious female headache specialist of the 1930s, was an early advocate of the use of ergotamine to treat migraine, yet she was one of the first to report ergotamine overuse headache. Although her life was short, her research, knowledge and ambition at a time when women had limited opportunities in medicine have left a mark.     

Raisins are a low to moderate glycemic index food with a correspondingly low insulin index

The objective of this study was to determine the glycemic index (GI) and insulin index (II) of raisins and evaluate if these values are similar in different populations. The study subjects consisted of 10 healthy sedentary individuals (S; age, 25.7 ± 1.3 years; body mass index [BMI] = 23.3 ± 1.7 kg/m²), 11 aerobically trained adults (A; age, 23.1 ± 1.0 years; BMI = 24.1 ± 0.3 kg/m²), and 10 prediabetic adults (P; age, 50.0 ± 2.6 years; BMI = 32.6 ± 1.9 kg/m²). Subjects consumed 50 g of available carbohydrate from raisins and from a glucose solution (reference food) on 2 separate occasions. Serum glucose and insulin concentrations were measured from capillary fingerstick blood samples at baseline and at 15, 30, 45, 60, 90, and 120 minutes (and 150 and 180 minutes for P group) postprandially. The GI of raisins was low (GI, ≤55) in the S (49.4 ± 7.4) and P (49.6 ± 4.8) groups and was moderate (GI, 55-69) in the A group (62.3 ± 10.5), but there were no differences among the subject groups (P = .437). The II of raisins was 47.3 ± 9.4, 51.9 ± 6.5, and 54.4 ± 8.9 for the S, A, and P groups, respectively. On average, the A group secreted 2- to 2.5-fold less insulin per gram of carbohydrate compared with the S and P groups (P < .05). Thus, raisins are a low to moderate GI food, with a correspondingly low II. The lower insulin response in the A group compared with the other groups suggests enhanced insulin sensitivity.     

Colposcopic genital findings in prepubertal girls assessed for sexual abuse

After the introduction of the colposcope for the examination of children suspected of being sexually abused in Leeds, a study was undertaken to describe the findings in detail. A total of 109 consecutive prepubertal girls, mean age 70.4 months were assessed including colposcopic genital and anal examination, and peer group review of reports and photographs. Fifty nine children had signs consistent with blunt force penetrating trauma (hymenal transection/major notch, scar, or hymenal attenuation). Transections were encountered most commonly at 6 o'clock (directly posterior). In 46 the hymenal orifice was gaping with thigh abduction only and in 47 the hymenal orifice transverse diameter was greater than 4 mm on labial separation. Overall, physical findings were commonly present and in only two cases were no signs recorded. Non-specific and frequent findings included patterns of labial and introital reddening. Supportive hymenal signs including swelling, rounding of edge, thickening, distortion, and loss of symmetry were common. Labial fusion was present in 20. Urethral dilatation with labial separation was noted in 14. Physical findings including normality are consistent with abuse and even minor anogenital signs as well as negative findings should be documented. Colposcopy and photography are valuable tools in peer review, teaching, and case management.     

Expression of resistance-related proteins in tumoral and peritumoral tissues of patients with lung cancer

Twenty tumoral and peritumoral tissues from patients with lung cancer were analyzed immunohistochemically for the drug resistance-related proteins P-glycoprotein (P-170), topoisomerase II (Topo-II), glutathione S-transferase-π (GST-π), metallothionein (MT), heat shock protein-70 (HSP-70) and the putative regulators of resistance (ErbB1, Fos and Jun). Protein expression of Topo-II, GST-π, MT, HSP-70, ErbB1, Fos and Jun was elevated in tumor tissue in comparison to normal tissue. The different expression of the proteins between tumoral and normal tissues was statistically significant for Topo-II (P = 0.05), MT (P = 0.03), and HSP-70 (P = 0.01), whereas ErbB1 showed a borderline significance. The expression of the proteins was frequently increased in smokers in comparison to non-smokers. In general, the increase of the proteins of smokers corresponded in tumoral and non-tumoral tissue. Different expression was only found with MT and HSP-70 which were higher in tissues of smokers.