Glucocorticoid effect on insulin sensitivity: a time frame

It is well known that glucocorticoids induce insulin resistance, but the exact time scale in humans is not well known. The aim of the study was to determine the time scale of effects of pharmacologic doses of glucocorticoids on insulin sensitivity. Subjects were treated with repeated methylprednisolone infusions and oral prednisone for Graves' orbitopathy. Insulin sensitivity was determined using euglycemic hyperinsulinemic clamp (EHGC) before, during the first glucocorticoid infusion and after 2 months of treatment. EHGC started 2 h after the start of the glucocorticoid infusion, and lasted for 2 h. In another group of patients, insulin sensitivity was determined by short insulin tolerance test (SITT) before and during the first glucocorticoid infusion. SITT started 15 min after the start of the glucocorticoid infusion and lasted for 15 min. Ten subjects were included in each protocol. All were euthyroid during the study period. Four hours after the start of the glucocorticoid infusion significant reduction of insulin sensitivity was observed, which did not change for a further 2 months of glucocorticoid treatment [before 7.82 (95% confidence interval (CI) 5.35-10.29), first infusion, 4.93 (95% CI 2.99-6.87), after 2 months 5.36 (95%CI 3.91-6.81) mg/kg/min]. No significant change in insulin sensitivity occurred during the first 30 min of glucocorticoid infusion [before 139.7 (95%CI 94.1-185.3), during 146.7 (95%CI 106.3-187.1) mumol/l/min]. In humans, glucocorticoid- induced insulin resistance develops quickly, in about 4 h, and does not change during further glucocorticoid treatment.     

Ribavirin shows immunomodulatory effects on activated microglia

Ribavirin (RBV) is synthetic purine nucleoside analogue, licensed as anti-viral drug that displays immunomodulatory actions on various immune cells. Our previous ex vivo studies have demonstrated immunosuppressive effects of RBV on reactive T-lymphocytes in experimental autoimmune encephalomyelitis. Here, we examined the effects of RBV on inflammatory response of microglia. RBV potency to down-regulate microglia inflammatory response was assessed by measuring microglia cell body size, and the production of nitric oxide (NO) and pro- and anti-inflammatory cytokines. RBV exerted cytotoxic effects on LPS-stimulated microglia, leaving non-stimulated microglia unaffected. The exposure of activated microglia to RBV led to: decrease in the level of NO as a result of decreased cell number, lower average cell surface, the reduction of membrane ruffling, the suppression of interleukin-6 release and promoted interleukin-10 production. On the other hand, RBV promoted LPS-induced interleukin-1 beta release. Our results imply that RBV is a complex immunomodulator showing both anti- and pro-inflammatory effects on activated microglia.     

Effect of Heat Input on the Ballistic Performance of Armor Steel Weldments

The purpose of this study is to examine the projectile penetration resistance of the base metal and heat-affected zones of armor steel weldments. To ensure the proper quality of armor steel welded joints and associated ballistic protection, it is important to find the optimum heat input for armor steel welding. A total of two armor steel weldments made at heat inputs of 1.29 kJ/mm and 1.55 kJ/mm were tested for ballistic protection performance. The GMAW welding carried out employing a robot-controlled process. Owing to a higher ballistic limit, the heat-affected zone (HAZ) of the 1.29 kJ/mm weldment was found to be more resistant to projectile penetration than that of the 1.55 kJ/mm weldment. The ballistic performance of the weldments was determined by analyzing the microstructure of weldment heat-affected zones, the hardness gradients across the weldments and the thermal history of the welding heat inputs considered. The result showed that the ballistic resistance of heat affected zone exist as the heat input was decreased on 1.29 kJ/mm. It was found that 1.55 kJ/mm does not have ballistic resistance.     

Tumor mutational burden assessed by targeted NGS predicts clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer

In non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here, we evaluated the predictive power of TMB measured by the Oncomine™ Tumor Mutational Load targeted sequencing assay in 76 NSCLC patients treated with ICIs. TMB was assessed retrospectively in 76 NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were classified as having either durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. TMB was significantly higher in patients with DCB than in patients with NDB (median TMB = 8.5 versus 6.0 mutations/Mb, Mann–Whitney p = 0.0244). 64% of patients with high TMB (cut-off = third tertile, TMB ≥ 9) were responders (DCB) compared to 33% and 29% of patients with intermediate and low TMB, respectively (cut-off = second and first tertile, TMB = 5–9 and TMB ≤ 4, respectively). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log-rank test p = 0.0014 for PFS and 0.0197 for OS). While identifying different subgroups of patients, combining PD-L1 expression and TMB increased the predictive power (from AUC 0.63 to AUC 0.65). Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. A combination of biomarkers might maximize the predictive precision for patient stratification. Our study supports TMB evaluation through targeted NGS in NSCLC patient samples as a tool to predict response to ICI therapy. We offer recommendations for a reliable and cost-effective assessment of TMB in a routine diagnostic setting. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Occupational risk of tuberculosis among health care workers at the Institute for Pulmonary Diseases of Serbia.

SETTING: The Institute for Pulmonary Diseases of Serbia, which specialises in diagnosis and treatment of lung diseases in a region with approximately 550-600 TB admissions per year. OBJECTIVE: To assess the occupational risk of tuberculosis (TB) among health care workers (HCWs) employed at this institution. DESIGN: Retrospective analysis of morbidity of TB among HCWs over a 12-year period (1986-1997). The incidence of TB among HCWs was estimated by the frequency of bacteriologically or histologically confirmed active disease. All HCWs at our institution underwent routine pre-employment screening, consisting of verification of BCG vaccination, PPD tuberculin reactivity, chest X-ray and laboratory evaluation. RESULTS: Of an average 267 employed HCWs, pulmonary TB occurred in nine (six nurses and three laboratory technicians). Cumulative incidence for HCWs was 3451/100,000, compared to 454/100,000 in the general population, for an incidence rate ratio of 7.6. CONCLUSION: The risk of TB among HCWs employed at the Institute for Pulmonary Diseases of Serbia in Belgrade is 7.6 times higher than that observed in the general population, suggesting occupational acquisition of TB.     

Responses of thenar muscles to transcranial magnetic stimulation of the motor cortex in patients with incomplete spinal cord injury

OBJECTIVE—Toinvestigate changes in electromyographic (EMG) responses totranscranial magnetic stimulation (TMS) of the motor cortex afterincomplete spinal cord injury in humans.
METHODS—A group of 10 patients with incomplete spinal cord injury (motor level C3-C8) wascompared with a group of 10 healthy control subjects. Surface EMGrecordings were made from the thenar muscles. TMS was applied with a 9 cm circular stimulating coil centred over the vertex. The EMG responsesto up to 50 magnetic stimuli were rectified and averaged.
RESULTS—Thresholds forcompound motor evoked potentials (cMEPs) and suppression of voluntarycontraction (SVC) elicited by TMS were higher (p<0.05) in the patientgroup. Latency of cMEPs was longer (p<0.05) in the patient group inboth relaxed (controls 21.3 (SEM 0.5) ms; patients 27.7 (SEM 1.3) ms)and voluntarily contracted (controls 19.8 (SEM 0.5) ms; patients 27.6 (SEM 1.3) ms) muscles. The latency of SVCwas longer (p<0.05) in the patients (51.8 (SEM 1.8) ms) than in the controls (33.4 (SEM 1.9) ms). The latency difference(SVC−cMEP) was longer in the patients (25.3 (SEM 2.4) ms) than in the controls (13.4 (SEM 1.6) ms).
CONCLUSION—The longerlatency difference between cMEPs and SVC in the patients may reflect aweak or absent early component of cortical inhibition. Such a changemay contribute to the restoration of useful motor function afterincomplete spinal cord injury.