History of NSAID Use in the Treatment of Headaches Pre and Post-industrial Revolution in the United States: the Rise and Fall of Antipyrine, Salicylic Acid, and Acetanilide

Abstract

Purpose of Review

Non-steroid anti-inflammatory drugs (NSAIDs) constitute a vital class of medications in today's headache regimen. However, up until the nineteenth century, they were largely unknown to most of the medical community. The purpose of this review is to explore the evolution of NSAIDs in the treatment of headaches spurred on by the Industrial Revolution in the USA.

Recent Findings

The currently available data on the impact of NSAIDs reflects their significant contribution to headache treatment.

Summary

The emergence of mass production spurred on by the Industrial Revolution, lead to widespread use of antipyrine, salicylic acid, and acetanilide. However, along with it came the growing awareness of consumer safety, leading to their ultimate downfall, and the subsequent birth of the Food and Drug Act.

http://bit.ly/2FRceHO

Unknown primary (CUP) of the head and neck : No advantages of bilateral radiotherapy, the strategy of ipsilateral radiotherapy can be recommended for the adjuvant treatment

Bilateral vs ipsilateral adjuvant radiotherapy in patients with cancer of unknown primary of the head and neck: An analysis of the clinical outcome and radiation‐induced side effects

Nguyen‐Son Le  Stefan Janik MD, PhD  Helmut Simmel MD  Boban M. Erovic MD, PD, MBA

First published: 19 January 2019 https://doi.org/10.1002/hed.25637

This work was presented at the 61st Annual Meeting of the Austrian Society of Oto‐Rhino‐Laryngology – Head and Neck Surgery, Vienna, Austria

Abstract

Background

The purpose of this study was to analyze and compare ipsilateral and bilateral adjuvant radiotherapy in patients with cancer of unknown primary (CUP) of the head and neck.

Methods

Overall survival, recurrence‐free survival, and radiation‐induced side effects were assessed in 76 patients with CUP who underwent ipsilateral (n = 29) or bilateral (n = 47) radiotherapy.

Results

At a median follow‐up of 41 months, the 5‐year overall survival and recurrence‐free rate were 67.9% and 71.5%, respectively. No statistically significant difference between ipsilateral and bilateral radiotherapy could be found regarding 5‐year overall survival, recurrence‐free survival, occurrence of a primary tumor, and distant metastasis. The analysis of radiation‐induced acute side effects showed a significant benefit of ipsilateral radiotherapy.

Conclusion

As the main parameters of the study regarding the outcome and radiation‐induced side effects showed no advantages of bilateral radiotherapy, the strategy of ipsilateral radiotherapy can be recommended for the adjuvant treatment of CUP patients.

Acanthosis Nigricans & Metabolic Syndrome : Metabolic syndrome refers to a clustering of metabolic risk factors including central obesity, glucose intolerance, hyperinsulinemia, low HDL cholesterol, high triglycerides and hypertension. High prevalence of Acanthosis Nigricans (AN) in subjects with metabolic syndrome. Also there was a positive correlation between severity of Acanthosis Nigricans (AN) and Metabolic syndrome.

Acanthosis nigricans: A cutaneous marker for metabolic syndrome p. 16

Nirali Girish Shah, Swapna S Khatu, Neeta R Gokhale, Yuvraj E More, Deepak Khismatrao

DOI:10.4103/mjdrdypu.mjdrdypu_44_18  

Background: Acanthosis Nigricans (AN) is an easily identifiable dermatoses characterized by thickened, hyperpigmented plaques. Metabolic syndrome refers to a clustering of metabolic risk factors including central obesity, glucose intolerance, hyperinsulinemia, low HDL cholesterol, high triglycerides and hypertension. AN is a skin marker associated with this syndrome. Aims and Objectives: This study aimed to determine the relationship between AN and metabolic syndrome by studying its clinico-epidemiological features and also the relation of severity of AN over neck with metabolic syndrome. Methodology: This is a case-control study. One hundred consecutive patients of AN attending dermatology OPD of a tertiary care hospital were included in this study. They were evaluated for AN and severity of AN over neck was assessed. Age and sex matched 100 controls were included in the study. Epidemiological, clinical and anthropometric characteristics (height, weight, waist circumference) were measured of all the cases and controls. Body Mass Index (BMI) was calculated. Fasting Blood Sugar, High Density Lipoprotein and Serum Triglyceride levels were estimated. Result: The average age of the patients was 32.4 years and females (62%) were more than the males (38%). Neck was involved in all the patients. There was statistically significant correlation of increasing severity of AN with each component of Metabolic syndrome. On comparing between cases and controls, each component of metabolic syndrome was raised in cases as compared to the controls. 70% cases had Metabolic syndrome which was statistically significant. Conclusion: There was a high prevalence of AN in subjects with metabolic syndrome. Also there was a positive correlation between severity of AN and Metabolic syndrome.

Salvage surgery for advanced stage head and neck squamous cell carcinoma following radiotherapy or chemoradiation

Abstract

Purpose

Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma (HNSCC) is known to result in poor prognosis. As there are only small and heterogeneous studies available with wide variety in outcome measures, our purpose was to select and pool literature according to specific criteria.

Methods

Systematic review and meta-analysis of clinical outcome after salvage surgery for recurrent advanced stage HNSCC following primary radiotherapy or chemoradiation.

Results

16 of 3956 screened studies were included for analysis (729 patients). Pooled 5-year OS was 37% (95% CI 30–45%, 12 studies, 17 outcome measurements, 540 patients). Outcome was presented for larynx (6 studies, 397 patients), hypopharynx (2 studies, 47 patients), larynx and hypopharynx combined (3 studies, 69 patients) or separately (1 study, 134 patients), oral cavity (1 study, 11 patients), oropharynx (1 study, 34 patients) and multiple subsites combined (2 studies, 37 patients). There was no significant difference in survival outcome between subsites (p_{heterogeneity} = 0.8116). The pooled tumor-positive resection margin rate was 32% and pooled re-operation rate 17%. Complication rates from the pooled data were: fistulas 33%, wound infections 24% and flap failure 3%. Treatment-related mortality rate was 1% and mean hospital stay was 23 days.

Conclusions

Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma after primary (chemo)radiotherapy is a good last resort curative treatment option, resulting in 37% overall survival at 5 years. As data from advanced stage non-laryngeal tumors were sparse, no solid conclusions can be drawn with regard to outcome differences between tumor subsites.

http://bit.ly/2DtmwMw

Neuropsychiatric symptoms following sore throat in a young boy

A previously healthy 6-year-old boy was referred to us by his primary provider, with a history of sudden onset behavioural abnormalities including irritability, sleep disturbance and anxiety. Physical examination revealed no significant findings; further analyses were not suggestive of meningitis, encephalitis, metabolic abnormalities, toxicity or any other obvious cause. On rechecking the patient's history, an episode of throat pain 1 week prior to the symptom onset was noted. Therefore, the possibility of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) was considered. The antistreptolysin O titre was high (1078 IU/mL), and it increased to 1194 IU/mL 4 weeks later, leading to a diagnosis of PANDAS. He was started on ampicillin and administered one dose of intravenous immunoglobulin. His abnormal behaviours subsided and he returned to a normal state within 48 hours of treatment. This report aims to provide insights into the symptomology and diagnosis of PANDAS in children.

http://bit.ly/2Mrfs6i

Urachal Mucinous Cystadenocarcinoma

A 57-year-old man presented with a 6-month history of pelvic fullness. He had no lower urinary tract symptoms or altered bowel habits. On examination, there was a non-tender pelvic mass which extended from the pubic symphysis to the level of the umbilicus. CT scan of the abdomen demonstrated a 22x11x11 cm cystic mass arising from the pelvis extending into the midline and superiorly to the umbilicus. Other than raised carcinoembryonic antigen of 7.6 ng/mL (<5.0), the remainder of his blood test were unremarkable. Flexible cystoscopy demonstrated a convex deformity of the bladder wall in keeping with the compression and displacement as seen on the CT. The patient underwent an open excision of the cystic structure (urachal remnant), partial cystectomy, partial excision of anterior abdominal wall and pelvic lymphadenectomy. A check cystogram performed 12 days following the initial operation was unremarkable.

http://bit.ly/2sIp5US

Correction: Exclusively plant, whole-food diet for polypharmacy due to persistent atrial fibrillation, ischaemic cardiomyopathy, hyperlipidaemia and hypertension in an octogenarian

http://bit.ly/2MsddiX

Rare cutaneous myiasis of the face due to Lunds fly (Cordylobia rodhaini) in a British traveller returning from Uganda

We present a rare cause for cutaneous furuncular myiasis in a 55-year-old British traveller returning from Uganda. Initially presenting with what appeared to be a cellulitic furuncle on her forehead, she returned to the emergency department 3 days later with extensive preseptal periorbital swelling and pain. Occlusive treatment with petroleum jelly was applied and one larva manually extracted and sent to London School of Tropical Medicine for examination. It was identified as Lund's Fly (Cordylobia rodhaini), a rare species from the rainforests of Africa with only one other case reported in the UK since 2015. Ultrasound imaging identified another larva, necessitating surgical exploration and cleaning. The lesion subsequently healed completely and the patient remains well.

http://bit.ly/2sGT27V

Phenytoin-induced hypothermia

A 60-year-old man with cerebral palsy and epilepsy was admitted with acute lethargy and deterioration in coordination. He was noted to be hypothermic at 35°C on admission. Routine work-up revealed toxic levels of phenytoin. No cause of hypothermia could be identified but as his phenytoin levels normalised, his body temperature also improved. There are three other reported cases of phenytoin- induced hypothermia in the literature. Could this be a rare cause of hypothermia?

http://bit.ly/2MqZZmB

Anaphylaxis to patent blue dye in a 17-year-old boy

Patent blue V dye (PBV) is frequently used as a perioperative drug for lymphangiography, as well as a food additive. Hypersensitivity to PBV is poorly documented in adults and had not been previously described in children. The diagnosis of PBV allergy depends on corroboration of history consistent with an IgE-mediated reaction and confirmatory skin tests. We present in this paper a paediatric case of PBV anaphylaxis and of biphasic reaction that exemplifies the challenges involved in diagnosing and managing this rare but potentially life-threatening allergic reaction.

http://bit.ly/2sJ5DYk

Floating fetus: a rare complication of balloon tamponade treatment of caesarean scar ectopic pregnancy

http://bit.ly/2MqZWap

Spontaneous subcapsular haematoma: a rare cause of acute kidney graft dysfunction

http://bit.ly/2sF7yx3

Chylothorax in a patient with HIV-related Kaposis sarcoma

We present a case of a 33-year-old man with a background of HIV and Kaposi's sarcoma (KS), who presented with a right sided chylothorax. He was managed with percutaneous chest drainage and talc pleurodesis, in addition to his chemotherapy and antiretroviral therapy for KS and HIV, respectively. Good clinical control of the chylothorax remained 4 months post drainage. This case report summarises the approach to investigating and managing pleural effusion, and in particular chylothorax, in HIV patients.

http://bit.ly/2MqZUPP

Spontaneous spinal subdural haematoma in a patient on apixaban

A 68-year-old man on apixaban presented to the emergency department with back pain following a long-haul flight. Investigations for pulmonary embolus and aortic dissection were negative and he was discharged with analgesia for mechanical back pain. He presented three more times with worsening back pain, third time with urinary retention and the fourth time with lower limb weakness and loss of coordination. He was found to have a spinal subdural haematoma on MRI and transferred to a tertiary centre, where he was managed conservatively and discharged for rehabilitation with good neurological recovery.

http://bit.ly/2sEOn6m

Rectal adenocarcinoma presenting with thigh muscle metastasis as the only metastatic site

Rectal carcinoma with metastasis to skeletal muscle is a rare finding. According to literature review, 17 cases of skeletal muscle metastasis from colorectal carcinoma have been documented where only six cases were rectal carcinomas.

We discuss a case of a middle-aged man with a known history of high-grade mucinous adenocarcinoma of the rectum, status post abdominoperineal resection followed by adjuvant radiotherapy and chemotherapy. During the planned chemotherapy course, a right proximal thigh subcutaneous mass was incidentally found which on subsequent biopsy proved to be metastatic from rectal primary site. On subsequent 18F-FDG (Fluorodeoxyglucose) positron emission tomography (PET)/CT scan after completion of chemotherapy for the purpose of treatment response evaluation, only FDG-avid lesion was residual right proximal thigh metastatic mass without involvement of other common sites, such as liver and lung. In this case, the 18F-FDG-PET/CT scan was able to exclude additional metastatic sites and also evaluate the patient's treatment response.

http://bit.ly/2MoWvRv

Radiation induced valvular disease: the internists prospective

Radiation-induced cardiac injury entails a wide spectrum of cardiovascular complications such as cardiomyopathy and valvular diseases among others. We present the internist's perspective and the challenges faced in managing these patients. There are guidelines addressing radiation-induced valvular disease (RIVD) including screening and treatment, but are often unrecognised by most internist's practice. A thorough cardiovascular examination and screening echocardiography may detect RIVD at an earlier stage. Early screening with transthoracic echocardiogram should be considered in asymptomatic or low-risk patients and more frequently in symptomatic and high-risk patients. The internists should educate their patients with prior chest irradiation, regarding the possible radiation related adverse cardiovascular effects and recommended screening. Lifestyle changes and aggressive cardiovascular risk modification should be emphasised, as concomitant hypertension, coronary artery disease and cardiomyopathy can have unfavourable effects in these patients.

http://bit.ly/2sI7CMh

Sacral schwannoma with intraosseous extension

http://bit.ly/2MplKDm

Rare case report of idiopathic gingival fibromatosis in childhood and its management

Idiopathic gingival fibromatosis (GF), also known as gingivomatosis, is a rare condition in childhood, with an unknown aetiology. The oral manifestations of the condition are varied and depend on the severity and age of involvement. This paper describe the case of a 5-year-old male child with extensive gingival enlargement covering almost all the maxillary and mandibular teeth resulted in difficulty with speech, mastication and poor aesthetics. Clinical and radiographic examination along with haematological investigations ruled out any systemic association. The case was managed with conventional scalpel blade surgery along with electrocautery under general anaesthesia yielding good results without any recurrence after a 12-month follow-up. The results revealed that the oral manifestations of GF depend on its severity and the age of onset. Timely intervention can help to prevent associated complications in a growing child.

http://bit.ly/2sGvvUs

Primary isolated hepatosplenic sarcoidosis mimicking malignancy and causing symptomatic hypercalcaemia

This is a case of a 67-year-old woman, known to have multiple medical problems, mainly papillary thyroid cancer status post-total thyroidectomy and cervical neck dissection in addition to radioactive iodine currently in remission for 1 year, who presented to the hospital with severe weakness and fatigue. The initial workup showed significant hypercalcaemia and suppressed Parathyroid hormone (PTH). The patient was treated with hydration and pamidronate and her hypercalcaemia and symptoms improved. The differential was wide, however, a CT scan of the chest, abdomen and pelvis did show multiple liver and splenic nodular lesions; therefore, malignancy was the highest possible diagnosis. Biopsy of the splenic lesion confirmed the diagnosis of sarcoidosis. Therefore, the patient was diagnosed with primary isolated nodular hepatosplenic sarcoidosis mimicking malignancy and causing significant symptomatic hypercalcaemia.

http://bit.ly/2MpZyZI

Low prevalence of Gram-positive isolates showing elevated lefamulin MIC results during the surveillance program for 2015-2016 and characterization of resistance mechanisms [Mechanisms of Resistance]

This study investigated the molecular mechanisms possibly associated with non-wildtype MICs for lefamulin among staphylococci and streptococci included in the lefamulin surveillance program for 2015-2016. A total of 2,919 Staphylococcus aureus, 276 coagulase-negative staphylococci (CoNS), 3,923 Streptococcus pneumoniae, 389 ß-hemolytic and 178 viridans group streptococci were included in the surveillance studies. Eleven (0.3% of all S. aureus) S. aureus with lefamulin MICs above the staphylococcal epidemiological cut-off (ECOFF) value (>0.25 μg/mL) were selected for this study. Eight (72.7%) S. aureus (lefamulin MIC, 0.5-4 μg/mL) carried vga(A or E), one isolate (MIC, 32 μg/mL) carried lsa(E), one isolate (MIC, 16 μg/mL) had an alteration in L4, and one strain (MIC, 0.5 μg/mL) did not carry any of the investigated resistance mechanisms. A total of 14 (5.1% of all CoNS) CoNS had lefamulin MICs (0.5 to >32 μg/mL) above ECOFF. Similar to S. aureus, 8 (57.1%) CoNS (lefamulin MIC, 1-8 μg/mL) carried vga(A or B), while 2 isolates (MIC, 4-32 μg/mL) carried cfr. High genetic diversity was observed among staphylococci, although 3 S. aureus belonged to ST398. Among 3 S. agalactiae and 3 viridans group streptococci (0.1% of all streptococci surveyed) selected for additional characterization, and all but 1 isolate carried lsa(E). This study documents a low occurrence of surveillance isolates exhibiting a non-wildtype MIC for lefamulin, and among these isolates, vga and lsa(E) prevailed in staphylococci and streptococci, respectively.

http://bit.ly/2R7i2Pf

Efficacy of Human-simulated Epithelial Lining Fluid Exposure of Meropenem-Nacubactam Combination against Class A Serine {beta}-lactamase-producing Enterobacteriaceae in the Neutropenic Murine Lung Infection Model [Experimental Therapeutics]

Nacubactam is a novel broad spectrum β-lactamase inhibitor that is currently under development as combination therapy with meropenem. This study evaluated the efficacy of human-simulated epithelial lining fluid (ELF) exposures of meropenem, nacubactam, and the combination meropenem-nacubactam against class A serine carbapenemase-producing Enterobacteriaceae isolates in the neutropenic murine lung infection model. Twelve clinical meropenem-resistant Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae isolates all harboring KPC or IMI-type β-lactamases were utilized in the study. Meropenem, nacubactam, and the combination meropenem-nacubactam (1:1) MICs were determined in triplicate via broth microdilution. At 2hr after intranasal inoculation, neutropenic mice were dosed with regimens that provided ELF profiles mimicking those observed in humans given meropenem 2g q8hr and nacubactam 2g q8hr (1.5hr infusions) alone or in combination. Efficacy was assessed as the change in log₁₀CFU/lung at 24hr compared with 0hr controls. Meropenem, nacubactam, and meropenem-nacubactam MICs were 8 – >64, 2 - >256 and 0.5 – 4 μg/mL, respectively. The average log₁₀CFU/lung at 0hr across all isolates was 6.31 ± 0.26. Relative to 0hr control, the mean bacterial growth at 24hr in the untreated control mice, meropenem human-simulated regimen (HSR), and nacubactam HSR treatment groups were 2.91 ± 0.27, 2.68 ± 0.42, and 1.73 ± 0.75 log₁₀CFU/lung, respectively. Meropenem-nacubactam combination HSR resulted in -1.50 ± 0.59 log₁₀CFU/lung reduction. Meropenem-nacubactam human-simulated ELF exposure produced enhanced efficacy against all class A serine carbapenemase-producing Enterobacteriaceae isolates tested in the neutropenic murine lung infection model.

http://bit.ly/2W81I4R

Antibacterial Activity of Lefamulin Against Pathogens Most Commonly Causing Community-Acquired Bacterial Pneumonia: SENTRY Antimicrobial Surveillance Program (2015-2016) [Susceptibility]

Lefamulin, the first semisynthetic pleuromutilin antibacterial for intravenous and oral treatment of community-acquired bacterial pneumonia (CABP), and comparators were evaluated for in vitro activity against a global collection of pathogens commonly causing CABP (n=8595) from the 2015–2016 SENTRY Antimicrobial Surveillance Program. Lefamulin was highly active against pathogens commonly Streptococcus pneumoniae including multidrug resistant and extensively drug resistant strains (MIC_50/90 for total and resistant subsets, 0.06/0.12 μg/mL; 100% inhibited at ≤1 μg/mL), Staphylococcus aureus including MRSA (both MIC_50/90, 0.06/0.12 μg/mL; 99.8% and 99.6% inhibited at ≤1 μg/mL, respectively), Haemophilus influenzae (MIC_50/90, 0.5/1 μg/mL; 93.8% inhibited at ≤1 μg/mL), and Moraxella catarrhalis (MIC_50/90, 0.06/0.12 μg/mL; 100% inhibited at ≤0.25 μg/mL), and its activity was unaffected by resistance to other antibacterial classes.

http://bit.ly/2R7hZ61

Software for Dosage Individualization of Voriconazole: a Prospective Clinical Study [Clinical Therapeutics]

Voriconazole is a first-line antifungal agent. Therapeutic drug monitoring is a standard of care. The best way to adjust dosages to achieve desired drug exposure endpoints is unclear due to nonlinear and variable pharmacokinetics. Previously described software was used to prospectively adjust voriconazole dosages. CYP2C19 and CYP3A4 and CYP3A5 genotype was determined. The primary endpoint was the proportion of patients with a Cmin at 120 hours in the range 1-3 mg/L using software to adjust voriconazole dosages. A total of 19 patients were enrolled and 14 were evaluable. Of these, 12/14 (85.7%, 95% CI 57.2 – 98.2%) had a Cmin at 120 hours post-treatment initiation of 1-3 mg/L, which was higher than the a priori expected proportion of 33%. There was no association of CYP genotype-derived metaboliser phenotype with voriconazole AUC. Software can be used to adjust the dosages of voriconazole to achieve drug exposures that are safe and effective.

http://bit.ly/2W81DOB

In vitro activity of Tedizolid against Mycobacterium tuberculosis [Susceptibility]

Tedizolid is a novel oxazolidinone with activities against Gram-positive microorganisms, including mycobacteria. We studied, the in vitro activity of Tedizolid against 120 M. tuberculosis strains, including susceptible, first-line-resistant and MDR isolates. Minimal Inhibitory Concentration (MIC) was tested using the Bactec 960 MGIT system. The MIC ₉₀ and MIC ₅₀ were 0,5 and 0.25 μg/ml respectively in both susceptible and resistant strains. Tedizolid could be an alternative in the treatment of resistant M.tuberculosis.

http://bit.ly/2RbmVXW

In vitro synergism of rifabutin with clarithromycin, imipenem and tigecycline against the Mycobacterium abscessus complex [Susceptibility]

Background

Infections caused by the difficult-to-treat Mycobacterium abscessus are increasing in frequency. Rifabutin, in contrast to rifampin, appears to be active in vitro against M. abscessus, especially against clarithromycin-resistant strains. However, exploring for potential synergy between rifabutin and available antimicrobials is currently limited.

Methods

In vitro synergism was evaluated by the checkerboard method for rifabutin and 10 antimicrobials in 31 mycobacterial strains. The fractional inhibitory concentration index (FICI) was calculated for each rifabutin-based combination. Colony morphology was recorded. Molecular subspeciation and macrolide resistance were determined by sequencing of the secA1, rpoB, hsp65, erm (41) and rrl genes.

Results

Rifabutin yielded an MIC₅₀ of 16 mg/L (range 2-32 mg/L) against 26 clinical M. abscessus isolates (comprising 13 M. abscessus subsp. abscessus and 13 M. abscessus subsp. massiliense) and 5 reference strains including M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii BCRC 16915, M. abscessus subsp. massiliense BCRC 16916, M. chelonae ATCC 35752 and M. peregrinum ATCC 700686. Significant synergism as classified by an FICI≤0.5 was demonstrated for the combinations of rifabutin and imipenem in 100% of M. abscessus subsp. abscessus vs. 69% of M. abscessus subsp. massiliense isolates, and for rifabutin and tigecycline in 77% of M. abscessus subsp. abscessus vs. 69% of M. abscessus subsp. massiliense isolates. Among the 6 clarithromycin resistant (MIC ≥8 mg/L) M. abscessus subsp. abscessus isolates, the combination of rifabutin and clarithromycin was 100% synergistic.

Conclusions

Rifabutin showed promising in vitro synergism with first-line anti-M. abscessus agents, especially for macrolide-resistant M. abscessus subsp. abscessus.

http://bit.ly/2Wbtsp9

Novel Polymyxin Combination with Antiretroviral Zidovudine Exerts Synergistic Killing against NDM-producing MDR Klebsiella pneumoniae [Pharmacology]

Polymyxins are used as a last-line therapy against multidrug-resistant (MDR) New Delhi metallo-β-lactamase (NDM) producing Klebsiella pneumoniae. However, polymyxin resistance can emerge with monotherapy; therefore, novel strategies are urgently needed to minimize the resistance and maintain their clinical utility. This study aimed to investigate the pharmacodynamics of polymyxin B in combination with the antiretroviral drug zidovudine against K. pneumoniae. Three isolates were evaluated in static time-kill studies (0 – 64 mg/L) over 48 h. A one-compartment in vitro pharmacokinetic/pharmacodynamic (PK/PD) model (IVM) was used to simulate humanized dosage regimens of polymyxin B (4 mg/L as continuous infusion) and zidovudine (as bolus dose thrice daily to achieve C_max = 6 mg/L) against K. pneumoniae BM1 over 72 h. The antimicrobial synergy of the combination was further evaluated in a murine thigh infection model against K. pneumoniae 02. In the static time-kill studies, polymyxin B monotherapy produced rapid and extensive killing against all three isolates followed by extensive regrowth, whereas zidovudine produced modest killing followed by significant regrowth at 24 h. Polymyxin B in combination with zidovudine significantly enhanced the antimicrobial activity (≥ 4 log₁₀CFU/mL) and minimized bacterial regrowth. In the IVM, the combination was synergistic and the total bacterial loads were below the limit of detection for up to 72 h. In the murine thigh infection model, the bacterial burden at 24 h in the combination group was ≥ 3 log₁₀CFU/thigh lower compared to each monotherapy against K. pneumoniae 02. Overall, polymyxin B-zidovudine combination demonstrates superior antimicrobial efficacy and minimized emergence of resistance to polymyxins.

http://bit.ly/2R3PUNf

The Anti-Staphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood to Potentiate MRSA Bacteriolysis [Experimental Therapeutics]

Bacteriophage-derived lysins are cell wall hydrolytic enzymes which represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and infective endocarditis (IE) when used in addition to antibiotics. In order to profile CF-301's activity in a clinically relevant milieu, we assessed its in vitro activity in human blood vs. in a conventional testing medium (cation-adjusted Mueller Hinton Broth [caMHB]). CF-301 exhibited substantially greater potency (32-≥100-fold) in human blood vs. caMHB in three standard microbiologic testing formats (e.g. broth dilution MICs, checkerboard synergy and time-kill assays). We demonstrated that CF-301 acted synergistically with two key human blood factors, human serum lysozyme (HuLYZ) and albumin (HSA), which normally have no nascent antistaphylococcal activity, against a prototypic MRSA strain (MW2). Similar in vitro enhancement of CF-301 activity was also observed in rabbit, horse and dog (but not rat or mouse) blood. Two well-established MRSA IE models in rabbit and rat were used to validate these findings in vivo by demonstrating comparable synergistic efficacy with standard-of-care anti-MRSA antibiotics, at > 100-fold lower lysin doses in the rabbit vs the rat model. The unique properties of CF-301 which enable bactericidal potentiation of antimicrobial activity via activation of 'latent' host factors in human blood may have important therapeutic implications for the durable improvements in clinical outcomes of serious, antibiotic-resistant staphylococcal infections.

http://bit.ly/2W81sCV

Dose Selection and Validation for Ceftazidime-Avibactam in Adults with Complicated Intra-Abdominal Infections, Complicated Urinary Tract Infections and Nosocomial Pneumonia [Minireviews]

Avibactam is a non-β-lactam β-lactamase inhibitor that has been approved in combination with ceftazidime for the treatment of complicated intra-abdominal infections, complicated urinary tract infections and nosocomial pneumonia, including ventilator-associated pneumonia. In Europe, ceftazidime-avibactam is also approved for the treatment of Gram-negative infections with limited treatment options. Selection and validation of the ceftazidime-avibactam dosage regimen was guided by an iterative process of population pharmacokinetic (PK) modelling, whereby population PK models for ceftazidime and avibactam were developed using PK data from clinical trials and updated periodically. These models were used in probability of target attainment (PTA) simulations using joint pharmacodynamic (PD) targets for ceftazidime and avibactam derived from preclinical data. Joint PTA was calculated based on the simultaneous achievement of the individual PK/PD targets (50% free time above the ceftazidime-avibactam minimum inhibitory concentration (MIC) for ceftazidime and free time above a critical avibactam threshold concentration of 1 mg/l for avibactam). The joint PTA analyses supported a ceftazidime-avibactam dosage regimen of 2,000 + 500 mg every 8 h by 2-h intravenous infusion for patients with creatinine clearance (CrCL) >50 ml/min across all approved indications and modified dosage regimens for patients with CrCL ≤50 ml/min. Subgroup simulations for individual Phase III patients showed that the dosage regimen was robust, with high target attainment (>95%) against MICs ≤8 mg/l achieved regardless of older age, obesity, augmented renal clearance or severity of infection. This review summarizes how the approved ceftazidime-avibactam dosage regimens were developed and validated using PK/PD targets, population PK modeling, and PTA analyses.

http://bit.ly/2R5ERmz

Molecular Epidemiology of Emerging Carbapenem Resistance in Acinetobacter nosocomialis and Acinetobacter pittii in Taiwan, 2010-2014 [Epidemiology and Surveillance]

This study investigated the molecular epidemiology of carbapenem-resistant Acinetobacter nosocomialis and Acinetobacter pittii (ANAP). Clinical isolates of Acinetobacter spp. collected by the biennial nationwide Taiwan Surveillance of Antimicrobial Resistance program from 2010-2014 were subjected to species identification, antimicrobial susceptibility testing, and PCR for detection of carbapenemase genes. Whole genome sequencing or PCR mapping was performed to study the genetic surroundings of the carbapenemase genes. Among 1041 Acinetobacter isolates, the proportion of ANAP increased from 11% in 2010 to 22% in 2014. The rate of carbapenem resistance in these isolates increased from 7.5% (3/40) to 22% (14/64), with a concomitant increase in their resistance to other antibiotics. The bla_OXA-72 and bla_OXA-58 genes were highly prevalent in carbapenem-resistant ANAP. Various genetic structures were found upstream of bla_OXA-58 in different plasmids. Among the plasmids found to contain bla_OXA-72 flanked by XerC/XerD, pAB-NCGM253-like was identified in 8 of 10 isolates. Conjugations of plasmids carrying bla_OXA-72 or bla_OXA-58 to A. baumannii were successful. In addition, three isolates with chromosome-located bla_OXA-23 embedded in AbGRI1-type structure with disruption of genes other than comM were detected. Two highly similar plasmids carrying class I integron containing bla_IMP-1 and aminoglycoside resistance genes were also found. The universal presence of bla_{OXA-272/213-like} on A. pittii chromosomes and their lack of contribution to carbapenem resistance indicate its potential to be a marker for species identification. The increase of ANAP along with their diverse mechanisms of carbapenem resistance may herald their further spread and warrants close monitoring.

http://bit.ly/2Waa5fY

The Efficacy of Intranasal Administration of the Recombinant Endolysin, SAL200, in a Lethal Murine Staphylococcus aureus Pneumonia Model [Experimental Therapeutics]

SAL200 is derived from a phage endolysin and is a novel candidate drug for the treatment of Staphylococcus aureus infection. We investigated the efficacy of the recombinant endolysin SAL200 in a lethal murine pneumonia model. Lethal pneumonia was established by intranasally administering a methicillin-susceptible (Newman) or methicillin-resistant (LAC) S. aureus strain into BALB/c mice. The mice were treated with single intranasal administration of SAL200 or phosphate-buffered saline at 2 h after S. aureus infection. The survival rates were recorded until 60 h after the bacterial challenge. The bacterial loads in the lungs and blood, histopathology of lung tissues, and serum cytokine levels were evaluated following the S. aureus challenge. The SAL200-treated group and control group exhibited 90-95% and 10-40% survival rates, respectively. The bacterial loads in the lungs of the SAL200-treated group were significantly lower by ~10-fold than those of the control group as early as 1 h after treatment. Histopathologic recovery of pneumonia was observed in the SAL200-treated mice. The cytokine levels were comparable between groups. These results suggest that direct administration of SAL200 into the lungs could be a potential adjunct treatment against severe pneumonia caused by S. aureus.

http://bit.ly/2R8Yha4

A Novel {beta}-lactam Enhancer Zidebactam Augments the In vivo Pharmacodynamic Activity of Cefepime in Neutropenic Mouse Lung A. baumannii Infection Model [Mechanisms of Action]

WCK 5222 is a combination of cefepime and high-affinity PBP2-binding β-lactam enhancer, zidebactam. The cefepime-zidebactam combination is active against multi-drug resistant Gram-negatives including carbapenemases- expressing Acinetobacter baumannii. The mechanism of action of the combination involves concurrent multiple penicillin binding protein inhibition leading to enhanced bactericidal action of cefepime. The aim of the present study was to assess the impact of zidebactam-mediated enhanced in vitro bactericidal action in modulating the cefepime's %fT>MIC required for in vivo killing of A. baumannii. Cefepime and cefepime-zidebactam MICs were comparable and ranged between 2 to 16 mg/L for A. baumannii strains (n = 5) employed in the study. Against these strains, the time-kill studies revealed an improved killing with the cefepime-zidebactam combination as compared to standalone constituents. Employing neutropenic mouse lung infection model, exposure-response analyses for all the A. baumannii showed that cefepime fT>MIC required for 1 log₁₀ kill was 38.9%. In the presence of non-effective dose of zidebactam, cefepime fT>MIC dropped significantly to the extent of 15.5%, still rendering comparable bactericidal effect. Thus, zidebactam mediated improvement in cefepime's bactericidal effect observed in time-kill studies manifested in vivo through lowering of cefepime's pharmacodynamic requirement. This is a first ever study demonstrating β-lactam enhancer role of zidebactam that helps augment in vivo activity of cefepime by reducing the magnitude of its pharmacodynamically relevant exposures against A. baumannii.

http://bit.ly/2W81eM5

Synergistic antifungal effect of amphotericin B-loaded PLGA nanoparticle with ultrasound against C. albicans biofilms [Experimental Therapeutics]

C. albicans is a human opportunistic pathogen that causes superficial and life-threatening infections. An important reason for the failure of current antifungal drugs is related to biofilm formation, mostly associated with implanted medical devices. The present study investigated the synergistic antifungal efficacy of low-frequency and low-intensity ultrasound combined with amphotericin B-loaded PLGA nanoparticles (AmB-NPs) on C. albicans biofilms. AmB-NPs were prepared by a double emulsion method and demonstrated lower toxicity than free AmB. We then established biofilms and treated them with ultrasound and AmB-NPs separately or jointly in vitro and in vivo. The results demonstrated that the activity, biomass, and proteinase and phospholipase activities of biofilms were decreased significantly after the combination treatment of AmB-NPs with 42 KHz ultrasound irradiation at an intensity of 0.30 W/cm² for 15 min compared with the controls, with AmB alone, or with ultrasound treatment alone (P < 0.01). The morphology of the biofilms was altered remarkably after joint treatment based on confocal laser scanning microscopy (CLSM), especially in regard to reduced thickness and loosened structure. Furthermore, the same synergistic effects were found in a subcutaneous catheter biofilm rat model. The number of colony forming units from the catheter exhibited a significant reduction after AmB-NPs and ultrasound joint treatment for 7 continuous days, and CLSM and scanning electron microscopy (SEM) images revealed that the biofilm on the catheter surface was substantially eliminated. This method may provide a new noninvasive, safe, and effective therapy for C. albicans biofilm infection.

http://bit.ly/2R43MXK

DS86760016, a leucyl-tRNA synthetase inhibitor, with activity against Pseudomonas aeruginosa [Experimental Therapeutics]

DS86760016 is a new leucyl-tRNA-synthetase inhibitor in the preclinical development stage. DS86760016 showed potent activity against extended spectrum multidrug-resistant Pseudomonas aeruginosa isolated from clinical samples and in-vitro biofilms. In a murine catheter associated urinary tract infection model, DS86760016 treatment resulted in significant eradication of P. aeruginosa counts from kidney, bladder and catheter without developing drug-resistance. Our data suggest that DS86760016 has the potential to act as a new drug for the treatment of Pseudomonas infections.

http://bit.ly/2W81avP

Arylacetamide deacetylase (AADAC) gene polymorphism and HIV infection affect the exposure of Rifapentine: a population pharmacokinetics analysis. [Experimental Therapeutics]

Rifapentine is a rifamycin used to treat tuberculosis. As for rifampicin, plasma exposures of rifapentine are associated with treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, PXR, CAR, and AADAC on rifapentine exposure. Two studies evaluating novel regimens amongst Southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In RIFAQUIN, rifapentine was administered in the continuation phase of antituberculosis treatment in 1200mg once-weekly or 900mg twice-weekly doses. In Daily-RPE 450 or 600mg were given daily during the intensive-phase of treatment. Nonlinear mixed-effects modelling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1144 drug-concentration measurements, from 326 patients, were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight of 56kg, fat-free-mass of 45kg), the values of clearance and volume of distribution were 1.33L/h and 25L, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have 10.4% lower clearance. HIV+ infected patients had 21.9% lower bioavailability. Once weekly doses of 1200 mg were associated reduced clearance (-13.2%), compared to more frequently administered doses. Bioavailability was 23.3% lower amongst patients participating in the Daily-RPE study compared to RIFAQUIN. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the different food concomitant to the dose. HIV coinfected patients had lower rifapentine exposures.

http://bit.ly/2R4pBWZ

Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies [Pharmacology]

Plazomicin is an aminoglycoside with activity against multidrug-resistant Enterobacteriaceae. Plazomicin is dosed on a mg/kg basis and administered by 30-min intravenous infusion every 24 h, with dose adjustments for renal impairment and body weight (BW) ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1–3). A three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration–time profiles. The base structural model included creatinine clearance (CL_CR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The range of α-, β-, and -phase half-lives for the analysis population are 0.328–1.58, 2.77–5.38, and 25.8–36.5 h, respectively. Total and renal clearance in a typical cUTI or HABP/VABP patient are 4.57 and 4.08 l/h, respectively. Starting dose adjustments for CL_CR are sufficient for minimizing variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a mg/kg basis with adjustments for CL_CR and BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renal impaired.

http://bit.ly/2WbsY2j

Various evolutionary trajectories lead to loss of the tobramycin-potentiating activity of the quorum sensing inhibitor baicalin hydrate in Burkholderia cenocepacia biofilms [Mechanisms of Resistance]

Combining antibiotics with potentiators that increase their activity is a promising strategy to tackle infections caused by antibiotic-resistant bacteria. As potentiators do not interfere with essential processes, it has been hypothesized that they are less likely to induce resistance. However, evidence supporting this hypothesis is lacking. In the present study, we investigated whether Burkholderia cenocepacia J2315 biofilms develop reduced susceptibility towards one such adjuvant, baicalin hydrate (BH). Biofilms were repeatedly and intermittently treated with tobramycin (TOB) alone or in combination with BH for 24 h. After treatment, the remaining cells were quantified using plate counting. After 15 cycles, biofilm cells were less susceptible to TOB and TOB+BH, compared to the start population, and the potentiating effect of BH towards TOB was lost. WGS was performed to probe which changes were involved in the reduced effect of BH and mutations in 14 protein-coding genes were identified (including mutations in genes involved in central metabolism and in BCAL0296, encoding an ABC transporter). No changes in the MIC or MBC of TOB or changes in the number of persister cells were observed. However, basal intracellular levels of reactive oxygen species (ROS) and ROS levels found after treatment with TOB were markedly decreased in the evolved populations. In addition, in evolved cultures with mutations in BCAL0296, a significantly reduced uptake of TOB was observed. Our results indicate that B. cenocepacia J2315 biofilms rapidly loose susceptibility towards the antibiotic-potentiating activity of BH and point to changes in central metabolism, reduced ROS production, and reduced TOB uptake as mechanisms.

http://bit.ly/2R4pxGJ

CMCdG, a novel nucleoside analog, exerts potent activity against wild-type and entecavir-resistant HBV with favorable safety feature [Antiviral Agents]

We designed, synthesized, and characterized a novel nucleoside analog, (1S,3S,5S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-hydroxy-1-(hydroxyl-methyl)-2-methylenecyclopentanecarbonitrile or 4'-cyano-methylenecarbocyclic-2'-deoxyguanosine (CMCdG) and evaluated its anti-HBV activity, safety, and related features. CMCdG's in vitro activity was determined using qPCR and Southern blotting assays and its cytotoxicity with MTT assay, while that of in vivo activity and safety were determined in wild-type HBV genotype-Ce (HBV_WT^Ce)- and ETV-resistant HBV (HBV_ETV-R^{L180M/S202G/M204V})-infected human-liver-chimeric mice. CMCdG potently inhibited HBV production in HepG2.2.15 cells (IC₅₀ ~30 nM) and HBV_WT^Ce-plasmid-transfected Huh7 cells (IC₅₀: 206 nM) and efficiently suppressed an ETV-resistant HBV_ETV-R^{L180M/S202G/M204V} (IC₅₀: 2,657 nM), while it showed no or least cytotoxicity (CC₅₀: >500 μM in most of hepatocytic cells examined). Two-week peroral administration of CMCdG (1 mg/kg/day, q.d.) to HBV_WT^Ce-infected human-liver-chimeric mice reduced viremia by ~2 logs. CMCdG also reduced HBV_ETV-R^{L180M/S202G/M204V} viremia by ~1 log in HBV_ETV-R^{L180M/S202G/M204V}-infected human-liver-chimeric mice, while ETV (1 mg/kg/day, q.d.) completely failed to reduce the viremia. None of the CMCdG-treated mice had significant drug-related changes in body-weights or serum human-albumin levels. Structural analyses using homology modeling, semi-empirical quantum methods, and molecular dynamics revealed that although ETV-triphosphates (TP) forms good van der Waals contacts with L180 and M204 of HBV_WT^Ce reverse transcriptase (RT), its contacts with M180 substitution are totally lost in the HBV_ETV-R^{L180M/S202G/M204V}-RT complex. However, CMCdG-TP retains good contacts with both HBV_WT^Ce- and HBV_ETV-R^{L180M/S202G/M204V}-RT complexes. The present data warrant further studies toward development of CMCdG as a potential therapeutic for infection with drug-resistant HBV and shed light on further development of more potent and safer anti-HBV agents.

http://bit.ly/2WbsR6T

APX001 Pharmacokinetic/Pharmacodynamic Target Determination against Aspergillus fumigatus in an in vivo Model of Invasive Pulmonary Aspergillosis [Experimental Therapeutics]

APX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity against Aspergillus fumigatus. The goal of current study was to determine the pharmacodynamic (PD) index and target of APX001 in an immunocompromised murine model of invasive pulmonary aspergillosis against 6 A. fumigatus isolates. Minimum effective concentration (MEC) values ranged from 0.03 to 0.06 mg/liter. Dose fractionation was performed against isolate AF293 using total doses of APX001 ranging from 81 to 768 mg/kg/day fractionated into every 3-, 6-, and 8- hourly regimens over a 96-h treatment duration. Efficacy was assessed by A. fumigatus quantitative PCR (qPCR) of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24h AUC/MEC ratio was the PK/PD index that best correlated with efficacy (coefficient of determination [lsqb]R²[rsqb] = 0.79). Treatment studies with the remaining strains utilized regimens of 40 to 1536 mg/kg of APX001 administered every 3 h for a 96-h duration. Exposure-response relationships for all strains were similar and the median free drug AUC/MEC PK/PD targets for stasis and 1-log kill endpoint were 47.6 and 89.4, respectively. The present studies demonstrated in vitro and in vivo APX001A/APX001 potency against A. fumigatus. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints.

http://bit.ly/2R7hrwZ

Imidazole derivatives as promising agents for the treatment of Chagas disease{dagger} [Experimental Therapeutics]

More than 100 years later after being firstly described, Chagas disease remains endemic in 21 Latin American countries and has spread to other continents. Indeed, this disease, caused by the protozoan parasite Trypanosoma cruzi, is no longer just a problem for the American continent but has become a global health threat. Current therapies, nifurtimox and benznidazole (Bz), are far from being adequate due to undesirable effects and their lack of efficacy in the chronic phases of the disease. In this work, we present an in-depth phenotypical evaluation in T.cruzi of a new class of imidazole compounds, discovered in a previous phenotypic screening against different trypanosomatids and designed as potential inhibitors of cAMP phosphodiesterases (PDEs). The confirmation of several activities similar or superior to Bz prompted a synthesis program of hit optimization and extended SAR, aimed at improving drug-like properties such as aqueous solubility, resulting in additional hits with IC₅₀ similar to Bz. The cellular effects of one representative hit, compound 9, on bloodstream trypomastigotes were further investigated. Transmission electron microscopy revealed cellular changes, after just 2 h of incubation with the IC₅₀ concentration, that were consistent with induced autophagy and osmotic stress - mechanisms previously linked to cAMP signaling. Compound 9 induced highly significant increases in both cellular and medium cAMP, confirming that inhibition of T.cruzi PDE(s) is part of its mechanism of action. The potent and selective activity of this imidazole-based PDE inhibitor class against T.cruzi constitutes a successful repurposing of research into inhibitors of mammalian PDEs.

http://bit.ly/2WbFQ8B

Frictional Keratosis, Contact Keratosis and Smokeless Tobacco Keratosis: Features of Reactive White Lesions of the Oral Mucosa

Abstract

White lesions of the oral cavity are quite common and can have a variety of etiologies, both benign and malignant. Although the vast majority of publications focus on leukoplakia and other potentially malignant lesions, most oral lesions that appear white are benign. This review will focus exclusively on reactive white oral lesions. Included in the discussion are frictional keratoses, irritant contact stomatitis, and smokeless tobacco keratoses. Leukoedema and hereditary genodermatoses that may enter in the clinical differential diagnoses of frictional keratoses including white sponge nevus and hereditary benign intraepithelial dyskeratosis will be reviewed. Many products can result in contact stomatitis. Dentrifice-related stomatitis, contact reactions to amalgam and cinnamon can cause keratotic lesions. Each of these lesions have microscopic findings that can assist in patient management.

http://bit.ly/2U9yVL4

Black and Brown: Non-neoplastic Pigmentation of the Oral Mucosa

Abstract

Black and brown pigmentation of the oral mucosa can occur due to a multitude of non-neoplastic causes. Endogenous or exogenous pigments may be responsible for oral discoloration which can range from innocuous to life-threatening in nature. Physiologic, reactive, and idiopathic melanin production seen in smoker's melanosis, drug-related discolorations, melanotic macule, melanoacanthoma and systemic diseases are presented. Exogenous sources of pigmentation such as amalgam tattoo and black hairy tongue are also discussed. Determining the significance of mucosal pigmented lesions may represent a diagnostic challenge for clinicians. Biopsy is indicated whenever the source of pigmentation cannot be definitively identified based on the clinical presentation.

http://bit.ly/2DsEw9V

Rule of thumb: a simple tool to estimate 1% scalp surface area

http://bit.ly/2T9UzyM

The Most Common Causes of Burnout among U.S. Academic Dermatologists Based on a Survey Study

http://bit.ly/2AYMGFw

Nail lichen planus

http://bit.ly/2T9Uviw

Letter to the Editor: Nail Lichen Planus: A True Nail Emergency

http://bit.ly/2AYMEgS

Therapeutic Pearl: Regenerative Healing Ability of the Digit Tip

Patient consent for publication available upon request. Ethics review board not required.

http://bit.ly/2T9UsTS

Screening for Depression and Suicidality in Psoriasis Patients: A Survey of U.S. Dermatologists

http://bit.ly/2R6Nnl6

Port-wine stains on the neck respond better to a pulsed dye laser than lesions on the face: An intrapatient comparison study with histopathology

To the Editor: Neck port-wine stains (PWSs) usually respond better than facial PWSs to treatment with a pulsed dye laser (PDL).1 Until now, however, self-controlled studies with objective evaluation of efficacy and anatomic features have not been reported. In this study, we investigated the morphologic and anatomic features of both facial and neck PWS lesions and put forward a possible explanation for the difference in the therapeutic efficacy of PDL.

http://bit.ly/2FWrWkO

Common Heritable Immunological Variations Revealed in Genetically Diverse Inbred Mouse Strains of the Collaborative Cross [IMMUNOGENETICS]

Variations in the proportion and number of specific immune cell types among healthy individuals are influenced by both heritable and nonheritable factors. Mouse models, subjected to fewer nonheritable factors than humans, allow the identification of genetic factors that shape the immune system. We characterized immunological trait variability in the Collaborative Cross (CC), a powerful genetic resource of recombinant inbred mouse strains derived from eight diverse founder strains. Of the 18 immunological traits studied in more than 60 CC strains, eight showed genome-wide significant linkage, revealing new genetic loci linked to specific immune traits. We also found that these traits were highly subject to heritable influences. As for humans, mouse immunological traits varied as a continuum rather than as discrete immunophenotypes. The CC thus represents a useful resource to identify factors that determine immunological variations, as well as defining other immune traits likely to be heritable in humans.

http://bit.ly/2DuFwdJ

IL-6 Signaling Blockade during CD40-Mediated Immune Activation Favors Antitumor Factors by Reducing TGF-{beta}, Collagen Type I, and PD-L1/PD-1 [IMMUNOTHERAPY AND VACCINES]

IL-6 plays a role in cancer pathogenesis via its connection to proteins involved in the formation of desmoplastic stroma and to immunosuppression by driving differentiation of myeloid suppressor cells together with TGF-β. Inhibition of IL-6 signaling in the tumor microenvironment may, thus, limit desmoplasia and myeloid suppressor cell differentiation. CD40 signaling can further revert myeloid cell differentiation toward antitumor active phenotypes. Hence, the simultaneous use of IL-6 blockade with CD40 stimuli may tilt the tumor microenvironment to promote antitumor immune responses. In this paper, we evaluated the mechanisms of LOAd713, an oncolytic adenovirus designed to block IL-6R signaling and to provide myeloid cell activation via a trimerized membrane-bound isoleucine zipper (TMZ) CD40L. LOAd713-infected pancreatic cancer cells were killed by oncolysis, whereas infection of stellate cells reduced factors involved in stroma formation, including TGF-β-1 and collagen type I. Virus infection prevented IL-6/GM-CSF–mediated differentiation of myeloid suppressors, but not CD163 macrophages, whereas infection of dendritic cells led to upregulation of maturation markers, including CD83, CD86, IL-12p70, and IFN-. Further, IL-6R blockade prevented upregulation of programed death ligand 1 (PD-L1) and PD-1 on the stimulated dendritic cells. These results suggest that LOAd713 can kill infected tumor cells and has the capacity to affect the tumor microenvironment by stimulating stellate cells and myeloid suppressors with TMZ-CD40L and IL-6R blockade. Gene transfer of murine TMZ-CD40L prolonged survival in an animal model. LOAd713 may be an interesting therapeutic option for cancers connected to IL-6 signaling, such as pancreatic cancer.

http://bit.ly/2Ua1aJL

IL-33 Augments Virus-Specific Memory T Cell Inflation and Potentiates the Efficacy of an Attenuated Cytomegalovirus-Based Vaccine [MUCOSAL IMMUNOLOGY]

Candidate vaccines designed to generate T cell–based immunity are typically vectored by nonpersistent viruses, which largely fail to elicit durable effector memory T cell responses. This limitation can be overcome using recombinant strains of CMV. Proof-of-principle studies have demonstrated the potential benefits of this approach, most notably in the SIV model, but safety concerns require the development of nonreplicating alternatives with comparable immunogenicity. In this study, we show that IL-33 promotes the accumulation and recall kinetics of circulating and tissue-resident memory T cells in mice infected with murine CMV. Using a replication-deficient murine CMV vector, we further show that exogenous IL-33 boosts vaccine-induced memory T cell responses, which protect against subsequent heterologous viral challenge. These data suggest that IL-33 could serve as a useful adjuvant to improve the efficacy of vaccines based on attenuated derivatives of CMV.

http://bit.ly/2FHPHOA

The Tale of IL-12 and IL-23: A Paradigm Shift [PILLARS OF IMMUNOLOGY]

http://bit.ly/2FQnR1G

Suppression of the IFN-{alpha} and -{beta} Induction through Sequestering IRF7 into Viral Inclusion Bodies by Nonstructural Protein NSs in Severe Fever with Thrombocytopenia Syndrome Bunyavirus Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Induction of type I IFNs during viral infection is crucial for host defense. IRF 3 and IRF7 play a critical role as key transcription factors in the activation of the IFN induction. Viruses have evolved a variety of strategies to evade innate immunity. Our previous studies have shown that the nonstructural protein (NSs) of the severe fever with thrombocytopenia syndrome virus (SFTSV) can suppress the IFN-β induction through its interaction with tank-binding kinase-1 and sequestering the inhibitor of nuclear factor kappa B kinase(IKK) complex into the inclusion bodies formed by NSs. In this study, we characterized the unique function of IRF7 in innate immunity and its role in inducing IFN-α in particular, regulated by NSs during the SFTSV infection in several cell types of human origin. Whereas IRF3 is constitutively expressed, IRF7 was significantly induced differentially in various cell types in response to SFTSV infection, promoted the induction of IFN-α2 and -α4, and further induced IFN-β, thus contributing to suppressing the viral replication. Our data indicate that NSs directly interacted with and sequestered IRF7 into the inclusion bodies, which is different from IRF3 indirectly interacting with NSs. Although interaction of NSs with IRF7 did not inhibit IRF7 phosphorylation, p-IRF7 was trapped in the inclusion bodies, resulting in a significant reduction of the IFN-α2 and -α4 induction and therefore enhanced viral replication. Interaction of the viral NSs with both IRF7 and IRF3 and subsequent sequestration of these transcription factors into viral inclusion bodies, a unique strategy used by this phlebovirus, may ensure effective evasion and suppression of host innate immunity.

http://bit.ly/2FEqJ2k

Manipulation of Ambient Housing Temperature To Study the Impact of Chronic Stress on Immunity and Cancer in Mice [BRIEF REVIEWS]

Mice are the preeminent research organism in which to model human diseases and study the involvement of the immune response. Rapidly accumulating evidence indicates a significant involvement of stress hormones in cancer progression, resistance to therapies, and suppression of immune responses. As a result, there has been a concerted effort to model human stress in mice. In this article, we discuss recent literature showing how mice in research facilities are chronically stressed at baseline because of environmental factors. Focusing on housing temperature, we suggest that the stress of cool housing temperatures contributes to the impact of other imposed experimental stressors and therefore has a confounding effect on mouse stress models. Furthermore, we propose that manipulation of housing temperature is a useful approach for studying the impact of chronic stress on disease and the immune response and for testing therapeutic methods of reducing the negative effects of chronic stress.

http://bit.ly/2FPx8XI

Human Anti-HIV-1 gp120 Monoclonal Antibodies with Neutralizing Activity Cloned from Humanized Mice Infected with HIV-1 [INFECTIOUS DISEASE AND HOST RESPONSE]

Broadly neutralizing, anti–HIV-1 gp120 mAbs have been isolated from infected individuals, and there is considerable interest in developing these reagents for Ab-based immunoprophylaxis and treatment. As a means to identify potentially new anti-HIV Abs, we exploited humanized NOD-scid IL2r^null mice systemically infected with HIV-1 to generate a wide variety of Ag-specific human mAbs. The Abs were encoded by a diverse range of variable gene families and Ig classes, including IgA, and several showed significant levels of somatic mutation. Moreover, the isolated Abs not only bound target Ags with similar affinity as broadly neutralizing Abs, they also demonstrated neutralizing ability against multiple HIV-1 clades. The use of humanized mice will allow us to use our knowledge of HIV-1 gp120 structure and function, and the immune response targeting this protein, to generate native human prophylactic Abs to reduce the infection and spread of HIV-1.

http://bit.ly/2FHgDxE

Dual TCR T Cells: Identity Crisis or Multitaskers? [BRIEF REVIEWS]

Dual TCR T cells are a common and natural product of TCR gene rearrangement and thymocyte development. As much as one third of the T cell population may have the capability to express two different TCR specificities on the cell surface. This discovery provoked a reconsideration of the classic model of thymic selection. Many potential roles for dual TCR T cells have since been hypothesized, including posing an autoimmune hazard, dominating alloreactive T cell responses, inducing allergy, and expanding the TCR repertoire to improve protective immunity. Yet, since the initial wave of publications following the discovery of dual TCR T cells, research in the area has slowed. In this study, we aim to provide a brief but comprehensive history of dual TCR T cell research, re-evaluate past observations in the context of current knowledge of the immune system, and identify key issues for future study.

http://bit.ly/2FWnToC

IRAK-M Associates with Susceptibility to Adult-Onset Asthma and Promotes Chronic Airway Inflammation [INNATE IMMUNITY AND INFLAMMATION]

IL-1R–associated kinase (IRAK)-M regulates lung immunity during asthmatic airway inflammation. However, the regulatory effect of IRAK-M differs when airway inflammation persists. A positive association between IRAK-M polymorphisms with childhood asthma has been reported. In this study, we investigated the role of IRAK-M in the susceptibility to adult-onset asthma and in chronic airway inflammation using an animal model. Through genetic analysis of IRAK-M polymorphisms in a cohort of adult-onset asthma patients of Chinese Han ethnicity, we identified two IRAK-M single nucleotide polymorphisms, rs1624395 and rs1370128, genetically associated with adult-onset asthma. Functionally, the top-associated rs1624395, with an enhanced affinity to the transcription factor c-Jun, was associated with a higher expression of IRAK-M mRNA in blood monocytes. In contrast to the protective effect of IRAK-M in acute asthmatic inflammation, we found a provoking impact of IRAK-M on chronic asthmatic inflammation. Following chronic OVA stimulation, IRAK-M knockout (KO) mice presented with significantly less inflammatory cells, a lower Th2 cytokine level, a higher IFN- concentration, and increased percentage of Th1 cells in the lung tissue than wild type mice. Moreover, lung dendritic cells (DC) from OVA-treated IRAK-M KO mice expressed a higher percentage of costimulatory molecules PD-L1 and PD-L2. Mechanistically, in vitro TLR ligation led to a greater IFN- production by IRAK-M KO DCs than wild type DCs. These findings demonstrated a distinctive role of IRAK-M in maintaining chronic Th2 airway inflammation via inhibiting the DC-mediated Th1 activation and indicated a complex role for IRAK-M in the initiation and progression of experimental allergic asthma.

http://bit.ly/2FIoOtx

Cutting Edge: Early Attrition of Memory T Cells during Inflammation and Costimulation Blockade Is Regulated Concurrently by Proapoptotic Proteins Fas and Bim [CUTTING EDGE]

Apoptosis of CD8 T cells is an essential mechanism that maintains immune system homeostasis, prevents autoimmunity, and reduces immunopathology. CD8 T cell death also occurs early during the response to both inflammation and costimulation blockade (CoB). In this article, we studied the effects of a combined deficiency of Fas (extrinsic pathway) and Bim (intrinsic pathway) on early T cell attrition in response to lymphocytic choriomeningitis virus infection and during CoB during transplantation. Loss of Fas and Bim function in Bcl2l11^–/–Fas^lpr/lpr mice inhibited apoptosis of T cells and prevented the early T cell attrition resulting from lymphocytic choriomeningitis virus infection. Bcl2l11^–/–Fas^lpr/lpr mice were also resistant to prolonged allograft survival induced by CoB targeting the CD40-CD154 pathway. These results demonstrate that both extrinsic and intrinsic apoptosis pathways function concurrently to regulate T cell homeostasis during the early stages of immune responses and allograft survival during CoB.

http://bit.ly/2FShyLa

Transthyretin Stimulates Tumor Growth through Regulation of Tumor, Immune, and Endothelial Cells [TUMOR IMMUNOLOGY]

Early detection of lung cancer offers an important opportunity to decrease mortality while it is still treatable and curable. Thirteen secretory proteins that are Stat3 downstream gene products were identified as a panel of biomarkers for lung cancer detection in human sera. This panel of biomarkers potentially differentiates different types of lung cancer for classification. Among them, the transthyretin (TTR) concentration was highly increased in human serum of lung cancer patients. TTR concentration was also induced in the serum, bronchoalveolar lavage fluid, alveolar type II epithelial cells, and alveolar myeloid cells of the CCSP-rtTA/(tetO)₇-Stat3C lung tumor mouse model. Recombinant TTR stimulated lung tumor cell proliferation and growth, which were mediated by activation of mitogenic and oncogenic molecules. TTR possesses cytokine functions to stimulate myeloid cell differentiation, which are known to play roles in tumor environment. Further analyses showed that TTR treatment enhanced the reactive oxygen species production in myeloid cells and enabled them to become functional myeloid-derived suppressive cells. TTR demonstrated a great influence on a wide spectrum of endothelial cell functions to control tumor and immune cell migration and infiltration. TTR-treated endothelial cells suppressed T cell proliferation. Taken together, these 13 Stat3 downstream inducible secretory protein biomarkers potentially can be used for lung cancer diagnosis, classification, and as clinical targets for lung cancer personalized treatment if their expression levels are increased in a given lung cancer patient in the blood.

http://bit.ly/2FHPM4Q

Classical Type 1 Dendritic Cells Dominate Priming of Th1 Responses to Herpes Simplex Virus Type 1 Skin Infection [ANTIGEN RECOGNITION AND RESPONSES]

CD4⁺ T cell responses are crucial for the control of many intracellular pathogens, yet the requirements for their induction are not fully understood. To better understand the role that various dendritic cell (DC) subtypes play in CD4⁺ T cell priming, we compared in vivo T cell responses to skin inoculation of mice with infectious or UV-inactivated HSV type 1. Localized infection elicited a Th1 response that was primed in skin-draining lymph nodes involving Ag presentation by migratory dermal and lymph node–resident DC. However, expansion and Th1 differentiation was impaired in response to UV-inactivated virus (UV-HSV), and this defect correlated with a restriction of Ag presentation to migratory CD103^– dermal DC. A similar differentiation defect was seen in infected mice lacking CD8α⁺ and CD103⁺ classical type 1 DC (cDC1). Finally, Th1 differentiation after UV-HSV inoculation was rescued by targeted Ag delivery to CD8α⁺ and CD103⁺ cDC1 using an anti-Clec9A Ab construct. This suggests that Ag presentation by cDC1 is crucial for optimal Th1 immunity to HSV type 1 infection and potentially other pathogens of the skin.

http://bit.ly/2FP5qdT

HIV Interferes with the Dendritic Cell-T Cell Axis of Macrophage Activation by Shifting Mycobacterium tuberculosis-Specific CD4 T Cells into a Dysfunctional Phenotype [INFECTIOUS DISEASE AND HOST RESPONSE]

HIV coinfection is the greatest risk factor for transition of latent Mycobacterium tuberculosis infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of M. tuberculosis–specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. M. tuberculosis–specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)–T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV–M. tuberculosis–infected (coinfected) human DCs can dysregulate the M. tuberculosis–specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control M. tuberculosis infection in macrophages. After coculture with coinfected DCs, M. tuberculosis Ag-specific CD4 T cells lost their ability to enhance control of M. tuberculosis infection in infected macrophages. Coinfection of DCs reduced proliferation of M. tuberculosis Ag-specific CD4 T cells without affecting their viability, led to increased expression of coinhibitory factors CTLA-4, PD-1, and Blimp-1, and decreased expression of costimulatory molecules CD40L, CD28, and ICOS on the T cells. Expression of the regulatory T cell markers FOXP3 and CD25, together with the immunosuppressive cytokines TGF-β and IL-10, was also significantly increased by coinfection compared with M. tuberculosis single infection. Our data suggest a pattern in which HIV, through its effect on DCs, impairs the ability of M. tuberculosis-specific CD4 T cells to maintain a latent TB within human macrophages, which could play an early role in the subsequent development of TB.

http://bit.ly/2FHaYrE

B Cell ADAM10 Controls Murine Lupus Progression through Regulation of the ICOS:ICOS Ligand Axis [AUTOIMMUNITY]

The role of ICOS and its ligand (ICOSL) have both been shown to be essential for proper humoral responses as well as autoimmune Ab development in mouse models of lupus. In this paper, we report a specific role for the metalloprotease ADAM10 on B cells in regulating both ICOSL and ICOS in a mouse model of increased humoral immunity using B6^{mir146a–/–} mice and a model of lymphoproliferative disease using the well-characterized lpr model. B6^lpr mice lacking ADAM10 on B cells (A10B^lpr) have decreased nodal proliferation and T cell accumulation compared with control B6^lpr mice. Additionally, A10B^lpr mice have a drastic reduction in autoimmune anti-dsDNA Ab production. In line with this, we found a significant reduction in follicular helper T cells and germinal center B cells in these mice. We also show that lymphoproliferation in this model is closely tied to elevated ICOS levels and decreased ICOSL levels. Overall, our data not only show a role of B cell ADAM10 in control autoimmunity but also increase our understanding of the regulation of ICOS and ICOSL in the context of autoimmunity.

http://bit.ly/2FRpEn7

Critical Adverse Impact of IL-6 in Acute Pneumovirus Infection [INNATE IMMUNITY AND INFLAMMATION]

Severe respiratory virus infections feature robust local host responses that contribute to disease severity. Immunomodulatory strategies that limit virus-induced inflammation may be of critical importance, notably in the absence of antiviral vaccines. In this study, we examined the role of the pleiotropic cytokine IL-6 in acute infection with pneumonia virus of mice (PVM), a natural rodent pathogen that is related to respiratory syncytial virus and that generates local inflammation as a feature of severe infection. In contrast to Influenza A, PVM is substantially less lethal in IL-6^–/– mice than it is in wild-type, a finding associated with diminished neutrophil recruitment and reduced fluid accumulation in lung tissue. Ly6C^hi proinflammatory monocytes are recruited in response to PVM via a CCR2-dependent mechanism, but they are not a major source of IL-6 nor do they contribute to lethal sequelae of infection. By contrast, alveolar macrophages are readily infected with PVM in vivo; ablation of alveolar macrophages results in prolonged survival in association with a reduction in virus-induced IL-6. Finally, as shown previously, administration of immunobiotic Lactobacillus plantarum to the respiratory tracts of PVM-infected mice promoted survival in association with diminished levels of IL-6. We demonstrated in this study that IL-6 suppression is a critical feature of the protective mechanism; PVM-infected IL-6^–/– mice responded to low doses of L. plantarum, and administration of IL-6 overcame L. plantarum–mediated protection in PVM-infected wild-type mice. Taken together, these results connect the actions of IL-6 to PVM pathogenesis and suggest cytokine blockade as a potential therapeutic modality in severe infection.

http://bit.ly/2FIN92D

Lupus-Associated Immune Complexes Activate Human Neutrophils in an Fc{gamma}RIIA-Dependent but TLR-Independent Response [AUTOIMMUNITY]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nucleic acids and nucleoproteins. Anti-dsDNA Abs are considered a hallmark of SLE, and previous studies have indicated that nucleic acid–containing immune complexes (ICs) induce B cell and dendritic cell activation in a TLR-dependent process. How ICs containing nucleic acids affect neutrophil function has not been well investigated. In this study, we report that nucleic acid–containing ICs derived from the sera of SLE patients induce human and mouse neutrophil activation through TLR-independent mechanisms. Soluble ICs containing Sm/RNP, an RNA Ag, activate human neutrophils to produce reactive oxygen species (ROS) and IL-8. In contrast, ICs containing DNA have to be immobilized to efficiently activate neutrophils. We found that deleting TLR7 or TLR9, the receptors for RNA and DNA, had no effect on mouse neutrophil activation induced by RNA-containing and immobilized DNA–containing ICs. Binding of ICs are mediated through FcRIIA and FcRIIIB. However, neutrophil activation induced by RNA- and DNA-containing ICs requires FcRIIA, as blocking FcRIIA inhibited ROS release from neutrophils. RNA-containing ICs induce calcium flux, whereas TLR7/8 ligand R848 do not. Surprisingly, chloroquine inhibits calcium flux induced by RNA-containing ICs, suggesting that this lesser known function of chloroquine is involved in the neutrophil activation induced by ICs. These data indicate the SLE-derived ICs activate neutrophils to release ROS and chemokines in an FcRIIA-dependent and TLR7- and TLR9-independent manner that likely contributes to local tissue inflammation and damage.

http://bit.ly/2FQ1F82

IRF5 Is Required for Bacterial Clearance in Human M1-Polarized Macrophages, and IRF5 Immune-Mediated Disease Risk Variants Modulate This Outcome [INNATE IMMUNITY AND INFLAMMATION]

Common IFN regulatory factor 5 (IRF5) variants associated with multiple immune-mediated diseases are a major determinant of interindividual variability in pattern recognition receptor (PRR)–induced cytokines in macrophages. PRR-initiated pathways also contribute to bacterial clearance, and dysregulation of bacterial clearance can contribute to immune-mediated diseases. However, the role of IRF5 in macrophage-mediated bacterial clearance is not well defined. Furthermore, it is unclear if macrophages from individuals who are carriers of low IRF5-expressing genetic variants associated with protection for immune-mediated diseases might be at a disadvantage in bacterial clearance. We found that IRF5 was required for optimal bacterial clearance in PRR-stimulated, M1-differentiated human macrophages. Mechanisms regulated by IRF5 included inducing reactive oxygen species through p40phox, p47phox and p67phox, NOS2, and autophagy through ATG5. Complementing these pathways in IRF5-deficient M1 macrophages restored bacterial clearance. Further, these antimicrobial pathways required the activation of IRF5-dependent MAPK, NF-B, and Akt2 pathways. Importantly, relative to high IRF5-expressing rs2004640/rs2280714 TT/TT immune-mediated disease risk-carrier human macrophages, M1-differentiated GG/CC carrier macrophages demonstrated less reactive oxygen species, NOS2, and autophagy pathway induction and, consequently, reduced bacterial clearance. Increasing IRF5 expression to the rs2004640/rs2280714 TT/TT levels restored these antimicrobial pathways. We define mechanisms wherein common IRF5 genetic variants modulate bacterial clearance, thereby highlighting that immune-mediated disease risk IRF5 carriers might be relatively protected from microbial-associated diseases.

http://bit.ly/2FKjrdm

High-Dose IL-2 Skews a Glucocorticoid-Driven IL-17+IL-10+ Memory CD4+ T Cell Response towards a Single IL-10-Producing Phenotype [CLINICAL AND HUMAN IMMUNOLOGY]

Glucocorticoids are known to increase production of the anti-inflammatory cytokine IL-10, and this action is associated with their clinical efficacy in asthmatics. However, glucocorticoids also enhance the synthesis of IL-17A by PBMCs, which, in excess, is associated with increased asthma severity and glucocorticoid-refractory disease. In this study, we show that the glucocorticoid dexamethasone significantly increased IL-10 production by human memory CD4⁺ T cells from healthy donors, as assessed by intracellular cytokine staining. In addition, dexamethasone increased production of IL-17A, IL-17F, and IL-22, with the most striking enhancement in cells coproducing Th17-associated cytokines together with IL-10. Of note, an increase in IFN-⁺IL-10⁺ cells was also observed despite overall downregulation of IFN- production. These dexamethasone-driven IL-10⁺ cells, and predominantly the IL-17⁺IL-10⁺ double-producing cells, were markedly refractory to the inhibitory effect of dexamethasone on proliferation and IL-2Rα expression, which facilitated their preferential IL-2–dependent expansion. Although lower concentrations of exogenous IL-2 promoted IL-10⁺ cells coproducing proinflammatory cytokines, higher IL-2 doses, both alone and in combination with dexamethasone, increased the proportion of single IL-10⁺ T cells. Thus, glucocorticoid-induced IL-10 is only accompanied by an increase of IL-17 in a low IL-2 setting, which is, nevertheless, likely to be protective owing to the induction of regulatory IL-17⁺IL-10⁺–coproducing cells. These findings open new avenues of investigation with respect to the role of IL-2 in glucocorticoid responsiveness that have potential implications for optimizing the benefit/risk ratio of glucocorticoids in the clinic.

http://bit.ly/2FQ1DNs

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells [SYSTEMS IMMUNOLOGY]

T cell development depends on sequential interactions of thymocytes with cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells. PSMB11 is a catalytic proteasomal subunit present exclusively in cTECs. Because proteasomes regulate transcriptional activity, we asked whether PSMB11 might affect gene expression in cTECs. We report that PSMB11 regulates the expression of 850 cTEC genes that modulate lymphostromal interactions primarily via the WNT signaling pathway. cTECs from Psmb11^–/– mice 1) acquire features of medullary thymic epithelial cells and 2) retain CD8 thymocytes in the thymic cortex, thereby impairing phase 2 of positive selection, 3) perturbing CD8 T cell development, and 4) causing dramatic oxidative stress leading to apoptosis of CD8 thymocytes. Deletion of Psmb11 also causes major oxidative stress in CD4 thymocytes. However, CD4 thymocytes do not undergo apoptosis because, unlike CD8 thymocytes, they upregulate expression of chaperones and inhibitors of apoptosis. We conclude that PSMB11 has pervasive effects on both CD4 and CD8 thymocytes via regulation of gene expression in cTECs.

http://bit.ly/2FIZZOp

Expression of a Functional IL-2 Receptor in Vascular Smooth Muscle Cells [CLINICAL AND HUMAN IMMUNOLOGY]

Many nonlymphoid cell types express at least two, if not all three, subunits of the IL-2R; although, compared with lymphocytes, relatively little is known about how IL-2 affects the function of nonlymphoid cells. The limited information available suggests that IL-2 has a substantial impact on cells such as gastrointestinal epithelial cells, endothelial cells, and fibroblasts. In a previous report from our laboratory, we noted that IL-2 and IL-2Rβ–deficient mice lose smooth muscle cells over time, eventually resulting in aneurysmal aortas and ectatic esophagi. This finding, combined with our work showing that IL-2 surrounds vascular smooth muscle cells by association with perlecan, led us to ask whether vascular smooth muscle cells express an IL-2R. Toward this end, we reported the expression of IL-2Rβ on human and murine vascular smooth muscle cells. We now report that vascular smooth muscle cells express all three subunits of the IL-2R, and that expression of IL-2Rα varies with vascular smooth muscle cell phenotype. Furthermore, we show that, through a functional IL-2R, IL-2 initiates signaling pathways and impacts vascular smooth muscle cell function. Finally, we demonstrate that IL-2 expression increases upon initiation of conditions that promote intimal hyperplasia, suggesting a mechanism by which the IL-2/IL-2R system may impact this widespread vascular pathology.

http://bit.ly/2FXfemf

In This Issue [IN THIS ISSUE]

http://bit.ly/2FH6BwL

BCL6-Mediated Silencing of PD-1 Ligands in Germinal Center B Cells Maintains Follicular T Cell Population [IMMUNE REGULATION]

The programmed cell death protein 1 (PD-1) ligands PD-L1 and PD-L2 on germinal center (GC) B cells deliver coinhibitory signals to follicular T cells. The PD-L1/L2–PD-1 axis modulates the quality and quantity of follicular T cells and has been shown to influence the GC responses. However, the transcriptional control of PD-1 ligands on GC B cells remains largely unknown. In this study, we report that the transcription factor BCL6 is a key negative regulator of the PD-1 ligands PD-L1 and PD-L2 in GC B cells. Acute deletion of Bcl6 in mature GC B cells resulted in marked upregulation of mRNA and protein abundance of PD-1 ligands. Moreover, the expression levels of BCL6 and PD-1 ligands were inversely correlated during GC B cell development and in human GC–derived lymphoma specimens. Mechanically, BCL6 directly bound to the promoter region of PD-L1 and intron 2 of PD-L2 to suppress their transcription. In addition, BCL6 indirectly inhibited the transcription of PD-1 ligands by repressing the expression of STAT1/STAT3 and IRF1. Moreover, BCL6 exerted these effects via its BTB domain. Finally, PD-1 blockade promoted cell survival to sustain the follicular T cell pool in the presence of Bcl6-deficinet GC B cells. In summary, B cell–specific expression of BCL6 dampens the PD-L1/L2–PD-1 signaling to maintain the size of follicular T cells during GC development.

http://bit.ly/2FSL5UW

Intensivist staffing and outcome in the ICU: daytime, nighttime, 24/7?

Purpose of review Many hospitals, particularly large academic centers, have begun to provide 24-h in-house intensive care attending coverage. Proposed advantages for this model include improved patient care, greater provider, nursing and patient satisfaction, better communication, and greater cost-effectiveness. This review will evaluate current evidence with respect to 24/7 coverage, including patient outcomes, cost-effectiveness, and impact on training/education. Recent findings Evidence surrounding 24-h intensivist staffing has been mixed. Although a subset of studies suggest a possible benefit to 24-h intensivist coverage, recent prospective studies have shown no difference in major patient outcomes, including mortality and ICU length of stay between patients in ICUs with and those without 24-h intensivist coverage. Summary Although some studies cite increased caregiver and patient satisfaction, outcome studies find no consistent effect on patient-centered outcomes such as mortality or length of stay. Downsides to in-house nighttime attending staffing include physician burnout, adverse effects on physician health, decreased trainee autonomy, and effects on trainee specialty choices because of undesirable lifestyle considerations. Tele-ICU and other novel approaches may allow for attending supervision without physical presence. Correspondence to Avery Tung, MD, 5841 S Maryland Ave MC 4028, Chicago, IL 60637, USA. Tel: +1 (773) 834 7937; E-mail: atung@dacc.uchicago.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2T6WGnd

Helicopter air ambulance services

Purpose of review Helicopter air ambulances are an integral component of modern trauma care, and are able to transport patients to facilities with greater capabilities, extract injured patients from hostile terrain, and speed transport to a trauma center. Recent findings HAA transport does not reduce the total time required to transport a patient, but it does reduce the time that the patient is between healthcare facilities. Factors that have been suggested to improve outcomes for trauma patients include the availability of advanced interventions, skilled personnel, speed, and trauma center access. Despite their potential benefits to the patient, HAA operations carry significant risks. HAA operations are among the most dangerous professions for both pilot and crew with a mortality rate greater than commercial fishing, loggers, and steelworkers. The US Federal Aviation Administration (FAA) has identified that the four most common causes of HAA accidents as inadvertent flight into instrument meteorological conditions, loss of control, controlled flight into terrain, and night conditions. Summary HAA operations are well tolerated and can improve patient care, but additional research is needed to improve our understanding of HAA operations and their effect on outcomes. Correspondence to Keith J. Ruskin, MD, FAsMA, FRAeS, Professor of Anesthesia and Critical Care and Biological Sciences Collegiate Division, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Avenue MC4028, Chicago, IL 60637, USA. Tel: +1 773 834 2369; e-mail: ruskin@uchicago.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2AZuSKg

Burn injury and blood transfusion

Purpose of review Blood transfusion is ubiquitous in major burn injury. The present article describes recent research findings directly impacting blood transfusion strategies in major burn injury both in the operating room and the ICU. Recent findings Transfusion strategies have been the focus of recent burn investigations. First, a randomized prospective trial encompassing both the ICU and operating room reported that a restrictive red blood cell transfusion threshold (7 g/dl) had equivalent outcomes to a traditional threshold (10 g/dl) for burns more than 20% in terms of mortality, infection, length of stay, duration of mechanical ventilation, and wound healing despite receiving significantly fewer transfusions. The second burn transfusion advance addresses coagulation. Although burn patients initially have elevated fibrinogen, thrombocytopenia and other coagulation disorders develop during excision. Blood product repletion should be based on measurements such as thromboelastography in addition to traditional tests. Finally, a recent randomized trial suggests that fresh-frozen plasma and platelets during burn excision more than 20% may decrease transfusion requirements. Summary A restrictive transfusion practice during burn excision and grafting is well tolerated and effective in reducing the number of transfusions without increasing complications. Repletion of coagulation products should focus on measured deficits of platelets, fibrinogen, and factors. Correspondence to Tina L. Palmieri, 2425 Stockton Blvd, Suite 718, Sacramento, CA 95817, USA. Tel: +1-916-453-2050; fax: +1-916-453-2373; e-mail: tlpalmieri@ucdavis.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2T7QATz

Resuscitative endovascular balloon occlusion of the aorta: an option for noncompressible torso hemorrhage?

Purpose of review Hemorrhage is the major cause of early death in severely injured patients. In civilian emergency medical services, the majority of life-threatening bleedings are found in noncompressible body regions (e.g. abdomen and pelvis). Resuscitative endovascular balloon occlusion of the aorta (REBOA) has therefore been discussed in recent years as a possible lifesaving procedure and numerous studies, meta-analyses and guidelines have been published. In this review, the data situation of REBOA in the management of bleeding trauma patients is discussed and practical implementation is depicted. Recent findings The typical indication for REBOA is a traumatic life-threatening hemorrhage below the diaphragm in patients unresponsive or only transiently responsive to the usual conservative therapeutic measures. REBOA appears to be a safe and effective procedure to reduce blood loss and stabilize the patient's hemodynamic status. However, surgical hemostasis has to be achieved within 30–60 min after occlusion of the aorta. Data on clear advantages of REBOA over resuscitative thoracostomy are inconclusive. Summary REBOA could play an important role in the management of the severely bleeding patient in the future. Together with transfusion and therapy of coagulation disorders, REBOA may be an additional tool in the anesthetist's hands for trauma management in interprofessional care concepts. Correspondence to Dr Jürgen Knapp, Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland. Tel: +41 31 632 04 96; e-mail: juergen.knapp@insel.ch Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2ATxj0P

The use of new procoagulants in blunt and penetrating trauma

Purpose of review Uncontrolled bleeding in trauma secondary to a combination of surgical bleeding and trauma-induced complex coagulopathy is a leading cause of death. Prothrombin complex concentrates (PCCs), recombinant activated factor seven (rFVIIa) and recombinant human prothrombin act as procoagulants by increasing thrombin generation and fibrinogen concentrate aids stable clot formation. This review summarizes current evidence for procoagulant use in the management of bleeding in trauma, and data and evidence gaps for routine clinical use. Recent findings Retrospective and prospective studies of PCCs (±fibrinogen concentrate) have demonstrated a decreased time to correction of trauma coagulopathy and decreased red cell transfusion with no obvious effect on mortality or thromboembolic outcomes. PCCs in a porcine model of dilutional coagulopathy demonstrated a sustained increase in thrombin generation, unlike recombinant human prothrombin which showed a transient increase and has been studied only in animals. In other retrospective studies, there is a suggestion that lower doses of PCCs may be effective in the setting of acquired coagulopathy. Summary There is increasing evidence that early correction of coagulopathy has survival benefits, and the use of procoagulants as first-line therapy has the potential benefit of rapid access and timely treatment. This requires confirmation in prospective studies. Correspondence to Pratima Chowdary, Consultant Haematologist, KD Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, UK;. e-mails: p.chowdary@nhs.net, p.chowdary@ucl.ac.uk Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2TagE0q

Ab initio thermodynamics of liquid and solid water [Applied Physical Sciences]

Thermodynamic properties of liquid water as well as hexagonal (Ih) and cubic (Ic) ice are predicted based on density functional theory at the hybrid-functional level, rigorously taking into account quantum nuclear motion, anharmonic fluctuations, and proton disorder. This is made possible by combining advanced free-energy methods and state-of-the-art machine-learning techniques....

http://bit.ly/2S0XAnL

AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis [Pharmacology]

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have...

http://bit.ly/2S6tKOG

Profile of Hao Wu [Profiles]

Researchers' understanding of cellular physiology has evolved over time with the identification of internal cell structures. Organelles, large and small, are key to cellular function and response to external stimuli. Harvard Medical School professor of structural biology Hao Wu, elected to the National Academy of Sciences in 2015, uses protein...

http://bit.ly/2W7u3Z3

Global reconstruction of historical ocean heat storage and transport [Earth, Atmospheric, and Planetary Sciences]

Most of the excess energy stored in the climate system due to anthropogenic greenhouse gas emissions has been taken up by the oceans, leading to thermal expansion and sea-level rise. The oceans thus have an important role in the Earth's energy imbalance. Observational constraints on future anthropogenic warming critically depend...

http://bit.ly/2Hs8TBk

Molecular origins and outcomes of status and stress in primates [Anthropology]

Social dominance hierarchies are common in human and nonhuman animals and profoundly affect the behavior, health, and well-being of every member of a community. Research on diverse species has expanded our understanding of how ecological and social forces shape interactions influencing social status, behavior, and the underlying biology (1, 2)....

http://bit.ly/2R6sYww

Correction for Miloȷević et al., Changing demographics of scientific careers: The rise of the temporary workforce [Correction]

COLLOQUIUM Correction for "Changing demographics of scientific careers: The rise of the temporary workforce," by Staša Milojević, Filippo Radicchi, and John P. Walsh, which was first published December 11, 2018; 10.1073/pnas.1800478115 (Proc Natl Acad Sci USA 115:12616–12623). The authors note that a reference was omitted from the article. The complete...

http://bit.ly/2R7uWwG

Dowsing for nodal lines in a topological semimetal [Physics]

In PNAS, Shao et al. (1) report a spectroscopic search for line degeneracies in the electronic bands of NbAs2, a topological semimetal (TSM). TSMs have attracted great interest recently as exemplars of the emergent physics that can arise in quantum condensed matter (2). They host quasiparticle excitations that cannot occur...

http://bit.ly/2WaV1Pp

High Rac1 activity is functionally translated into cytosolic structures with unique nanoscale cytoskeletal architecture [Biophysics and Computational Biology]

Rac1 activation is at the core of signaling pathways regulating polarized cell migration. So far, it has not been possible to directly explore the structural changes triggered by Rac1 activation at the molecular level. Here, through a multiscale imaging workflow that combines biosensor imaging of Rac1 dynamics with electron cryotomography,...

http://bit.ly/2CAZyBI

Innate and adaptive immunity combined for cancer treatment [Immunology and Inflammation]

In PNAS, Kaplanov et al. (1) report on how IL-1β orchestrates recruitment of immunosuppressive monocytes and their polarization in IL-10–producing macrophages during tumor development. This mechanism consequently inhibits and limits CD8+ T cell-driven immune responses and enables tumor outgrowth. Therapeutic blockade of IL-1β and inhibition of monocyte recruitment synergized and...

http://bit.ly/2R7EbNI

Conserved transcriptomic profiles underpin monogamy across vertebrates [Evolution]

Social monogamy, typically characterized by the formation of a pair bond, increased territorial defense, and often biparental care, has independently evolved multiple times in animals. Despite the independent evolutionary origins of monogamous mating systems, several homologous brain regions and neuropeptides and their receptors have been shown to play a conserved...

http://bit.ly/2HtS2OD

Native mass spectrometry reveals the conformational diversity of the UVR8 photoreceptor [Biophysics and Computational Biology]

UVR8 is a plant photoreceptor protein that regulates photomorphogenic and protective responses to UV light. The inactive, homodimeric state absorbs UV-B light, resulting in dissociation into monomers, which are considered to be the active state and comprise a β-propeller core domain and intrinsically disordered N- and C-terminal tails. The C...

http://bit.ly/2CHzEvY

Body camera footage leads to lower judgments of intent than dash camera footage [Psychological and Cognitive Sciences]

Police departments use body-worn cameras (body cams) and dashboard cameras (dash cams) to monitor the activity of police officers in the field. Video from these cameras informs review of police conduct in disputed circumstances, often with the goal of determining an officer's intent. Eight experiments (N = 2,119) reveal that...

http://bit.ly/2sOStsV

Neoproterozoic glacial origin of the Great Unconformity [Earth, Atmospheric, and Planetary Sciences]

The Great Unconformity, a profound gap in Earth's stratigraphic record often evident below the base of the Cambrian system, has remained among the most enigmatic field observations in Earth science for over a century. While long associated directly or indirectly with the occurrence of the earliest complex animal fossils, a...

http://bit.ly/2W5KpkR

In This Issue [This Week in PNAS]

DNA methylation and orange fruit ripening Sweet orange fruits at 90–210 days after bloom (Left to Right). Tomatoes ripen according to a complex developmental process regulated by active DNA demethylation and an associated genome-wide loss of DNA methylation. Whether global DNA demethylation contributes to ripening in other fruits remains unclear....

http://bit.ly/2R7EeZU

Computer simulations suggest that prostate enlargement due to benign prostatic hyperplasia mechanically impedes prostate cancer growth [Engineering]

Prostate cancer and benign prostatic hyperplasia are common genitourinary diseases in aging men. Both pathologies may coexist and share numerous similarities, which have suggested several connections or some interplay between them. However, solid evidence confirming their existence is lacking. Recent studies on extensive series of prostatectomy specimens have shown that...

http://bit.ly/2R6Z3EA

The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation [Biochemistry]

Lysine methylation, catalyzed by protein lysine methyltransferases (PKMTs), is a key player in regulating intracellular signaling pathways. However, the role of PKMTs and the methylation of nonhistone proteins during the cell cycle are largely unexplored. In a recent proteomic screen, we identified that the PKMT SETD6 methylates PLK1—a key regulator...

http://bit.ly/2S0hcIR

Fluidization of collisionless plasma turbulence [Physics]

In a collisionless, magnetized plasma, particles may stream freely along magnetic field lines, leading to "phase mixing" of their distribution function and consequently, to smoothing out of any "compressive" fluctuations (of density, pressure, etc.). This rapid mixing underlies Landau damping of these fluctuations in a quiescent plasma—one of the most...

http://bit.ly/2WdpLiS

News Feature: What are the limits of deep learning? [Computer Sciences]

The much-ballyhooed artificial intelligence approach boasts impressive feats but still falls short of human brainpower. Researchers are determined to figure out what's missing. There's no mistaking the image: It's a banana—a big, ripe, bright-yellow banana. Yet the artificial intelligence (AI) identifies it as a toaster, even though it was trained...

http://bit.ly/2HrZKsG

Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques [Anthropology]

Low social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health...

http://bit.ly/2R7zFPd

Forage silica and water content control dental surface texture in guinea pigs and provide implications for dietary reconstruction [Ecology]

Recent studies have shown that phytoliths are softer than dental enamel but still act as abrasive agents. Thus, phytolith content should be reflected in dental wear. Because native phytoliths show lower indentation hardness than phytoliths extracted by dry ashing, we propose that the hydration state of plant tissue will also...

http://bit.ly/2HrZHNw

Evaluation of Quality of Life and Pattern of Improvement of Bronchial Asthma in Chronic Rhinosinusitis Patients Treated by Functional Endoscopic Sinus Surgery

Abstract

Chronic inflammatory disorders of the upper airways are extremely prevalent and have a major impact on public health. Sinusitis and bronchial asthma are closely interrelated diseases and sinusitis is known to influence bronchial asthma in its severity and chronicity. Causal relationships have been proposed but not yet proved. The relationship between sinusitis and asthma is academically interesting and has important diagnostic and therapeutic implications. The present study is designed to evaluate the efficacy of functional endoscopic sinus surgery done as treatment for chronic rhinosinusitis on bronchial asthma patients, in terms of quality of life and pattern of improvement. Objectives of the study were to determine whether bronchial asthma and quality of life improved after functional endoscopic sinus surgery. This was an open labelled randomised control trial, done at ENT Department of Medical College, Thiruvananthapuram. Those in Group A underwent functional endoscopic sinus surgery and group B patients were given only medicines as per standard protocol. All of them received asthma treatment depending on asthma attacks and severity and followed up at specific intervals. Quality of life status and pattern of improvement of bronchial asthma among these patients were evaluated. Patients of chronic rhinosinusitis treated by functional endoscopic sinus surgery showed significant improvement in the mean asthma symptom score, asthma medication use score, pulmonary function test results, and quality of life assessment scores. Functional endoscopic sinus surgery could be considered early in the natural course of chronic rhinosinusitis with concomitant bronchial asthma.

http://bit.ly/2FHHo58