Genetic alterations of 9p24 in lymphomas and their impact for cancer (immuno-)therapy

Abstract

Chromosome 9 harbors several relevant oncogenes related to hematolymphoid malignancies and one specific region, 9p24, has come into the focus of attention in the last years as it contains recurrently mutant genes of therapeutic interest. The most prominent genes of this locus are programmed death ligands 1 and 2 (PDL1/PDL2), with the amplification of PDL1 being a hallmark of both classical Hodgkin and primary mediastinal B cell lymphoma, and Janus kinase 2 (JAK2), which is point-mutated in myeloproliferative neoplasms and other myeloid malignancies, and rearranged in PCM1-JAK2-positive myeloid/lymphoid neoplasms with eosinophila. Finally, this locus contains the lysine (K)-specific demethylase 4C (KDM4C/JMJD2C), which is also relevant for oncogenesis. Activation of these genes is effectuated, as exemplified, by multiple mechanisms, which is rather unique to oncogenes, since they are usually affected by just one type of mutation, and points towards the central role of these genes in tumor initiation and growth. Amplifications and, less frequently, translocations are the most common findings for PDL1/PDL2 and JAK2 in lymphomas. In this review, we describe the role of genes located on chromosome 9p24 and their derived proteins in diverse subtypes of lymphomas, with a special focus on PDL1 and PDL2, which are becoming a central target of immunotherapy, not only in classical Hodgkin lymphoma but also in various types of solid cancers. We also elucidate the role of the surgical pathologists in this setting — concerning what they can contribute — both diagnostically and predictively.

https://ift.tt/2PnMLYK

Patterns of failure in high-metastatic node number human papillomavirus-positive oropharyngeal carcinoma

Publication date: October 2018

Source: Oral Oncology, Volume 85

Author(s): Nicholas C.J. Lee, Jacqueline R. Kelly, Henry S. Park, Yi An, Benjamin L. Judson, Barbara A. Burtness, Zain A. Husain

Abstract

Background

The 8th edition American Joint Committee on Cancer staging system for resected HPV-positive oropharynx carcinoma (HPV+ OPC) highlights high node number as a critical determinant of survival. We sought to characterize outcomes and patterns of failure in patients with high pathologically involved node number oropharynx cancer.

Methods

We retrospectively identified 116 HPV+ OPC patients sequentially treated with neck dissection and either resection or intraoperative brachytherapy of the primary tumor between 2010 and 2016. External beam radiation was given based on the pathologic findings. Cox proportional hazards regression was used for multivariate analysis.

Results

With a median follow-up of 27 months, the 3-year overall survival and progression free survival (PFS) were 89% and 81%, respectively. On multivariate analysis, ≥5 involved lymph nodes was significantly associated with worse PFS (hazard ratio 4.3, 95% confidence interval (CI) 1.5–12.0, P = 0.001). Rates of 3-year locoregional recurrence (LRR) in patients with ≤4 vs ≥5 were 6% and 22% (log-rank P = 0.12). Rates of 3-year distant metastases (DM) were 12% and 53% between ≤4 and ≥5 (log-rank P < 0.001).

Conclusion

Our findings confirm that patients with 5 or more involved lymph nodes appear to have substantially worsened rates of disease recurrence. While these patients appear to be at high risk of both LRR and DM, the predominant mechanism of failure is distant, and the rate of DM in this group was over 50%. Dedicated clinical trials in this patient population are warranted with a focus on mitigating the high DM rate.

https://ift.tt/2LcAnHV

Management of otitis media with effusion in children. Société française d’ORL et de chirurgie cervico-faciale clinical practice guidelines

Publication date: August 2018

Source: European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 135, Issue 4

Author(s): F. Blanc, D. Ayache, M.N. Calmels, O. Deguine, M. François, N. Leboulanger, E. Lescanne, R. Marianowski, J. Nevoux, R. Nicollas, S. Tringali, N. Tessier, V. Franco-Vidal, P. Bordure, M. Mondain

Abstract

The Société française d'ORL et de chirurgie cervico-faciale clinical practice guidelines concern the management of otitis media with effusion (OME) in children under the age of 12 years. They are based on extensive review of MEDLINE and Cochrane Library publications in English or French from 1996 to 2016 concerning the methods of diagnosis and assessment of otitis media with effusion, as well as the efficacy of tympanostomy tubes and medical and surgical treatments of OME.

https://ift.tt/2nS40Fb

Editorial Board

Publication date: August 2018

Source: European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 135, Issue 4

Author(s):

https://ift.tt/2LdIofw

Contents

Publication date: August 2018

Source: European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 135, Issue 4

Author(s):

https://ift.tt/2nThxMI

Hypermucoviscous Klebsiella pneumoniae liver abscess requiring liver resection

Description 

A 41-year-old healthy woman from China presented to her local hospital with a 4-day history of fevers, malaise and epigastric pain. On examination, she had localised right upper quadrant abdominal pain on palpation. Laboratory investigations showed leukocytosis (13.8x10⁹/L), thrombocytopaenia (82x10⁹/L) and elevated alanine transaminase (184 U/L). An abdominal CT scan revealed a 10x8x9 cm multiloculated collection within the right liver lobe, with a second nodular septated collection under the left subcapsular region (figure 1). Her blood cultures returned positive for Klebsiella pneumoniae, resistant to ampicillin and susceptible to cefazolin, ciprofloxacin and meropenem. She was admitted to hospital and started on ceftriaxone.

Figure 1

Abdominal CT showing large multiloculated liver abscesses in segments 2/3 of the left liver lobe (white arrow) and segments 6/7 of the right liver lobe (black arrow).

Diagnostic and therapeutic ultrasound-guided 10F drains were inserted into both abscesses...

https://ift.tt/2LcHnnZ

Paediatric parapharyngeal ganglioneuroma

A 17-year-old man initially presented to his primary care physician with throat pain for 1 week and was started on amoxicillin. After four additional days of ongoing pain and difficulty swallowing with decreased oral intake, he presented to the emergency department. Exam showed fullness to the right posterior oropharynx and palpable mass in the right neck without stridor. Initial imaging was soft tissue neck CT with contrast, which showed cystic 8 cm mass in the parapharyngeal space. Patient additionally underwent MRI, which showed an 8.6 cm mass in the right posterior oropharynx with obliteration of the vallecula. Differential diagnosis included abscess; therefore, ear, nose, and throat (ENT) specialist was consulted for possible drainage. Intraoperatively, there was no abscess; alternatively a biopsy was obtained, which was identified by pathology as a ganglioneuroma. Patient was referred to paediatric ENT specialist, underwent extensive resection confirming diagnosis of ganglioneuroma and did well postoperatively.

https://ift.tt/2Plm0Em

Euglycaemic diabetic ketoacidosis in bariatric surgery patients with type 2 diabetes taking canagliflozin

A 52-year-old type 2 diabetic man previously on canagliflozin developed severe anion gap metabolic acidosis and markedly elevated beta-hydroxybutyrate on postoperative day (POD) 2 status post laparoscopic Roux-en-Y gastric bypass. An insulin drip and aggressive intravenous fluid repletion were initiated, and electrolytes were monitored and repleted. His anion gap closed, and he was discharged on POD 4. This euglycaemic diabetic ketoacidosis prolonged his hospital stay by 2 days.

https://ift.tt/2LdKrQM

Bowel perforation in chronic idiopathic megarectum and megacolon

Description 

A 24-year-old man with autism spectrum disorder presented to accident and emergency complaining of a 1-week history of abdominal pain and diarrhoea. He had a history of chronic constipation with multiple previous admissions stretching 4 years back. On examination, he had a tender, distended abdomen with quiet bowel sounds. His CT scan on admission (figure 1) showed a dilated (up to 18 cm) rectum and sigmoid colon filled with faeces. The patient was managed conservatively with oral laxatives and regular enemas. However, the patient refused the enemas and was maintained on oral laxatives. Two days later, the patient complained of worsening abdominal pain. On examination, he had a peritonitic abdomen and reduced consciousness level. Biochemical investigations revealed worsening renal function and that the patient was now acidotic. A chest X-ray revealed free air beneath the diaphragm. A repeat CT scan (figures 2 and 3

https://ift.tt/2nThDUr

Asymptomatic dysphagia causing recurrent aspiration pneumonia

52-year-old male patient with known bipolar disorder and innate cerebral palsy causing widespread spasticity problems. Treated for 2 years with antidepressants and electroconvulsive therapy. He repeatedly presented with—and was treated for—pneumonia resulting in more than 20 episodes of hospital admission. He underwent numerous examinations until a diagnosis of dysphagia was established using video fluoroscopic swallowing examination (modified barium swallow). Eventually, as all other treatment regimens had proven effortless, percutaneous gastrostomy feeding tube was inserted and intensive training with a specialised occupational therapist was started. This treatment regimen caused the recurrent episodes of pneumonia to vanish. It is important to acknowledge that otherwise silent dysphagia may cause recurrent pneumonia.

https://ift.tt/2N2rdPP

Trisomy 5 as the sole chromosomal anomaly in acute lymphoblastic leukaemia

Trisomy 5 as the sole cytogenetic aberration in acute lymphoblastic leukaemia (ALL) is exceedingly rare. As such, its prognostic and therapeutic relevance remains unknown. We report a case of an 18-year-old young man who was diagnosed with B cell ALL with trisomy 5 as the sole chromosomal abnormality. He was treated with chemotherapy and went into complete remission. On the 14th month of treatment, he relapsed with central nervous system involvement characterised by leukaemic infiltration of the optic nerve and facial palsy. He subsequently underwent reinduction chemotherapy with aggressive intrathecal chemotherapy followed by posterior globe and whole brain radiation therapy. He is currently on his 26th month of treatment, in second remission, with complete resolution of leukaemic infiltrative optic neuropathy and facial paralysis. As more cases of this nature are reported, we will be able to determine the relevance of this distinct cytogenetic entity.

https://ift.tt/2nU9E9L

Colobronchial fistula: a rare cause of non-resolving pneumonia in Crohns disease

We discuss the case of a 44-year-old man with a refractory left lower lobe pneumonia progressing to a pulmonary abscess caused by a colobronchial fistula, a rare complication of underlying Crohn's disease. The patient presented with weight loss and signs of a pulmonary consolidation, which responded incompletely to the targeted antibiotic treatment. The causative colobronchial fistula was demonstrated by CT-guided puncture and retrograde injection of contrast medium. After fistula excision, the patient recovered rapidly with a weight gain of 4 kg within a few weeks.

https://ift.tt/2N7JpI9

Charcot osteoarthropathy of the knee secondary to neurosyphilis: a rare condition managed by a challenging arthrodesis

The Charcot joint or neuropathic osteoarthropathy was first described as an arthritic sequela of neurosyphilis (tabes dorsalis). It results in significant joint destruction and instability. Nowadays, it is a very rare condition and represents a considerable challenge to the orthopaedic surgeon. The authors describe the case of a patient diagnosed with neurosyphilis who was requested an orthopaedic consultation for an enlarged and unstable knee. The diagnosis of Charcot knee was made and based on the clinical and radiographical findings combined with the patient's medical history. Knee arthrodesis was the surgical treatment chosen to preserve the limb and only succeeded at second attempt. At 4 years of follow-up, it proved to be an effective surgical treatment. In this article, we focus on the importance of early recognition of joint changes in these patients in order to prevent irreversible joint loss.

https://ift.tt/2PrISC7

Quadruple torsion of the fallopian tube in an 18-year-old virgin: a rare twist

In this report, we describe an 18-year-old nulliparous virgo, with no medical history, who presented herself at the emergency department with symptoms of lower abdominal pain and nausea with vomiting. On examination, an echogenic unilocular cyst with possible relation to the right ovary was found. The working diagnosis was an ovarian torsion. She underwent a diagnostic laparoscopy which revealed a quadruple torsion of the fallopian tube with hydrosalpinx. Detorsion of the tube was performed, and the tube was drained using diathermic incision. After the surgery, the patient recovered rapidly. Ultrasonic evaluation 38 days later showed an echogenic area measuring 2x3 cm suspected for persistent hydrosalpinx. Because of the asymptomatic postoperative period, the patient was treated conservatively, and no further treatment was performed.

https://ift.tt/2Lb9Z1a

Non-cutaneous AIDS-associated Kaposis sarcoma presenting as recurrent rectal abscesses

Kaposi's sarcoma is a fatal disease that typically presents with cutaneous manifestations in immunocompromised individuals. There are a small number of documented cases where patients diagnosed with this disease present without cutaneous lesions. We present a 35-year-old man with recurrent rectal abscesses and fistula-in-ano, which required multiple drainage procedures. Further investigation revealed a diagnosis of HIV-AIDS, and biopsy of a rectal mass confirmed the diagnosis of visceral Kaposi's sarcoma, despite the absence of cutaneous involvement. Workup revealed hepatic metastasis and a second pulmonary primary malignancy. The patient denied chemotherapy or further intervention and was subsequently lost to follow-up. Prompt diagnosis of Kaposi's sarcoma and initiation of treatment is vital to decrease disease progression. A high index of suspicion should be present in immunocompromised patients, and clinicians must recognise atypical presentations in order to improve long-term survival.

https://ift.tt/2Pou0Vf

Primary amelanotic malignant melanoma of cervix masquerading as squamous cell carcinoma presenting with extensive metastases

Amelanotic melanoma of cervix is a rare and aggressive neoplasm and only few cases have been reported in the literature. We report a rare case of an amelanotic melanoma of the uterine cervix with extensive metastases and multiple subcutaneous nodules. Due to the unusual site and amelanotic nature of the lesion, chances of misdiagnosis are high and immunohistochemical markers for melanoma help establish the diagnosis. The possibility of metastasis from a primary malignant melanoma of the skin needs to be ruled out. The present case was initially misdiagnosed and treated on the regimen for squamous cell carcinoma, but progressed despite chemotherapy. After a thorough re-evaluation and applying extensive panel of immunohistochemistry, the diagnosis of an amelanotic malignant melanoma of uterine cervix was established.

https://ift.tt/2LcF5oT

Internal iliac artery transposition for vascular reconstruction in a patient with life-threatening iatrogenic common iliac artery injury

Major vascular injury during surgery is life threatening and can be a nightmare for any surgeon.

We share our experience of a 42-year-old woman where right common iliac artery and both common iliac veins were accidentally injured during lumbar discectomy leading to haemorrhagic shock. Patient was resuscitated and explored. A 4 cm segment of right common iliac artery was found lacerated along with perforations of both iliac veins. Proximal segment of internal iliac artery was mobilised quickly and vascular continuity was restored by end-to-end anastomosis of this segment to the proximal segment of common iliac artery after excising the damaged segment. Iliac veins were repaired primarily. Patient made an uneventful recovery. We share this technique as it was found expeditious and effective and may benefit surgeons working in this field.

https://ift.tt/2nWh4tk

Fever in a returning traveller: visceral leishmaniasis triggering haemophagocytic lymphohistiocytosis

We present the case of a 23-year-old student admitted with fever, night sweats and splenomegaly. These non-specific signs and symptoms posed a diagnostic challenge which was further complicated by a history of recent foreign travel. The range of potential diagnoses required a variety of investigations in order to reach the final diagnosis. The incidental finding of an incompetent bicuspid aortic valve and an inflamed gallbladder further clouded the diagnostic process. Despite treatment with broad spectrum antibiotics, the patient continued to deteriorate. Serological testing finally provided a diagnosis of visceral leishmaniasis. The patient subsequently developed haemophagocytic lymphohistiocytosis, a life-threatening immune hyperactivity state that very rarely complicates leishmaniasis infection. With the use of amphotericin B and high-dose steroids, the patient made an excellent recovery.

https://ift.tt/2N7NpYP

Progressive supranuclear palsy responding to intravenous thiamine: superimposed Wernickes encephalopathy?

Progressive supranuclear palsy (PSP) may be a risk factor for thiamine deficiency. The classic symptoms of PSP (postural instability, supranuclear vertical gaze palsy and dementia) overlap with the clinical triad of Wernicke's encephalopathy (cognitive impairment, gait problems and ocular abnormality). Therefore, superimposed thiamine deficiency in patients with PSP may aggravate the pre-existing symptoms of PSP. Here, we are reporting a 64-year-old woman having supranuclear ocular palsy, gait instability and dementia for the past 2–3 years. The patient fulfilled the diagnostic criteria of PSP. In parallel, she fulfilled the Caine's criteria of Wernicke's encephalopathy. Her serum thiamine level was low. Supplementation of thiamine led to marked improvement in the symptoms which had been present for many years. These symptoms were originally presumed to be due to PSP. This case highlights the needs to identify superimposed thiamine deficiency in patients with PSP.

https://ift.tt/2Prldlq

Multiple renal calculi due to hypercalcaemia induced by over-the-counter vitamin D intoxication

Renal stone disease is a common and painful condition. Even though it is rarely fatal, patients describe it as the worst pain in their life. While dietary calcium may decrease the risk of stone formation, patients on supplemental calcium are at higher risk. Moreover, patients with diabetes are more prone to develop renal calculi. Hypervitaminosis D is a rare cause of hypercalcaemia. This is a case of an elderly diabetic man who developed multiple calcium oxalate renal stones due to hypercalcaemia following calcium–vitamin D supplementation.

https://ift.tt/2N7MYh9

Misplaced Foley catheter in ureter in a female with neurogenic bladder: a rare complication report

Accidental placement of Foley catheter in ureter is a rare phenomenon. It is more common in females with neurogenic bladder who have hypocontractile bladder or there can be iatrogenic placement during surgical procedures. We describe a case of a female suffering from upper motor neuronal lesion due to trauma at T8 level (American Spinal Injury grade A) following which she developed neurogenic bladder. A Foley catheter was unintentionally placed in the ureter and subsequently removed through a novel technique of percutaneous ultrasound-guided balloon puncture. It is not only imperative to diagnose and manage such an aberrant Foley catheter placement but also more importantly proper steps must be taken to prevent such a complication from occurring in these patients.

https://ift.tt/2N5HHH2

Mediastinal metastasectomy from a primary germ cell testicular tumour resulting in occult thoracic duct injury and chylothorax

A 22-year-old man underwent mediastinal metastasectomy for a testicular germ cell tumour via median sternotomy. Intraoperatively, the tumour was massive, measuring 88 mm in anterior-posterior (AP) diameter. It was densely adherent to the trachea and aggressive debulking resulted in tracheal injury. Therefore, the patient was kept nil by mouth for 3 days postoperatively and was discharged uneventfully. He represented only 2 days later with a large right-sided chylothorax. His chylothorax was managed conservatively with insertion of an intercostal catheter (ICC) and a low-fat diet. Over the course of 9 days, the ICC drained approximately 5 L of fluid. His admission was further complicated by severe gastroparesis requiring feeding Nasojejunal (NJ) tube placement. The delayed feeding in this case resulted in late detection of the occult thoracic duct injury. This case illustrates that conservative and multidisciplinary management of a postoperative chylothorax from a suspected thoracic duct injury achieves favourable outcomes avoiding further surgical intervention.

https://ift.tt/2nTkAof

Malignant proliferating trichilemmal tumour

Proliferating trichilemmal tumours are benign but locally aggressive skin neoplasms arising from hair follicles. Rarely, they can become malignant and must be appropriately managed to prevent recurrence and metastasis. One must have a low threshold for diagnosing this rare neoplasm.

https://ift.tt/2N5HjIA

Tracking a painful episode after a joint replacement using patient-reported outcome measures (PROMs)

Patient-reported outcome measures (PROMs) are an important tool in measuring the benefit of a surgery for patients and for clinicians. The results of such assessment tools can be used to monitor patient progress or initiate intervention. The scores also provide a reproducible evaluation of functional recovery and well-being after surgery. We report the case of a 68-year-old woman who underwent left unicondylar knee replacement in November 2011 followed by right unicondylar knee replacement in April 2012. Prospective, web-based electronic PROMs were used preoperatively and every 6–12 months postoperatively to monitor the improvement in pain and function symptoms. These outcome measures were beneficial in helping to monitor an episode of new pain in her left knee, without requiring invasive or extensive investigation.

https://ift.tt/2PnEUdI

Delirium and topographical disorientation associated with glioblastoma multiforme tumour progression into the isthmus of the cingulate gyrus

Since there is no cure for glioblastoma multiforme (GBM), the goal of treatment becomes prolonging the survival through cytoreduction while minimising neurological deficits. In this case report, laser interstitial thermal therapy (LITT) was used once the tumour progressed into the isthmus of the cingulate gyrus. One year after temporal lobectomy, disorders of memory, emotion, personality and navigation, likely related to limbic system involvement along with hallucinations and fluctuating cognition occurred as the tumour progressed. After ablation of the posterior cingulum, worsening of topographical disorientation was observed.

Per literature review, delirium has been noted in patients with strokes involving the right-sided temporo-parieto-occipital junction, and topographical disorientation has been associated with lesions of the right posterior cingulum. Alternative causes of these deficits were ruled out, leaving structural changes as the primary explanation. This is the first report of the neurological deficits associated with tumour progression and vasogenic oedema in this region.

https://ift.tt/2LbvnDa

CD200 expression is a feature of solid pseudopapillary neoplasms of the pancreas

Abstract

CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.

https://ift.tt/2whGQvF

Dupilumab improves symptoms, quality of life, and productivity in uncontrolled persistent asthma

Publication date: Available online 21 August 2018

Source: Annals of Allergy, Asthma & Immunology

Author(s): Jonathan Corren, Mario Castro, Pascal Chanez, Leonardo Fabbri, Vijay N. Joish, Nikhil Amin, Neil M.H. Graham, Vera Mastey, Adeline Abbé, Christine Taniou, Puneet Mahajan, Ariel Teper, Gianluca Pirozzi, Laurent Eckert

https://ift.tt/2MqK6Qt

Differences in airway structural changes assessed by three-dimensional computed tomography in asthma and asthma-COPD overlap

Publication date: Available online 21 August 2018

Source: Annals of Allergy, Asthma & Immunology

Author(s): Mitsuru Niwa, Tomoyuki Fujisawa, Masato Karayama, Kazuki Furuhashi, Kazutaka Mori, Dai Hashimoto, Hideki Yasui, Yuzo Suzuki, Hironao Hozumi, Noriyuki Enomoto, Yutaro Nakamura, Naoki Inui, Takafumi Suda

Abstract

Background: Asthma- COPD overlap (ACO) is a clinical phenotype sharing features of asthma and COPD. Multidetector row computed tomography (MDCT) can be used to evaluate the airway structure; however, differences between asthma and ACO seen on MDCT are poorly understood.

Objective: To investigate the difference in airway structural between asthma and ACO using MDCT in patients with clinical asthma.

Methods:Sixty-four patients with asthma were allocated to an asthma group (neversmokers and ex-smokers with a smoking history of <10 pack-years) or an ACO group (patients with a ≥10-pack-year smoking history and FEV1/ FVC <0.7). The asthma group was further divided into patients with airflow limitation (AL; FEV1/FVC <0.7) and those without AL. Wall thickness (WT) and airway inner luminal area in the third-generation to fifth-generation bronchi were evaluated using MDCT in both study groups and in 29 healthy controls.

Results: There were 43 patients in the asthma group (20 with AL, 23 without AL) and 16 in the ACO group. Patients with asthma and ACO had significantly greater WT than the healthy controls. WT in the third-generation bronchi was significantly greater in the ACO group than in the asthma group. The ACO group and the asthma with AL group were matched for age, disease duration, FEV1/FVC. WT in the third-generation bronchi was still greater in the ACO group than in the asthma with AL group.

Conclusion: Patients with ACO have a thicker airway wall than those with asthma, suggesting that airway remodeling is more prominent in ACO than in asthma.

https://ift.tt/2wkUfDs

The effect of diabetes mellitus on the pharmacokinetics and pharmacodynamics of tuberculosis treatment [Clinical Therapeutics]

Background: Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics and pharmacodynamics of anti-TB drugs remains poorly-characterized.

Methods: Newly-diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (pre-dose, 0.5, 2, 6 hours post-dose) during intensive and continuation phases of treatment. The effect of DM and HbA1c on the maximum concentration (C_max) of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed.

Results: Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in C_max of pyrazinamide and isoniazid (but not rifampicin) with DM or increasing HbA1c. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations [adjusted GMR: 0.74, p=.032]. In adjusted Cox models, female gender (aHR=1.75, p=0.001), lower Xpert smear grade (aHR=1.40, p<0.001) and pyrazinamide C_max (aHR=0.99, p=0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampicin concentrations were associated with faster time to culture conversion in patients with DM only. Pyrazinamide C_max above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) [OR: 1.92, p=.041].

Conclusion: DM and higher HbA1c increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampicin or isoniazid). Higher pyrazinamide concentrations, though, were associated with worse microbiologic and clinical outcomes. DM status also appeared to influence PK-PD relationships for isoniazid and rifampicin.

https://ift.tt/2nSyUgD

Characterizing the Effects of Glutathione as an Immunoadjuvant in the Treatment of Tuberculosis [Experimental Therapeutics]

Mycobacterium tuberculosis (M. tb) is the etiological agent that is responsible for causing tuberculosis (TB), which continues to affect millions of people worldwide, with an ever-increasing resistance to antibiotics. We tested the synergistic effects of N-acetyl cysteine (NAC, the precursor molecule for the synthesis of glutathione) and individual first-line antibiotics typically given for the treatment of TB such as Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) and Pyrazinamide (PZA) to improve the ability of macrophages to control intracellular M. tb infection. Glutathione (GSH), a pleiotropic antioxidant molecule has been previously shown to display both antimycobacterial and immune-enhancing effects. Our results indicate that there was not only an increase in beneficial immunomodulatory effects, but a greater reduction in the intracellular viability of M. tb when macrophages were treated with the combination of antibiotics (INH/RIF/EMB or PZA) and NAC.

https://ift.tt/2LaGn43

Biolog phenotype microarray: a tool for the identification of multidrug resistance efflux pumps inducers [Mechanisms of Resistance]

Multidrug resistance efflux pumps frequently present low levels of basal expression. However, antibiotic resistant mutants that overexpress these resistance determinants are selected during infection. In addition, increased expression of efflux pumps can be induced by environmental signals/cues, which can lead to situations of transient antibiotic resistance. Herein, we have applied a novel high-throughput methodology in order to identify inducers able of triggering the expression of the Stenotrophomonas maltophilia SmeVWX and SmeYZ efflux pumps. To that goal, bioreporters in which the expression of the yellow fluorescent protein (YFP) is linked to the activity of either smeVWX or smeYZ promoters were developed and used for the screening of potential inducers of the expression of these efflux pumps using Biolog phenotype microarrays. YFP production was measured by flow cytometry and the levels of expression of smeV and smeY in the presence of a set of selected compounds were also determined by real-time RT-PCR. The expression of smeVWX was induced by iodoacetate, clioquinol and selenite, while boric acid, erythromycin, chloramphenicol and lincomycin triggered smeYZ expression. The susceptibility to antibiotics that are known substrates of the efflux pumps decreased in the presence of the inducers. However, the analyzed multidrug efflux systems did not contribute to S. maltophilia resistance to the studied inducers. To sum up, the use of fluorescent bioreporters in combination with Biolog plates is a valuable tool for identifying inducers of the expression of bacterial multidrug efflux pumps, and likely of other bacterial systems whose expression is regulated in response to signals/cues.

https://ift.tt/2nTYCkQ

Deletion of one 23S rDNA (rrl) copy contributes to the development of resistance to linezolid in Staphylococcus warneri [Letters]

Staphylococcus warneri, one of the emerging coagulase negative staphylococci, could be responsible for bone and joint infections (1-3), where linezolid (LZD) seems to be a good alternative treatment (4, 5)....

https://ift.tt/2OObILU

Short-Term Peripheral Venous Catheter-Related Bloodstream Infections: Evidence for Increasing Prevalence of Gram-Negative Microorganisms from a 25-Year Prospective Observational Study [Epidemiology and Surveillance]

Aim of this study was to describe the etiology and outcome of short-term peripheral venous catheter (PVC)-related blood-stream infections (PVCRBSI) in a 25-year period (1992-2016) and to identify predictive factors of gram-negative PVCRBSI.

This was a prospective observational study including all episodes of PVCRBSI. A multivariate logistic regression model adjusted for calendar year was built to explore factors associated with gram-negative etiology.

Over the study period, 711 episodes of PVCRBSI were identified. Incidence rate of PVCRBSI increased from 0.06 to 0.13 episodes/1000patient-days. Gram-negative etiology was demonstrated in 162 (22.8%) episodes. There was a significant increase in the proportion of gram-negative etiology (22.6% in 1992-1996 versus 33.2% in 2012-2016). Independent predictive factors of gram-negative PVCRBSI were being in the hospital for more than 7 days with a catheter in situ for more than 3 days (aOR 1.80, 95%CI 1.20-2.69), surgery in the previous month (aOR 2.39, 95%CI 1.40-4.09), and antimicrobial treatment with beta-lactams (aOR 1.80, 95%CI 1.16-2.78).

In conclusion, we reported an increase in the prevalence of gram-negative PVCRBSI over the last 25 years. Factors associated with gram-negative etiology were being in the hospital for more than 7 days with a catheter in situ for more than 3 days, having undergone surgery and having received antimicrobial treatment with beta-lactams.

https://ift.tt/2nVprFa

Identifying vancomycin as an effective antibiotic for killing Borrelia burgdorferi [Experimental Therapeutics]

Borrelia burgdorferi is the causative agent of Lyme borreliosis. Antibiotic therapy of early acute infection is effective for most patients, but 10-20% go on to develop Post-Treatment Lyme Disease Syndrome. The nature of PTLDS remains unknown, but currently approved antibiotics for treatment of Lyme disease do not appear to impact these symptoms after they have developed. We reason that minimizing the time the pathogen interacts with the host will diminish the probability of developing PTLDS, irrespective of its nature. This calls for an efficient eradication of the pathogen during acute infection. In search of a superior killing antibiotic, we examined approved antibiotics for their ability to kill B. burgdorferi. Vancomycin proved more effective in killing the pathogen in vitro than ceftriaxone, the standard of care for disseminated B. burgdorferi infection. Both compounds were also the most effective in killing stationary phase cells. This is surprising, given that inhibitors of cell wall biosynthesis are known to only kill growing bacteria. We found that peptidoglycan synthesis continues in stationary cells of B. burgdorferi, explaining this paradox. A combination of vancomycin and gemifloxacin sterilized a stationary phase culture of B. burgdorferi. Examination of the action of antibiotics in immune-deficient SCID mice showed that doxycycline, a standard of care for uncomplicated acute infection, did not clear the pathogen. By contrast, both ceftriaxone and vancomycin cleared the infection. A trial examining early use of more potent antibiotics on development of PTLDS may be warranted.

https://ift.tt/2OOprlZ

An optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone Macozinone (PBTZ169) [Susceptibility]

The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampicin, pyrazinamide and ethambutol) for the treatment of tuberculosis (TB) is menaced by the emergence of multidrug (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. Intensive efforts have been made to develop new antibiotics or to repurpose old drugs and several of these are currently being evaluated in clinical trials for their anti-tubercular activity. Among the new candidate drugs is macozinone (MCZ), the piperazine-containing benzothiazinone, PBTZ169, which is currently being evaluated in phase I/II clinical trials.

Here, we determined the in vitro and in vivo activity of MCZ in combination with a range of anti-TB drugs in order to design a new regimen against active TB. Two-drug combinations with MCZ were tested against M. tuberculosis using checkerboard and CFU enumeration after drug exposure assays. MCZ was observed to have no interactions with all first- and second-line anti-TB drugs. At the MIC of each drug, MCZ with either bedaquiline (BDQ), clofazimine (CLO), delamanid (DMD) or sutezolid (STZ) reduced the bacterial burden by two logs compared to the drugs alone, indicating synergism. MCZ also displays synergism with clomiphene (CLM), a potential inhibitor of the undecaprenyl pyrophosphate synthase (UppS) in mycobacteria. For all the other drugs tested in combination with MCZ, no synergistic activity was observed. Neither antagonism nor increased cytotoxicity were found for most combinations, suggesting that MCZ could be added to different TB regimens without any significant adverse effects.

https://ift.tt/2nW1kGK

Voriconazole resistance in clinical and environmental isolates of Aspergillus flavus - frequency and investigation into the role of multidrug efflux pumps. [Mechanisms of Resistance]

The magnitude of azole resistance in Aspergillus flavus and the underlying mechanism is obscure. We evaluated the frequency of azole resistance in a collection of clinical (n=121) and environmental isolates (n=68) of A. flavus by broth microdilution method. Six (5%) clinical isolates displayed voriconazole minimum inhibitory concentration (MIC) greater than the epidemiological cut-off value. Two of these isolates with non-wild-type MIC were isolated from same patient and were genetically distinct, which was confirmed by amplified length polymorphism. Mutations associated with azole resistance were not present in the lanosterol 14-α demethylase coding genes (cyp51A, cyp51B and cyp51C). Basal and voriconazole-induced expression of cyp51A homologs and various efflux pump genes was analyzed in three each of non-wild type and wild-type isolates. All the efflux pump genes screened showed low basal expression irrespective of the azole susceptibility of the isolate. However, the non-wild type isolates demonstrated heterogeneous overexpression of many efflux pumps and the target enzyme coding genes in response to induction with voriconazole (1μg/mL). The most distinctive observation was approximately 8-9 fold voriconazole-induced overexpression of an ortholog of Candida albicans ABC multidrug efflux transporter, Cdr1 in two non-wildtype isolates as compared to the reference strain A. flavus ATCC204304 and other wild type strains. Although the dominant marker of azole resistance in A. flavus is still elusive, the current study proposes the possible role of multidrug efflux pumps, especially Cdr1B overexpression in contributing azole resistance in A. flavus.

https://ift.tt/2OObvbA

In Vitro Susceptibility Testing of a Novel Benzimidazole, SPR719, Against Nontuberculous Mycobacteria [Susceptibility]

Nontuberculous mycobacteria (NTM) infections are increasing globally. Mycobacterium avium complex (MAC) and M. abscessus are the most frequently encountered NTM among clinical laboratories, and treatment options are extremely limited. In this study, the in vitro potency of a novel benzimidazole, SPR719, the microbiologically active form of the orally available prodrug SPR720, was tested against several species of NTM.

MICs were performed on 161 isolates of NTM of 13 taxa (seven species, three subspecies and three groups/complexes) in cation adjusted Mueller Hinton Broth as described and recommended by the Clinical and Laboratory Standards Institute (CLSI M24-A2). Comparator antimicrobials included amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, linezolid, minocycline, moxifloxacin, tigecycline, and trimethoprim/sulfamethoxazole (TMP/SMX) for the rapidly growing species (RGM); amikacin and clarithromycin for the MAC; amikacin, ciprofloxacin, clarithromycin, doxycycline, linezolid, moxifloxacin, rifabutin, rifampin and TMP/SMX for the other slowly growing NTM. SPR719 was found to be potent against multiple clinical strains of NTM with an MIC₅₀ range of 0.25 – 4 μg/mL for several species of NTM. These findings support the further advancement of SPR720 for the treatment of NTM disease.

https://ift.tt/2nW1jTc

Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam following Intravenous Administration of ETX2514SUL to Healthy Adult Subjects [Pharmacology]

ETX2514 is a novel β-lactamase inhibitor that broadly inhibits Ambler class A, C and D β-lactamases. ETX2514 combined with sulbactam (SUL) in vitro restores sulbactam activity against Acinetobacter baumannii. ETX2514/sulbactam (ETX2514SUL) is under development for the treatment of A. baumannii infections. The objective of this study was to determine and compare plasma, epithelial lining fluid (ELF) and alveolar macrophages (AM) concentrations following intravenous (i.v.) ETX2514 and sulbactam. Plasma, ELF, and AM concentrations of ETX2514 and sulbactam were measured by LC-MS/MS in 30 healthy adult subjects following repeated dosing (ETX2514 [1 g] and sulbactam [1 g] q6h, as a 3-hour i.v. infusion, for a total of 3 doses). A bronchoalveolar lavage (BAL) was performed once in each subject at either 1, 2.5, 3.25, 4 or 6 h after the start of the last infusion. Penetration ratios were calculated from AUC_0–6 values for total plasma and ELF using mean and median concentrations at the BAL sampling times. Respective ELF AUC_0-6, based on mean and median concentrations, were 40.1 and 39.4 mg·h/liter for ETX2514 and 34.7 and 34.5 mg·h/liter for sulbactam. Respective penetration ratios of ELF to total/unbound plasma concentrations, based on mean/median AUC_0-6, of ETX2514 were 0.36/0.40 and 0.35/0.39, whereas these same ratio values were 0.5/0.81 and 0.50/0.80 for sulbactam. ETX2514 and sulbactam concentrations in AM were measurable and fairly constant throughout the dosing interval (median values of 1.31 and 1.01 mg/liter, respectively). These data support further study of ETX2514SUL for treatment of pneumonia caused by multidrug-resistant A. baumanni.

https://ift.tt/2OPF3FO

Contributions of yap1 mutation and subsequent atrF upregulation to voriconazole resistance in Aspergillus flavus [PublishAheadOfPrint]

Aspergillus flavus is the second most significant pathogen that causes invasive aspergillosis; however, its emergence risks and mechanisms of voriconazole (VRC) resistance have not yet been elucidated in detail. Here, we demonstrate that repeated exposure of A. flavus to sub-inhibitory concentrations of VRC in vitro causes the emergence of a VRC-resistant mutant with a novel resistance mechanism. The VRC-resistant mutant shows a MIC of 16 μg/mL for VRC, and of 0.5 μg/mL for itraconazole (ITC). Whole-genome sequencing analysis showed that the mutant possesses a point mutation in yap1, which encodes a bZIP transcription factor working as the master regulator of oxidative stress response, but no mutations in the cyp51 genes. This point mutation in yap1 caused substitution of Leu558 to Trp (Yap1^Leu558Trp) in the putative nuclear export sequence in the carboxy-terminal cysteine-rich domain of Yap1. This Yap1^Leu558Trp substitution was confirmed as being responsible for the VRC-resistant phenotype, but not for ITC, by the revertant to Yap1^wild-type with homologous gene replacement. Furthermore, Yap1^Leu558Trp caused marked upregulation of the atrF ATP-binding cassette transporter, and the deletion of atrF restored susceptibility to VRC in A. flavus. These findings provide new insights into VRC-resistance mechanisms via a transcriptional factor mutation that is independent of the cyp51 gene mutation in A. flavus.

https://ift.tt/2nRbgRM

Carbapenem resistance caused by high-level expression of OXA-663 {beta}-lactamase in an OmpK36-deficient Klebsiella pneumoniae clinical isolate [PublishAheadOfPrint]

Carbapenem resistance is mainly mediated by carbapenemases or extended-spectrum β-lactamases (ESBL) plus loss of porins. However, we have identified a Klebsiella pneumoniae clinical isolate that contains neither carbapenemases nor ESBLs. Instead, we found that high-level expression of a novel bla_OXA-10-derived β-lactamase gene, bla_OXA-663, in conjunction with OmpK36 deficiency results in high-level carbapenem resistance. This finding demonstrates the combinatorial complexity of factors including β-lactamase activity, its expression levels, and porin activity that yield carbapenem resistance.

https://ift.tt/2LdYdDj

Crystal structures of full-length lanosterol 14{alpha}-demethylases of prominent fungal pathogens Candida albicans and Candida glabrata provide tools for antifungal discovery [PublishAheadOfPrint]

Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections but cure rates are not optimal for immune compromised patients and individuals with co-morbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug resistant fungal pathogens. We have addressed the need to improve the potency, spectrum and specificity for azoles by expressing in Saccharomyces cerevisiae functional, recombinant, hexahistidine-tagged, full-length Candida albicans LDM (CaLDM6xHis) and Candida glabrata LDM (CgLDM6xHis) and determining their X-ray crystal structures. The crystal structures of CaLDM6xHis, CgLDM6xHis and ScLDM6xHis have the same fold and bind itraconazole in near identical conformations. The catalytic domains of the full-length LDMs have the same fold as the CaLDM6xHis catalytic domain in complex with posaconazole, with minor structural differences within the ligand binding pocket. Our structures give insight into the LDM reaction mechanism and phenotypes of single site CaLDM mutations. This study provides a practical basis for the structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.

https://ift.tt/2nUjQzh

Heterologous expression of full-length lanosterol 14{alpha}-demethylases of prominent fungal pathogens Candida albicans and Candida glabrata provides tools for antifungal discovery [PublishAheadOfPrint]

Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections but cure rates are modest for immune compromised patients and individuals with co-morbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug resistant fungal pathogens. We have addressed these problems by expressing in Saccharomyces cerevisiae functional, hexahistidine-tagged, full-length Candida albicans LDM (CaLDM6xHis) and Candida glabrata LDM (CgLDM6xHis) for drug discovery purposes and determining their X-ray crystal structures. In comparison with S. cerevisiae overexpressing LDM6xHis (ScLDM6xHis), the reduced susceptibility of CgLDM6xHis to all azole drugs tested correlated with its level of overexpression. In contrast, the reduced susceptibility to short- (fluconazole, voriconazole) but not medium- (VT-1161) or long-tailed azoles (itraconazole and posaconazole) indicates CaLDM6xHis works best when co-expressed with its cognate NADPH-cytochrome P450 reductase (CaNcp1A) rather than the host reductase (ScNcp1). Overexpression of LDM or Ncp1 modified the ergosterol content of yeast and affected growth inhibition by the polyene antibiotic amphotericin B. Affinity-purified recombinant Candida LDMs bind carbon monoxide and show tight type II binding of a range of azole drugs including itraconazole, posaconazole, fluconazole, and voriconazole. This study provides a practical basis for the phenotypic-, biochemical- and structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.

https://ift.tt/2OTBnTv

Unintentional injection to the bone with a pediatric epinephrine auto-injector

Skin-to-bone distance (STBD) in children prescribed a pediatric epinephrine auto-injector (EAI) for anaphylaxis is not commonly measured in practice. Recent evidence suggests that children with STBD less than ...

https://ift.tt/2BuI3pl

Bullous erythroderma: novel association of pityriasis rubra pilaris with bullous pemphigoid

Clinical and Experimental Dermatology, EarlyView.


https://ift.tt/2MsYAPK

Exceptional mucocutaneous manifestations with amyloid nephropathy: a case report

Amyloidosis is a very rare disease that is difficult to diagnose because of the unspecific early clinical manifestations of the disease. Accurate and early diagnosis is extremely important because the effect o...

https://ift.tt/2BuZia6

Neural therapy of an athlete’s chronic plantar fasciitis: a case report and review of the literature

The focus of this case report is on the role of inflammation as a contributor to pain in plantar fasciitis and its cure by the injection of local anesthetics.

https://ift.tt/2MGLRbe

Conventional cardiopulmonary resuscitation-induced refractory cardiac arrest due to latent left ventricular outflow tract obstruction due to a sigmoid septum: a case report

Patients with left ventricular outflow tract obstruction who do not exhibit a dynamic pressure gradient at rest, experience pressure gradient increases of ≥ 30 mmHg only during specific situations; this is cal...

https://ift.tt/2BwHyes

The challenges of treating tracheobronchitis in a laryngectomee due to nontypeable Haemophilus influenzae: a case report

Laryngectomees run the risk of developing severe respiratory tract infections especially during the winter and when they do not wear a stoma cover. A case of severe tracheobronchitis in a laryngectomee is pres...

https://ift.tt/2PqblbG

Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome

Publication date: Available online 20 August 2018

Source: Clinical Immunology

Author(s): Ying Luo, Yu Xia, Wenjing Wang, Zhichuan Li, Yan Jin, Yifeng Gong, Tingyan He, Qiu Li, Chengrong Li, Jun Yang

Abstract

Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.

https://ift.tt/2w1b0UH

Efficacy and safety of ixekizumab, an interleukin-17A monoclonal antibody, in real-world patients with psoriasis: 12-week results from a Canadian multicenter retrospective study

Background: The discovery of targeted therapies that selectively bind to interleukin (IL)-17A and neutralize the bioactivity of this cytokine has led to the development of the next generation of biologic treatments for psoriasis. Most recently, ixekizumab, an IL-17A monoclonal antibody was approved for the treatment of moderate to severe plaque psoriasis in adult patients. Current efficacy and safety data are limited to results from phase III randomized controlled trials (RCT). Although these studies have shown unprecedented outcomes, how dermatologist prescribe and monitor ixekizumab in the real world is based on results obtained from patients enrolled in clinical trials.

https://ift.tt/2Pry6vZ

Hydroa vacciniforme–like lymphoma in an adult resident of the United States

Introduction: Hydroa vacciniforme–like lymphoproliferative disorders (HVLPDs) are a spectrum of diseases resulting from chronic Epstein-Barr virus (EBV) infection of T cells and natural killer cells. These include classic hydroa-vacciniforme (HV), severe HV, and HV-like lymphoma (HVLL). The latter 2 conditions rarely occur outside Asian and Latin American youth. Here we present an unusual case of adult-onset HVLPD in the United States.

https://ift.tt/2N3Xvu1

Consistency of response by weight across subgroups of patients with psoriasis treated with guselkumab: Results from the VOYAGE 1 and 2 trials

Objective: To evaluate the consistency of response of guselkumab (GUS) across predetermined weight quartile subgroups of psoriasis patients.

https://ift.tt/2MA74nt

Is apremilast a promising treatment for psoriasis and psoriatic arthritis?

Introduction and objective: Apremilast (APR), is a small molecule that selectively inhibits the phosphodiesterase 4 (PDE-4) which modulates the release of pro- and antiinflammatory mediators. it was approved in February 2015 in Italy for the treatment of moderate-to-severe psoriasis and psoriatic arthritis (PsA) in adults. The aim of the authors is to assess the efficacy as well as the safety of the PDE-4 inhibitor apremilast both in PsA and psoriasis (Pso).

https://ift.tt/2N0XXsL

Evaluation of the protection of a broad-spectrum SPF50+ sunscreen against DNA damage

Introduction and objectives: UV exposure causes many skin damages. UV damages DNA, proteins, and lipids, which can result in harmful consequences, such as carcinogenesis and skin aging. Formation of DNA photoproducts caused by UV exposure needs to be investigated in vivo to assess sunscreens' level of protection against solar genotoxicity. The objective of the present study was to evaluate how the tested broad-spectrum sunscreen protect against the formation of photoproducts.

https://ift.tt/2MBF7eY

Dermatology boot camp: A model for initiating new residents into dermatology clinical care

Entering dermatology residency is an immersive experience requiring specialty-specific skills that are not routinely emphasized in medical school and internship training. To provide a practical introduction to dermatologic clinical care emphasizing ACGME dermatology milestones, we developed a concentrated 8-hour curriculum for first-year dermatology residents that encompasses 3 pillars of patient care: clinical visit competencies, procedural techniques, and professionalism and collegiality. A variety of diverse teaching approaches are employed, emphasizing respect for one another and patients, to allow instruction in pertinent practical and intellectual skills.

https://ift.tt/2N3XupX

Improvement of chin profile with the use of calcium hydroxylapatite with integral lidocaine

Background and objective: Adequate chin projection is associated with strength in the male jawline, balance to a female face, and a harmonious balance with the nose. The criterion standard to improve the chin profile is surgical placement of a solid implant. However, the emergence of fillers to shape and improve facial features provides new options to achieve immediate results with minimal downtime. Calcium hydroxylapatite plus integral lidocaine (CaHA(+); Merz North America, Inc.) is a filler that provides immediate volume improvement and lasts for ≥1 year.

https://ift.tt/2MFhQIY

Gender differences for those who have second primary malignancies within the first year of survival after malignant melanoma diagnosis: A United States population-based study

Introduction: Little has been reported about gender differences in those with second primary malignancies (SPM) within 1 year of melanoma (MM) diagnosis. The aim of this study is to explore gender differences as evidenced by tumor type within the first year of MM survival status using the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database.

https://ift.tt/2Bv3I0w

Endoglin is highly expressed in human mast cells

Background: CD 105 is a glycoprotein of cell membrane, for which an immunohistochemical antibody has been used as marker of endothelial cells from capillaries in proliferation. Mast cells originate from hematopoietic stem cells located in the bone marrow and migrate through the blood stream to target tissues. These cells are a component of normal tissue, though they play an important role in the regulation of several processes, including inflammation, allergy and neoplasia. The aim of this study was to evaluate the use of CD105 as a biologic marker of mast cells compared with the criterion standard stain.

https://ift.tt/2Pn4f7D

Disseminated pruritic papules

A 60-year-old Arabic man with a medical history of diabetes mellitus was admitted to the hospital for an unprovoked deep vein thrombosis with pruritus, nonproductive cough, and abdominal pain. His pruritus had been ongoing over the preceding four months and he has developed diffuse erythematous to hyperpigmented papules with some having a central keratotic core and others with hemorrhagic crusting. He had minimal to no improvement in his pruritus on mid-potency topical corticosteroids in combination with antihistamines.

https://ift.tt/2BtDADi

Cutaneous nontuberculous mycobacteria infection: A retrospective study of 78 cases

Introduction: The incidence of cutaneous nontuberculous Mycobacteria (NTM) infection is increasing in both immunosuppressed and immunocompetent patients. These infections are often misdiagnosed due to nonspecific presentation.

https://ift.tt/2Prgiku

Köhlmeier-Degos disease: Does the benign form really exist?

A 46-year-old woman was referred to us for evaluation of asymptomatic erythematous papules with central umbilication and atrophy in trunk and extremities. Histologic features were compatible with Degos disease. She had no systemic manifestations and the laboratory and the radiologic findings were no significant. 6 years after the diagnosis the patient complained of headache and weakness. Initial evaluation revealed a subdural hygroma on CT. Then she developed a hemiparesis, and MRI showed a subacute ischemia in the territory supplied by the middle cerebral artery.

https://ift.tt/2N9waX2

Infantile myofibromatosis: A diagnostic conundrum

A 2-day-old boy was referred to dermatology with a history of skin lesions present since birth. He was born at 39+6 weeks by cesarean section owing to failure to progress to a primiparous mother with gestational diabetes. On examination, he had 6 firm, tumid, red-violaceous nodules on the body. The largest was on the left side of the neck which had reportedly grown since birth; ultrasound did not reveal any Doppler flow. In addition, similar lesions were noted on the torso, with smaller nodules on the groin, lower abdomen and calf.

https://ift.tt/2MBpPXw

Impact of genital lichen sclerosus treatments on occurrence of vulvar neoplasms in 275 adult women

Background: Lichen sclerosus (LS) is a chronic inflammatory disease most commonly affecting the genital area of women. LS-associated vulvar neoplasms are known to occur. Treatment of LS is thought to reduce malignancy risk. A recent report showed reduction in vulvar neoplasms in those compliant with maintenance therapy. We performed a single-institution, retrospective chart review to identify vulvar neoplasm occurrence in women with biopsy-proven genital LS and to determine whether a correlation exists between LS treatments and vulvar neoplasm occurrence.

https://ift.tt/2N3ScL1

Hallopeau’s continuous acrodermatitis: Management

Introduction: Hallopeau's continuous acrodermatitis (ACH) is a chronic inflammatory disease affecting the fingers and/or toes, characterized by an erythematous-desquamative plaque with sterile pustular eruptions. It is a rare or perhaps underdiagnosed and more frequent pathology in middle-aged women, according to the few cases reported.

https://ift.tt/2PqGhIM

Familial aplasia cutis congenita: A case report

Introduction: Aplasia cutis congenita is a rare congenital disorder. The incidence has been estimated at 1 per 10,000 live births. It is characterized by the absence of certain layers of the skin. At birth, it commonly presents as a solitary well localized lesion on the scalp. Infrequently, a widespread area can be involved. The etiology remains unclear. Genetic factors, environmental causes and teratogens have been implicated.

https://ift.tt/2Buzhrv

Erlotinib-induced erosive pustular dermatosis of the scalp complicated by MRSA infection

Introduction: Erosive pustular dermatosis (EPD) of the scalp is a rare entity characterized by erosive, follicular, papulopustular eruptions with nonspecific chronic inflammatory findings on histopathology. EPD of the scalp has been associated with epidermal growth factor receptor (EGFR) inhibitor therapy such as gefitinib or erlotinib with only a few reported cases. Herein, we report an impressive presentation of EPD of the scalp complicated by secondary methicillin-resistant Staphlococcus aureus (MRSA) infection during treatment with erlotinib for stage IV lung cancer.

https://ift.tt/2MJSdXo

Efficacy of sinecatechins 10% as proactive sequential therapy of external and perianal genital warts after laser therapy: An exploratory trial

Background: External genital warts (EGW) are the most common viral sexually transmitted infection. Ablative treatments like cryotherapy, curettage and CO2 laser therapy offer rapid onset of effect, fast clearance, and reduction of virus load. However, these procedures are associated with high recurrence rates (RR) of 20%-77% in the short and medium term and do not provide sustained clearance. After laser therapy removal of EGW a RR up to 60% has been reported. Topical sinecatechins 10% is a patient-applied regimen for the treatment of EGW with a low RR (6.5%) at 3 months after completion of the therapy in the pivotal trials conducted so far.

https://ift.tt/2BtJqEP

Eccrine poroma: An unusual presentation and evaluation with the use of dermoscopy and optical-coherence tomographic imaging

Eccrine poromas (EP) are benign cutaneous adnexal neoplasms that commonly present as solitary plaques, papules, or nodules on the lower extremities. Both clinically, and on dermoscopy, EP can be hard to distinguish from other skin tumors, including amelanotic melanoma and eccrine porocarcinoma. Dermoscopy and optical-coherence tomography (OCT) are 2 noninvasive imaging devices that can increase the diagnostic accuracy of benign and malignant cutaneous diseases. Thus, understanding the dermoscopic features of EP and characterizing it on OCT imaging may help improve diagnostic accuracy.

https://ift.tt/2ML4Odf

Diagnosis and management of childhood psoriasis: A prospective study

Retrospective studies show that approximately one third of adults with psoriasis recall onset in childhood however the true prevalence in children remains unknown. It affects 2.0%-3.5% of the population worldwide and has been reported as high as 8.5% depending on the population studied. Psoriasis can have a significant impact on quality of life in both children and adolescents by impacting self-esteem, family and social relations and school. Children suffering from psoriasis also have higher prevalence of obesity, hypertension, diabetes mellitus, rheumatoid arthritis, Crohn's disease and psychiatric disorders.

https://ift.tt/2Bu2McL

B Cell Defects Observed in Nod2 Knockout Mice Are a Consequence of a Dock2 Mutation Frequently Found in Inbred Strains [IMMUNE SYSTEM DEVELOPMENT]

Phenotypic differences among substrains of laboratory mice due to spontaneous mutations or pre-existing genetic variation confound the interpretation of targeted mutagenesis experiments and contribute to challenges with reproducibility across institutions. Notably, C57BL/6 Hsd mice and gene-targeted mice that have been backcrossed to this substrain have been reported to harbor a duplication in exons 28 and 29 of Dock2. In this study, we demonstrate the presence of this Dock2 variant in the widely used Nod2^–/– mice. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic innate immune receptor associated with inflammatory bowel disease susceptibility. Consistent with a role of NOD2 in an immunological disorder, Nod2^–/– mice bred at our institution displayed multiple B cell defects including deficiencies in recirculating B cells, marginal zone B cells, and B1a cells in vivo, as well as defects in class switch recombination in vitro. However, we found that these effects are due to the Dock2 variant and are independent of Nod2 deletion. Despite originating from the same gene-targeted founder mice, Nod2^–/– mice from another source did not harbor the Dock2 variant or B cell defects. Finally, we show that Dock2^–/– mice display the same B cell defects as mice harboring the Dock2 variant, confirming that the variant is a loss-of-function mutation and is sufficient to explain the alterations to the B cell compartment observed in Nod2^–/– mice. Our findings highlight the effects of confounding mutations from widely used inbred strains on gene-targeted mice and reveal new functions of DOCK2 in B cells.

https://ift.tt/2vWezeM

Targeting Antigen-Specific B Cells Using Antigen-Expressing Transduced Regulatory T Cells [IMMUNE REGULATION]

Controlling immune responses in autoimmunity and to biotherapeutics is an unmet need. In hemophilia, for example, up to one third of patients receiving therapeutic factor VIII (FVIII) infusions develop neutralizing Abs termed "inhibitors." To address this problem in a mouse model of hemophilia A, we used an Ag-specific regulatory T cell (Treg) approach in which we created a novel B cell–targeting chimeric receptor composed of an FVIII Ag domain linked with the CD28-CD3 transmembrane and signaling domains. We termed these "BAR" for B cell–targeting Ab receptors. CD4⁺CD25^hiCD127^low human Tregs were retrovirally transduced to express a BAR containing the immunodominant FVIII C2 or A2 domains (C2- and A2-BAR). Such BAR-Tregs specifically suppressed the recall Ab response of spleen cultures from FVIII-immunized mice in vitro and completely prevented anti-FVIII Ab development in response to FVIII immunization. Mechanistic studies with purified B cells and T cells from tolerized or control recipients demonstrated that the FVIII-specific B cells were directly suppressed or anergized, whereas the T cell response remained intact. Taken together, we report in this study a successful proof-of-principle strategy using Ag-expressing Tregs to directly target specific B cells, an approach which could be adapted to address other adverse immune responses as well.

https://ift.tt/2Brrsms

Id3 Restricts {gamma}{delta} NKT Cell Expansion by Controlling Egr2 and c-Myc Activity [IMMUNE SYSTEM DEVELOPMENT]

NKT cells are neonatal-derived T lymphocytes that are grouped together with invariant NKT cells based on their shared innate-like developmental program characterized by the transcription factor PLZF (promyelocytic leukemia zinc finger). Previous studies have demonstrated that the population size of NKT cells is tightly controlled by Id3-mediated inhibition of E-protein activity in mice. However, how E proteins promote NKT cell development and expansion remains to be determined. In this study, we report that the transcription factor Egr2, which also activates PLZF expression in invariant NKT cells, is essential for regulating NKT cell expansion. We observed a higher expression of Egr family genes in NKT cells compared with the conventional T cell population. Loss of function of Id3 caused an expansion of NKT cells, which is accompanied by further upregulation of Egr family genes as well as PLZF. Deletion of Egr2 in Id3-deficient NKT cells prevented cell expansion and blocked PLZF upregulation. We further show that this Egr2-mediated NKT cell expansion is dependent on c-Myc. c-Myc knockdown attenuated the proliferation of Id3-deficient NKT cells, whereas c-Myc overexpression enhanced the proliferation of Id3/Egr2–double-deficient NKT cells. Therefore, our data reveal a regulatory circuit involving Egr2–Id3–E2A, which normally restricts the population size of NKT cells by adjusting Egr2 dosage and c-Myc expression.

https://ift.tt/2BuQpNC

Effects of Masker Envelope Fluctuations on the Temporal Effect

ABSTRACT

Under certain conditions, detection thresholds in simultaneous masking improve when the onset of a short sinusoidal probe is delayed from the onset of a long masker. This improvement, known as the temporal effect, is largest for broadband maskers and is smaller or absent for narrowband maskers centered on the probe frequency. This study tests the hypothesis that small or absent temporal effects for narrowband maskers are due to the inherent temporal envelope fluctuations of Gaussian noise. Temporal effects were measured for narrowband noise maskers with fluctuating ("fluctuating maskers") and flattened ("flattened maskers") temporal envelopes as a function of masker level (Exp. I) and in the presence of fluctuating and flattened precursors (Exp. II). The temporal effect was absent for fluctuating narrowband maskers and as large as ~ 7 dB for flattened narrowband maskers. The AC-coupled power of the temporal envelopes of precursors and maskers accounted for 94 % of the variance in probe detection thresholds measured with fluctuating and flattened precursors and maskers. These results suggest that masker temporal envelope fluctuations contribute to the temporal effect and should be considered in future modeling efforts.

https://ift.tt/2vZ0jC2

Dupilumab improves symptoms, quality of life, and productivity in uncontrolled persistent asthma

Asthma is a heterogeneous disease consisting of phenotypes defined, in part, by clinical parameters such as age of onset, presence of allergic features, degree of airway obstruction, obesity, gender, and smoking history.1-3 These characteristics may be associated with outcome and treatment response.3 Poor asthma control has been associated with increased risk of asthma exacerbations, asthma-related hospitalization,4,5 poor quality of life (QoL),6 adverse impact on productivity,7,8 and possibly, increased risk of mortality.

https://ift.tt/2N6d6cy

Differences in airway structural changes assessed by three-dimensional computed tomography in asthma and asthma-COPD overlap

Background: Asthma- COPD overlap (ACO) is a clinical phenotype sharing features of asthma and COPD. Multidetector row computed tomography (MDCT) can be used to evaluate the airway structure; however, differences between asthma and ACO seen on MDCT are poorly understood.Objective: To investigate the difference in airway structural between asthma and ACO using MDCT in patients with clinical asthma.Methods:Sixty-four patients with asthma were allocated to an asthma group (neversmokers and ex-smokers with a smoking history of <10 pack-years) or an ACO group (patients with a ≥10-pack-year smoking history and FEV1/ FVC <0.7).

https://ift.tt/2Pmdl4N

Analysis of KIR3DP1 Polymorphism Provides Relevant Information on Centromeric KIR Gene Content [IMMUNOGENETICS]

Four killer cell Ig-like receptor (KIR) genes, collectively referred to as framework genes, characterize almost all KIR haplotypes. In particular, KIR3DL3 and KIR3DL2 mark the ends of the locus, whereas KIR3DP1 and KIR2DL4 are located in the central part. A recombination hot spot, mapped between KIR3DP1 and KIR2DL4, splits the haplotypes into two regions: a centromeric (Cen) region (spanning from KIR3DL3 to KIR3DP1) and a telomeric region (from KIR2DL4 to KIR3DL2), both varying in KIR gene content. In this study, we analyzed KIR3DP1 polymorphism in a cohort of 316 healthy, unrelated individuals. To this aim, we divided KIR3DP1 alleles into two groups by the use of a sequence-specific primer– PCR approach. Our data clearly indicated that KIR3DP1 alleles present on haplotypes carrying Cen-A or Cen-B1 regions differ from those having Cen-B2 motifs. Few donors (~3%) made exceptions, and they were all, except one, characterized by uncommon haplotypes, including either KIR deletions or KIR duplications. Consequently, as KIR2DL1 is present in Cen-A and Cen-B1 regions but absent in Cen-B2 regions, we demonstrated that KIR3DP1 polymorphism might represent a suitable marker for KIR2DL1 gene copy number analysis. Moreover, because Cen-B1 and Cen-B2 regions are characterized by different KIR3DP1 alleles, we showed that KIR3DP1 polymorphism analysis also provides information to dissect between Cen-B1/Cen-B1 and Cen-B1/Cen-B2 donors. Taken together, our data suggest that the analysis of KIR3DP1 polymorphism should be included in KIR repertoire evaluation.

https://ift.tt/2MCEi5A

A Convergent Immunological Holy Trinity of Adaptive Immunity in Lampreys: Discovery of the Variable Lymphocyte Receptors [PILLARS OF IMMUNOLOGY]

https://ift.tt/2vWeE24

Pre-Existing Maternal Antibodies Cause Rapid Prenatal Rejection of Allotransplants in the Mouse Model of In Utero Hematopoietic Cell Transplantation [TRANSPLANTATION]

In utero hematopoietic cell transplantation (IUHCT) is a nonmyeloablative nonimmunosuppressive alternative to postnatal hematopoietic stem cell transplantation for the treatment of congenital hemoglobinopathies. Anti-HLA donor-specific Abs (DSA) are associated with a high incidence of graft rejection following postnatal hematopoietic stem cell transplantation. We determine if DSA present in the mother can similarly cause graft rejection in the fetus following IUHCT. Ten million C57BL/6 (B6, H2k^b) bone marrow cells were transplanted in utero into gestational day 14 BALB/c (H2k^d) fetuses. The pregnant BALB/c dams carrying these fetuses either had been previously sensitized to B6 Ag or were injected on gestational days 13–15 with serum from B6-sensitized BALB/c females. Maternal–fetal Ab transmission, Ab opsonization of donor cells, chimerism, and frequency of macrochimeric engraftment (chimerism >1%) were assessed by flow cytometry. Maternal IgG was transmitted to the fetus and rapidly opsonized donor cells following IUHCT. Donor cell rejection was observed as early as 4 h after IUHCT in B6-sensitized dams and 24 h after IUHCT in dams injected with B6-sensitized serum. Efficient opsonization was strongly correlated with decreased chimerism. No IUHCT recipients born to B6-sensitized dams or dams injected with B6-sensitized serum demonstrated macrochimeric engraftment at birth compared with 100% of IUHCT recipients born to naive dams or dams injected with naive serum (p < 0.001). In summary, maternal donor–specific IgG causes rapid, complete graft rejection in the fetus following IUHCT. When a third-party donor must be used for clinical IUHCT, the maternal serum should be screened for DSA to optimize the chance for successful engraftment.

https://ift.tt/2w0YTXD

Pillars Article: Somatic Diversification of Variable Lymphocyte Receptors in the Agnathan Sea Lamprey. Nature. 2004. 430: 174-180 [PILLARS OF IMMUNOLOGY]

https://ift.tt/2BuQz7G

Functional Evidence of Pulmonary Extracellular Vesicles in Infectious and Noninfectious Lung Inflammation [INNATE IMMUNITY AND INFLAMMATION]

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a highly complex process that can be triggered by both noninfectious (sterile) and infectious stimuli. Inflammatory lung responses are one of the key features in the pathogenesis of this devastating syndrome. How ALI/ARDS-associated inflammation develops remains incompletely understood, particularly after exposure to sterile stimuli. Emerging evidence suggests that extracellular vesicles (EVs) regulate intercellular communication and inflammatory responses in various diseases. In this study, we characterized the generation and function of pulmonary EVs in the setting of ALI/ARDS, induced by sterile stimuli (oxidative stress or acid aspiration) and infection (LPS/Gram-negative bacteria) in mice. EVs detected in bronchoalveolar lavage fluid (BALF) were markedly increased after exposure of animals to both types of stimuli. After sterile stimuli, alveolar type-I epithelial cells were the main source of the BALF EVs. In contrast, infectious stimuli–induced BALF EVs were mainly derived from alveolar macrophages (AMs). Functionally, BALF EVs generated in both the noninfectious and infectious ALI models promoted the recruitment of macrophages in in vivo mouse models. Furthermore, BALF EVs differentially regulated AM production of cytokines and inflammatory mediators, as well as TLR expression in AMs in vivo. Regardless of their origin, BALF EVs contributed significantly to the development of lung inflammation in both the sterile and infectious ALI. Collectively, our results provide novel insights into the mechanisms by which EVs regulate the development of lung inflammation in response to diverse stimuli, potentially providing novel therapeutic and diagnostic targets for ALI/ARDS.

https://ift.tt/2w0QDqx

The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity [BRIEF REVIEWS]

The field of red cell biology is undergoing a quiet revolution. Long assumed to be inert oxygen carriers, RBCs are emerging as important modulators of the innate immune response. Erythrocytes bind and scavenge chemokines, nucleic acids, and pathogens in circulation. Depending on the conditions of the microenvironment, erythrocytes may either promote immune activation or maintain immune quiescence. We examine erythrocyte immune function through a comparative and evolutionary lens, as this framework may offer perspective into newly recognized roles of human RBCs. Next, we review the known immune roles of human RBCs and discuss their activity in the context of sepsis where erythrocyte function may prove important to disease pathogenesis. Given the limited success of immunomodulatory therapies in treating inflammatory diseases, we propose that the immunologic function of RBCs provides an understudied and potentially rich area of research that may yield novel insights into mechanisms of immune regulation.

https://ift.tt/2vZ3rhg

Correction: Both HIV-Infected and Uninfected Cells Express TRAILshort, Which Confers TRAIL Resistance upon Bystander Cells within the Microenvironment [CORRECTIONS]

https://ift.tt/2MJBcfY

Cutting Edge: Deletion of Ezrin in B Cells of Lyn-Deficient Mice Downregulates Lupus Pathology [CUTTING EDGE]

Genetic deletion of the Src family tyrosine kinase Lyn in mice recapitulates human systemic lupus erythematosus, characterized by hyperactive BCR signaling, splenomegaly, autoantibody generation, and glomerulonephritis. However, the molecular regulators of autoimmunity in Lyn-deficient mice and in human lupus remain poorly characterized. In this study, we report that conditional deletion of the membrane–cytoskeleton linker protein ezrin in B cells of Lyn-deficient mice (double knockout [DKO] mice) ameliorates B cell activation and lupus pathogenesis. B cells from DKO mice respond poorly to BCR stimulation, with severe downregulation of major signaling pathways. DKO mice exhibit reduced splenomegaly as well as significantly lower levels of autoantibodies against a variety of autoantigens, including dsDNA, histone, and chromatin. Leukocyte infiltration and deposition of IgG and complement component C3 in the kidney glomeruli of DKO mice are markedly reduced. Our data demonstrate that ezrin is a novel molecular regulator of B cell–associated lupus pathology.

https://ift.tt/2BuQwZy

NK Cell-Derived IFN-{gamma} Protects against Nontuberculous Mycobacterial Lung Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

In developed countries, pulmonary nontuberculous mycobacteria (NTM) infections are more prevalent than Mycobacterium tuberculosis infections. Given the differences in the pathogenesis of NTM and M. tuberculosis infections, separate studies are needed to investigate the pathological effects of NTM pathogens. Our previous study showed that anti–IFN- autoantibodies are detected in NTM-infected patients. However, the role of NK cells and especially NK cell–derived IFN- in this context has not been studied in detail. In the current study, we show that NK1.1 cell depletion increases bacterial load and mortality in a mouse model of pulmonary NTM infection. NK1.1 cell depletion exacerbates NTM-induced pathogenesis by reducing macrophage phagocytosis, dendritic cell development, cytokine production, and lung granuloma formation. Similar pathological phenomena are observed in IFN-–deficient (IFN-^–/–) mice following NTM infection, and adoptive transfer of wild-type NK cells into IFN-^–/– mice considerably reduces NTM pathogenesis. Injection of rIFN- also prevents NTM-induced pathogenesis in IFN-^–/– mice. We observed that NK cells represent the main producers of IFN- in the lungs and production starts as soon as 1 d postinfection. Accordingly, injection of rIFN- into IFN-^–/– mice 1 d (but not 2 wk) postinfection significantly improves immunity against NTM infection. NK cells also stimulate mycobacterial killing and IL-12 production by macrophages. Our results therefore indicate that IFN- production by NK cells plays an important role in activating and enhancing innate and adaptive immune responses at early stages of pulmonary NTM infection.

https://ift.tt/2MJBcwu

Human Extrafollicular CD4+ Th Cells Help Memory B Cells Produce Igs [CLINICAL AND HUMAN IMMUNOLOGY]

Follicular helper T (Tfh) cells are necessary for germinal center B cell maturation during primary immune responses; however, the T cells that promote humoral recall responses via memory B cells are less well defined. In this article, we characterize a human tonsillar CD4⁺ T cell subset with this function. These cells are similar to Tfh cells in terms of expression of the chemokine receptor CXCR5 and the inhibitory receptor PD-1, IL-21 secretion, and expression of the transcription factor BCL6; however, unlike Tfh cells that are located within the B cell follicle and germinal center, they reside at the border of the T cell zone and the B cell follicle in proximity to memory B cells, a position dictated by their unique chemokine receptor expression. They promote memory B cells to produce Abs via CD40L, IL-10, and IL-21. Our results reveal a unique extrafollicular CD4⁺ T cell subset in human tonsils, which specialize in promoting T cell–dependent humoral recall responses.

https://ift.tt/2vWeBTW

A Fixed Spatial Structure of CD8+ T Cells in Tissue during Chronic HSV-2 Infection [MUCOSAL IMMUNOLOGY]

Tissue-resident CD8⁺ T cells (T_rm) can rapidly eliminate virally infected cells, but their heterogeneous spatial distribution may leave gaps in protection within tissues. Although T_rm patrol prior sites of viral replication, murine studies suggest they do not redistribute to adjacent uninfected sites to provide wider protection. We perform mathematical modeling of HSV-2 shedding in Homo sapiens and predict that infection does not induce enough T_rm in many genital tract regions to eliminate shedding; a strict spatial distribution pattern of mucosal CD8⁺ T cell density is maintained throughout chronic infection, and trafficking of T_rm across wide genital tract areas is unlikely. These predictions are confirmed with spatial analysis of CD8⁺ T cell distribution in histopathologic specimens from human genital biopsies. Further simulations predict that the key mechanistic correlate of protection following therapeutic HSV-2 vaccination would be an increase in total T_rm rather than spatial reassortment of these cells. The fixed spatial structure of T_rm induced by HSV-2 is sufficient for rapid elimination of infected cells but only in a portion of genital tract microregions.

https://ift.tt/2w0cizr

Characterization of a Synovial B Cell-Derived Recombinant Monoclonal Antibody Targeting Stromal Calreticulin in the Rheumatoid Joints [CLINICAL AND HUMAN IMMUNOLOGY]

Rheumatoid arthritis (RA) is characterized by formation of synovial ectopic lymphoid structures (ELS) supporting B cell autoreactivity toward locally generated citrullinated (cit) antigens, including those contained in neutrophil extracellular traps (NETs). However, only a minority of RA-rmAbs from B cells isolated from ELS⁺ RA tissues react against NETs. Thus, alternative cellular sources of other potential autoantigens targeted by locally differentiated B cells remain undefined. RA fibroblast–like synoviocytes (FLS) have been implicated in the release of RA-associated autoantigens. In this study, we aimed to define stromal-derived autoantigens from RA-FLS targeted by RA-rmAbs. Seventy-one RA-rmAbs were screened toward RA-FLS by living-cell immunofluorescence (IF). Western blotting was used to identify potential autoantigens from RA-FLS protein extracts. Putative candidates were validated using colocalization immunofluorescence confocal microscopy, ELISA, immunoprecipitation assay, and surface plasmon resonance on unmodified/cit proteins. Serum immunoreactivity was tested in anti-citrullinated peptide/protein Abs (ACPA)⁺ versus ACPA^– RA patients. Ten out of 71 RA-rmAbs showed clear reactivity toward RA-FLS in immunofluorescence with no binding to NETs. One stromal-reactive RA-rmAb (RA057/11.89.1) decorated a ~58-kDa band that mass spectrometry and Western blotting with a commercial Ab identified as calreticulin (CRT). Confocal microscopy demonstrated significant cellular colocalization between anti-CRT RA057/11.89.1 in RA-FLS. RA057/11.89.1 was able to immunoprecipitate rCRT. Deimination of CRT to cit-CRT moderately increased RA057/11.89.1 immunoreactivity. cit-CRT displayed increased blocking capacity compared with unmodified CRT in competitive binding assays. Finally, anti–cit-CRT Abs were preferentially detected in ACPA⁺ versus ACPA^– RA sera. We identified a synovial B cell–derived RA-rmAb locally differentiated within the ELS⁺ RA synovium reacting toward CRT, a putative novel autoantigen recently described in RA patients, suggesting that FLS-derived CRT may contribute to fuel the local autoimmune response.

https://ift.tt/2BuQv7W

Mechanistic Insights into CpG DNA and IL-15 Synergy in Promoting B Cell Chronic Lymphocytic Leukemia Clonal Expansion [TUMOR IMMUNOLOGY]

Malignant cell growth within patients with B cell chronic lymphocytic leukemia (B-CLL) is largely restricted to lymphoid tissues, particularly lymph nodes. The recent in vitro finding that TLR-9 ligand (oligodeoxynucleotide [ODN]) and IL-15 exhibit strong synergy in promoting B-CLL growth may be particularly relevant to growth in these sites. This study shows IL-15–producing cells are prevalent within B-CLL–infiltrated lymph nodes and, using purified B-CLL cells from blood, investigates the mechanism for ODN and IL-15 synergy in driving B-CLL growth. ODN boosts baseline levels of phospho-RelA(S529) in B-CLL and promotes NF-B–driven increases in IL15RA and IL2RB mRNA, followed by elevated IL-15Rα and IL-2/IL-15Rβ (CD122) protein. IL-15->CD122 signaling during a critical interval, 20 to 36–48 h following initial ODN exposure, is required for optimal induction of the cycling process. Furthermore, experiments with neutralizing anti–IL-15 and anti-CD122 mAbs indicate that clonal expansion requires continued IL-15/CD122 signaling during cycling. The latter is consistent with evidence of heightened IL2RB mRNA in the fraction of recently proliferated B-CLL cells within patient peripheral blood. Compromised ODN+IL-15 growth with limited cell density is consistent with a role for upregulated IL-15Rα in facilitating homotypic trans IL-15 signaling, although there may be other explanations. Together, the findings show that ODN and IL-15 elicit temporally distinct signals that function in a coordinated manner to drive B-CLL clonal expansion.

https://ift.tt/2MJSjyA

A Pilot Study To Investigate the Immune-Modulatory Effects of Fasting in Steroid-Naive Mild Asthmatics [CLINICAL AND HUMAN IMMUNOLOGY]

A fasting mimetic diet blunts inflammation, and intermittent fasting has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting, we designed a pilot study in mild asthmatic subjects to assess the effect of fasting on the NLRP3 inflammasome, Th2 cell activation, and airway epithelial cell cytokine production. Subjects with documented reversible airway obstruction and stable mild asthma were recruited into this study in which pulmonary function testing (PFT) and PBMCextraction was performed 24 h after fasting, with repeated PFT testing and blood draw 2.5 h after refeeding. PFTs were not changed by a prolonged fast. However, steroid-naive mild asthmatics showed fasting-dependent blunting of the NLRP3 inflammasome. Furthermore, PBMCs from these fasted asthmatics cocultured with human epithelial cells resulted in blunting of house dust mite–induced epithelial cell cytokine production and reduced CD4⁺ T cell Th2 activation compared with refed samples. This pilot study shows that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naive asthmatics as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient level–dependent regulation of inflammation in asthma. Our findings support the evaluation of this concept in a larger study as well as the potential development of caloric restriction interventions for the treatment of asthma.

https://ift.tt/2MDEVvO

In This Issue [IN THIS ISSUE]

https://ift.tt/2LbwLFV

Membrane-Associated Proteinase 3 on Granulocytes and Acute Myeloid Leukemia Inhibits T Cell Proliferation [IMMUNE REGULATION]

Proteinase 3 (P3), a serine protease expressed by myeloid cells, localized within azurophil granules, and also expressed on the cellular membrane of polymorphonuclear neutrophils (PMN), is the target of autoimmunity in granulomatosis with polyangiitis. PR1, an HLA-A2 restricted nonameric peptide derived from P3, has been targeted effectively in myeloid leukemia. We previously showed (Molldrem et al. 2003. J. Clin. Invest. 111: 639–647) that overexpression of P3 in chronic myeloid leukemia induces apoptosis of high-affinity PR1-specific T cells, leading to deletional tolerance and leukemia outgrowth. In this study, we investigated the effect of membrane P3 (mP3)–expressing PMN and acute myeloid leukemia (AML) blasts on the proliferation of CD4 and CD8 T cells in vitro. We demonstrate that mP3-expressing PMN significantly inhibits autologous healthy donor T cell proliferation but does not affect cytokine production in activated T cells and that this effect requires cell proximity and was abrogated by P3 blockade. This inhibition required P3 enzyme activity. However, suppression was not reversed by either the addition of catalase or the inhibition of arginase I. In addition to P3 blockade, anti–low density lipoprotein receptor-related protein 1 (LRP1) Ab also restored T cells' capacity to proliferate. Last, we show dose-dependent inhibition of T cell proliferation by mP3-expressing AML blasts. Together, our findings demonstrate a novel mechanism whereby PMN- and AML-associated mP3 inhibits T cell proliferation via direct LRP1 and mP3 interaction, and we identify P3 as a novel target to modulate immunity in myeloid leukemia and autoimmune disease.

https://ift.tt/2BrrvyE

Myeloid Dendritic Cells Induce HIV Latency in Proliferating CD4+ T Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

HIV latency occurs predominantly in long-lived resting CD4⁺ T cells; however, latent infection also occurs in T cell subsets, including proliferating CD4⁺ T cells. We compared the establishment and maintenance of latent infection in nonproliferating and proliferating human CD4⁺ T cells cocultured with syngeneic myeloid dendritic cells (mDC). Resting CD4⁺ T cells were labeled with the proliferation dye eFluor 670 and cultured alone or with mDC, plasmacytoid dendritic cells, or monocytes in the presence of staphylococcal enterotoxin B (SEB). Cells were cultured for 24 h and infected with CCR5-tropic enhanced GFP (EGFP) reporter HIV. Five days postinfection, nonproductively infected EGFP^– CD4⁺ T cells that were either nonproliferating (eFluor 670^hi) or proliferating (eFluor 670^lo) were sorted and cultured for an additional 7 d (day 12) with IL-7 and antiretrovirals. At day 5 postinfection, sorted, nonproductively infected T cells were stimulated with anti–CD3/CD28, and induced expression of EGFP was measured to determine the frequency of latent infection. Integrated HIV in these cells was confirmed using quantitative PCR. By these criteria, latent infection was detected at day 5 and 12 in proliferating T cells cocultured with mDC and monocytes but not plasmacytoid dendritic cells, where CD4⁺ T cells at day 12 were poor. At day 5 postinfection, nonproliferating T cells expressing SEB-specific TCR Vβ-17 were enriched in latent infection compared with non–SEB-specific TCR Vβ-8.1. Together, these data show that both nonproliferating and proliferating CD4⁺ T cells can harbor latent infection during SEB-stimulated T cell proliferation and that the establishment of HIV latency in nonproliferating T cells is linked to expression of specific TCR that respond to SEB.

https://ift.tt/2LbRsBz

Mannose Metabolism Is Essential for Th1 Cell Differentiation and IFN-{gamma} Production [IMMUNE REGULATION]

Glucose-derived mannose is a common component of glycoproteins, and its deficiency leads to a severe defect in protein glycosylation and failure in basic cell functions. In this work, we show that mannose metabolism is essential for IFN- production by mouse Th1 cells. In addition, we demonstrate that the susceptibility of Th1 cells to glycolysis restriction depends on the activation conditions and that under diminished glycolytic flux, mannose availability becomes the limiting factor for IFN- expression. This study unravels a new role for glucose metabolism in the differentiation process of Th1 cells, providing a mechanistic explanation for the importance of glycolysis in immune cell functions.

https://ift.tt/2MDzqNn

Kavain Reduces Porphyromonas gingivalis-Induced Adipocyte Inflammation: Role of PGC-1{alpha} Signaling [INNATE IMMUNITY AND INFLAMMATION]

A link between obesity and periodontitis has been suggested because of compromised immune response and chronic inflammation in obese patients. In this study, we evaluated the anti-inflammatory properties of Kavain, an extract from Piper methysticum, on Porphyromonas gingivalis–induced inflammation in adipocytes with special focus on peroxisome proliferation–activated receptor coactivator α (PGC-1α) and related pathways. The 3T3-L1 mouse preadipocytes and primary adipocytes harvested from mouse adipose tissue were infected with P. gingivalis, and inflammation (TNF-α; adiponectin/adipokines), oxidative stress, and adipogenic marker (FAS, CEBPα, and PPAR-) expression were measured. Furthermore, effect of PGC-1α knockdown on Kavain action was evaluated. Results showed that P. gingivalis worsens adipocyte dysfunction through increase of TNF-α, IL-6, and iNOS and decrease of PGC-1α and adiponectin. Interestingly, although Kavain obliterated P. gingivalis–induced proinflammatory effects in wild-type cells, Kavain did not affect PGC-1α–deficient cells, strongly advocating for Kavain effects being mediated by PGC-1α. In vivo adipocytes challenged with i.p. injection of P. gingivalis alone or P. gingivalis and Kavain displayed the same phenotype as in vitro adipocytes. Altogether, our findings established anti-inflammatory and antioxidant effects of Kavain on adipocytes and emphasized protective action against P. gingivalis–induced adipogenesis. The use of compounds such as Kavain offer a portal to potential therapeutic approaches to counter chronic inflammation in obesity-related diseases.

https://ift.tt/2Brro6c

miR-340 Alleviates Psoriasis in Mice through Direct Targeting of IL-17A [IMMUNE REGULATION]

Th17 cell is a well-known lineage of CD4⁺ effector Th cells that selectively produce IL-17A and play critical roles during the pathogenesis of autoimmune disease. A microRNA (miRNA) is a small noncoding RNA molecule that functions in posttranscriptional regulation of gene expression. Recently, an increasing number of studies have demonstrated that multiple miRNAs are dysregulated in patients with various autoimmune diseases and mediate autoimmune disease pathologic condition at least in part through the regulation of Th17 response. However, among the few miRNAs identified so far that play possible roles in the differentiation of Th17 cells, they all regulate the Th17 response through targeting negative or positive regulators of Th17 differentiation. In the current study, we sought to identify new miRNAs that can directly regulate the expression of IL-17A, the most important cytokine produced by Th17 cells. Our results showed that the 3' untranslated region of mouse IL-17A can act as a negative regulatory element to downregulate gene expression. Further study revealed that miR-340 can specifically bind to the 3' untranslated region of mouse IL-17A and downregulate the expression of endogenous IL-17A. More importantly, we demonstrated that treatment with miR-340 alleviates the clinical severity of imiquimod-induced psoriasis in mice through the downregulation of IL-17A. These data indicate that miR-340 may be a useful therapeutic target for the treatment of psoriasis and other IL-17A–mediated autoimmune diseases.

https://ift.tt/2Brrta0

Effects of Masker Envelope Fluctuations on the Temporal Effect

ABSTRACT

Under certain conditions, detection thresholds in simultaneous masking improve when the onset of a short sinusoidal probe is delayed from the onset of a long masker. This improvement, known as the temporal effect, is largest for broadband maskers and is smaller or absent for narrowband maskers centered on the probe frequency. This study tests the hypothesis that small or absent temporal effects for narrowband maskers are due to the inherent temporal envelope fluctuations of Gaussian noise. Temporal effects were measured for narrowband noise maskers with fluctuating ("fluctuating maskers") and flattened ("flattened maskers") temporal envelopes as a function of masker level (Exp. I) and in the presence of fluctuating and flattened precursors (Exp. II). The temporal effect was absent for fluctuating narrowband maskers and as large as ~ 7 dB for flattened narrowband maskers. The AC-coupled power of the temporal envelopes of precursors and maskers accounted for 94 % of the variance in probe detection thresholds measured with fluctuating and flattened precursors and maskers. These results suggest that masker temporal envelope fluctuations contribute to the temporal effect and should be considered in future modeling efforts.

https://ift.tt/2vZ0jC2

IL-10 inducible CD8 + regulatory T-cells are enriched in patients with multiple myeloma and impact the generation of antigen-specific T-cells

Abstract

Tumor-mediated immunosuppression via regulatory T-cells is a key player among the various immune-escape mechanisms in multiple myeloma. We analyzed the generation, distribution, function and immunophenotype of CD8⁺CD28⁻ regulatory T-cells in patients with multiple myeloma. Functionality of CD8⁺CD28⁻ T-cells was assessed by immunological assays using ex vivo generated antigen-specific T-cells from patients with plasma cell dyscrasias and healthy donors. Detailed analysis of distribution, immunophenotype and cytotoxic potential of CD8⁺CD28⁻ T-cells was performed by flow cytometry and ELISA. We found that the amount of CD8⁺CD28⁻ T-cells was directly correlated with the suppression of antigen-specific T-cell responses in patients with plasma cell dyscrasia. Analyzing the CD8⁺CD28⁻ T-cells in detail, increased numbers of these cells were observed in the bone marrow (i.e., tumor microenvironment) of patients with plasma cell dyscrasia. Furthermore, we identified the expression of lymphocyte function-associated antigen 1 (LFA-1) as a marker of immunosuppression and defined the CD8⁺CD28⁻CD57⁺LFA-1^high population as the relevant immunosuppressive compartment. These regulatory T-cells act as immunosuppressors via soluble factors and incubation with IL-10 augmented their immunosuppressive capacity. The immunosuppressive regulatory network of IL-10 and the CD8⁺CD28⁻CD57⁺LFA-1^high regulatory T-cells show unique characteristics and contribute to the tumor immune escape mechanism in patients with multiple myeloma.

https://ift.tt/2L7Miqh

Erstlinientherapie des mRCC: ein Update

Zusammenfassung

Hintergrund

Neue medikamentöse Perspektiven lassen auf Fortschritte in der Erstlinientherapie des metastasierten Nierenzellkarzinoms (mRCC) hoffen.

Fragestellung

Die aktuelle First-Line-Therapie beim mRCC, Erweiterung der Therapieoptionen durch Tivozanib und Cabozantinib und zukünftig erwartete Substanzen werden diskutiert.

Material und Methode

Aktuelle DGHO-Empfehlungen, Diskussion pivotaler Studien zur Erstlinientherapie des mRCC.

Ergebnisse

Derzeit sind 6 zielgerichtete Wirkstoffe in der Erstlinie des mRCC relevant: Bevacizumab plus Interferon-α (INF-α), Pazopanib, Sunitinib, Tivozanib, Cabozantinib und Temsirolimus. Die Substanzen werden risikostratifiziert eingesetzt. Ein neuer zugelassener Wirkstoff ist Tivozanib. In der zulassungsrelevanten Studie war der Tyrosinkinaseinhibitor (TKI) einer Therapie mit Sorafenib hinsichtlich des progressionsfreien Überlebens (PFS) überlegen (11,9 vs. 9,1 Monate; HR 0,797). Die Verträglichkeit von Tivozanib erwies sich als gut mit weniger Hand-Fuß-Syndromen und Diarrhö: Off-Target-Effekte im Vergleich zu anderen VEGFR-TKI könnten hier einen Therapievorteil bedeuten. Eine Zulassungserweiterung für Cabozantinib ergänzt die Optionen in der Erstlinientherapie für Patienten mit intermediärem und hohem Risiko. Die sich abzeichnende Einführung der Immunkombinationstherapie aus Nivolumab plus Ipilimumab könnte künftig eine wichtige Rolle spielen: Ergebnisse der CheckMate-214-Studie bestätigen die Verbesserung der Ansprechrate und die Verlängerung des Gesamtüberlebens gegenüber Sunitinib beim mRCC mit intermediärem oder hohem Risiko.

Schlussfolgerungen

Tivozanib ergänzt die Erstlinientherapie des mRCC um eine wirksame und gut verträgliche Substanz. Auch für Cabozantinib folgte eine Zulassungserweiterung für die Erstlinie. Mit Nivolumab plus Ipilimumab wird die erste Immunkombinationstherapie in der Erstlinie erwartet.

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Endokrine Spätfolgen nach onkologischer Therapie im Kindesalter

Zusammenfassung

Hintergrund

Da die Überlebensraten nach einer Krebserkrankung im Kindesalter während der letzten Jahrzehnte kontinuierlich zunahmen, steigt die Anzahl der Langzeitüberlebenden stetig. Viele dieser Patienten haben ein erhöhtes Risiko, im Laufe ihres Lebens Spätfolgen zu entwickeln, die durch die Krebsbehandlung verursacht wurden. Deren Auftreten hängt von der erhaltenen Behandlung ab und kann verschiedene Organe betreffen. Endokrine Spätschäden gehören zu den häufigsten Spätfolgen.

Fragestellung

Im vorliegenden Übersichtsartikel werden die verschiedenen endokrinen Spätfolgen sowie das empfohlene Vorgehen zu ihrer Diagnose und Behandlung dargestellt.

Ergebnisse

Endokrine Spätfolgen betreffen bis zu 50 % der Langzeitüberlebenden nach einer Krebserkrankung im Kindesalter und treten insbesondere nach einer Bestrahlung auf. Sie beinhalten sowohl Funktionsstörungen als auch sekundäre Malignome, die, abhängig von der erhaltenen Therapie, in unterschiedlicher Häufigkeit auftreten. Insbesondere die Schilddrüse, die Gonaden und die Hypophyse sind von Spätfolgen betroffen, wobei auch das Risiko für seltenere endokrine Erkrankungen nach einer onkologischen Behandlung erhöht ist. Durch die unspezifische Symptomatik dieser Erkrankungen beruht die Diagnose auf laborchemischen Untersuchungen, die in manchen Fällen durch Stimulationstests oder weiterführende bildgebende Diagnostik ergänzt werden müssen.

Diskussion

Viele endokrine Spätkomplikationen einer onkologischen Therapie im Kindesalter können gut behandelt werden, wenn sie rechtzeitig erkannt werden. In nationalen und internationalen Leitlinien werden daher risikoadaptierte Vorsorgeuntersuchungen empfohlen, die in spezialisierten Nachsorgezentren lebenslang durchgeführt werden sollten.

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