Objective: Therapeutic options for ischaemic stroke, such as thrombolysis or thrombectomy, are time sensitive. Multiple innovations have been established to reduce the symptom-to-needle time. One such innovation is the prealerting of emergency department (ED) or stroke unit staff by prehospital personnel of suspected stroke patients. The diagnosis of stroke can sometimes be difficult, with stroke mimics being a recognized issue. The prealert mobilizes ED, stroke and imaging personnel, which, for a true-positive, improves door-to-needle times. However, there are a proportion of false-positive prealerts (nonstrokes) that have a significant resource activation implication. The aim of this study was to evaluate the positive predictive value of a prealert for stroke and transient ischaemic attack (TIA). Methods: Ambulance service prealert forms for stroke and TIA collated by the ED were compared with the Scottish Stroke Audit database findings, ED electronic notes and imaging reports to establish whether the prealert was a true-positive or a false-positive. Results: A prealert was obtained for 77 patients as query stroke/TIA. The true-positive rate was 52 and the false-positive rate was 25. The positive predictive value was 0.675. The median symptom-to-arrival time for prealerted patients was 97 min and the door-to-needle time for thrombolysis (n=17 patients) was 38 min. Conclusion: The diagnosis of true-positive stroke can be difficult in the prehospital environment. Although prealert has been shown to improve the patient's journey in terms of door-to-thrombolysis times, we have identified that the prealert has a significant false-positive rate that has important resource allocation and activation consequences. Further analysis of this may inform paramedic training and improve protocols for information handover. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Δευτέρα 22 Μαΐου 2017
Anterior single implants with different neck designs: 5 Year results of a randomized clinical trial
Abstract
Background
The design of the implant neck might be significant for preservation of marginal bone.
Purpose
To compare the 5-year radiographic and clinical outcome of single anterior implants provided with a smooth neck, a rough neck or a scalloped rough neck.
Materials and Methods
93 Patients with a missing anterior tooth in the maxilla were included. At random, patients received an implant with a 1.5 mm smooth neck ("smooth group"), a rough neck with grooves ("rough group") or a scalloped rough neck with grooves ("scalloped group"). Implants were installed in healed sites. Follow-up visits were conducted after final crown delivery and 1 year and 5 years later.
Results
Scalloped implants showed significantly more initial marginal bone resorption. The total amount of bone loss was 1.26 ± 0.90 mm in the smooth group, 1.20 ± 1.1 mm in the rough group and 2.28 ± 0.97 mm in the scalloped group (P < .05). Survival rates were 96.2% for the smooth and scalloped group and 100% for the rough group. Scalloped implants showed deeper pocket depths, more bleeding and more technical complications. There were no differences in esthetic outcome nor in patient satisfaction.
Conclusions
For anterior single tooth replacements, scalloped implants show less favorable radiographic and clinical outcome compared to regular implants with a smooth neck or rough neck.
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Breast cancer metastasis: Putative therapeutic role of vascular cell adhesion molecule-1
Abstract
Background
Breast cancer is a notable cause of cancer-related death in women worldwide. Metastasis to distant organs is responsible for ~90% of this death. Breast cells convert to malignant cancer cells after acquiring the capacity of invasion/intravasation into surrounding tissues and, finally, extravasation/metastasis to distant organs (i.e., lymph nodes, lungs, bone, brain). Metastasis to distant organs depends on interactions between disseminated tumor cells (DTCs) and the endothelium of blood vessels present in the tumor microenvironment. Among several known endothelial adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) has been found to be involved in this process. It has been shown that VCAM-1 is aberrantly expressed in breast cancer cells and that it can bind to its natural ligand α4β1integrin, also denoted as very late antigen 4 (VLA-4). This binding appears to be responsible for the metastasis of breast cancer cells to lung, bone and brain. The α4β1 integrin - VCAM-1 interaction thus represents a potential therapeutic target for metastatic breast cancer cells. The development of inhibitors of this interaction may be instrumental for the clinical management of breast cancer patients.
Conclusions
This study focuses on recent progress on the role of VCAM-1, an important glycoprotein belonging to the immunoglobulin (Ig) superfamily of cell surface adhesion molecules in breast cancer angiogenesis, survival and metastasis. Targeting VCAM-1, expressed on the surface of breast cancer cells, and/or its specific ligand VLA-4/α4β1 integrin, expressed on cells at the site of metastasis, may be a useful strategy to reduce breast cancer cell invasion and metastasis. Various approaches to therapeutically target VCAM-1 and VLA-4 are also discussed.
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Necrotic cutaneous vasculitic skin lesions: a case of atypical Henoch-Schönlein purpura in a child with heterozygosity for factor V Leiden
Description
A Caucasian boy aged 5 years presented with acute onset of a non-tender, palpable purpuric rash to his lower limbs, preceded by a mild upper respiratory tract infection. Clinical findings were consistent with Henoch-Schönlein purpura (HSP) and he was discharged with community follow-up to monitor his lesions, blood pressure and urinalysis.
However, he clinically deteriorated over the following week with two further admissions due to evolving purpuric skin lesions (figure 1) and development of severe joint pain requiring opioid analgesia. There was no clinical evidence of renal or intestinal involvement.
Figure 1
Initial presentation of the purpuric Henoch Schonlein purpura rash.
Over a subsequent 6-week period, his purpuric lesions progressed to full thickness skin necrosis (figure 2). This was confirmed by a plastic surgery assessment and he was referred for a tertiary rheumatology review. He underwent a series...
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Surgery in late melanoma adrenal metastasis
Metastatic melanoma to adrenal gland are very infrequent, being generally associated with additional evidence of systemic disease and, consequently, with short-term survival. However, the prognosis and the therapeutic management vary depending on some important oncological features. Long-term survival rates have been described after complete resection of metastatic disease. Here, we report the case of a woman aged 41 years diagnosed with a cutaneous melanoma on the right side of her paravertebral region, level III of Clark, in 2002, who underwent surgical excision of the tumour with negative margins and a negative sentinel node. She posteriorly developed pulmonary metastasis in 2006 and 2009, both resected with curative intention and in 2013, she was diagnosed with an adrenal metastasis. Therefore, she was submitted to an uneventful right laparoscopic adrenalectomy. The pathology report described metastasis of a cutaneous melanoma, negative for BRAF mutation. The patient is actually disease-free after 30 months of follow-up.
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Unusual course of a haematoma of the thigh
Description
A Caucasian woman aged 56 years presented to emergency room (ER) department with leucorrhoea and fever since 48 hours. She was a smoker, had no diabetes history, no prosthetic material and denied use of injected drugs.
A month before, the patient had a closed inguinal trauma due to fall from height with a muscle strain of the anterior right thigh. Despite rest and analgesics, she went to ER several times because of progressive local pain and swelling. After 3 weeks, a local ultrasound scan showed a 3 cm size haematoma associated with probable rupture of obturator internus and rectus femoris muscles. On the following days, she developed fetid leucorrhoea associated with movements and compression of the anterior thigh. On physical examination and analyses, she had sepsis criteria and the abdomen/pelvic CT scan (figure1A, B) and MRI (figure1C, D) showed an abscess of 105x25mm size, complicated with...
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Bottom of an iceberg: undiagnosed aortic aneurysm masquerading as vocal cord palsy
Description
A previously healthy woman aged 60 years was referred to a tertiary referral cancer centre with change of voice for 1 week suspecting neoplastic aetiology on account of her tobacco chewing habit of more than 20 years. No history of voice abuse, fever or cough was there preceding the onset of the change of voice. She did not have any previous history of hospitalisation or diagnosed comorbidities. On clinical examination, her pulse rate was 82 bpm; blood pressure was 130/90 mm Hg and respiratory rate was 12/min.
Video laryngoscopy examination revealed left vocal cord palsy with no obvious lesion. A whole-body F18 FDG PET–CT scan revealed the presence of 6.6x4.8x6.7 cm lobulated sacullar aneurysm arising from the aortic arch between the origins of the left common carotid and subclavian arteries (figures 1 and 2). The likely mycotic aneurysm caused significant surrounding metabolically active inflammatory changes (figure 3). The...
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Middle Ear Function and Pathophysiology in Andean Children Living at High Altitudes
High Altitude Medicine & Biology , Vol. 0, No. 0.
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Trabectedin and Eribulin: Where Do They Fit in the Management of Soft Tissue Sarcoma?
Opinion Statement
Trabectedin and eribulin are two agents that have been recently approved for the treatment of specific soft tissue sarcoma subtypes. They have proved to be a much-needed line of additional treatment for patients with these rare tumors, but their activity remains admittedly modest in most cases. Further exploitation of these novel agents is likely to require a more granular understanding of the salient mechanisms of action. For example, if as some studies suggest, eribulin derives its benefit from restructuring of tumor vasculature to improve efficacy of subsequent lines of therapy, then patients may benefit from its use earlier in the treatment pathway. The sequencing of trabectedin with other agents is also worth examining. In a disease like myxoid liposarcoma, consideration should be given to using trabectedin before other salvage regimens like gemcitabine and docetaxel, given its tolerability and excellent efficacy against this sarcoma subtype. Also, to be further investigated is the use of trabectedin in sarcoma subtypes which were excluded from the phase III study, but in which activity has been documented in earlier trials and subsequent reports. Combinations of trabectedin with other agents, particularly doxorubicin, have been explored, but the data to date do not support the routine use of these regimens.
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Sequencing of ALK Inhibitors in ALK+ Non-Small Cell Lung Cancer
Opinion statement
Major therapeutic advances have occurred over the last several years in the management of advanced ALK+ NSCLC patients. Crizotinib was the first agent approved for the management of ALK+ NSCLC patients after it demonstrated significantly greater clinical benefit compared to chemotherapy. Several next generation ALK inhibitors have demonstrated clinical benefit in patients with crizotinib refractory NSCLC patients including in the CNS. Based on available data, therapy with a next generation ALK inhibitor can be initiated following therapy with crizotinib without any assessment of the molecular mechanisms of resistance. The appropriate therapy for patients with progressive disease following two ALK inhibitors is not well defined. In patients with an ALK-resistant mutation in their tumor, an ALK inhibitor with activity against the mutation would be the most appropriate therapy. In others, chemotherapy and PD-1 directed agents can be considered. Clinical data suggests that ALK+ patients are less likely to benefit from PD-1 directed agents and therefore chemotherapy should be considered prior to these agents for the management of ALK+ NSCLC patients.
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Immune Checkpoint Inhibitor Therapy: What Line of Therapy and How to Choose?
Opinion statement
Immunotherapy is now an established part of the treatment paradigm for advanced non-small cell lung cancer (NSCLC), but the line of therapy and the sequence of agents are still in flux. In this time when much is to be learned, the optimal therapy for most patients in both the first-line and previously treated settings is in the context of a clinical trial. For standard therapy, however, there are good data to support the practice of programmed death-ligand 1 (PD-L1) testing in the front-line advanced setting and to use pembrolizumab as first-line therapy for those with ≥50% PD-L1 expression. In those who have progressed after receiving platinum-based chemotherapy in the first-line, multiple PD-1/PD-L1 agents are available and currently approved, including nivolumab, pembrolizumab, and atezolizumab. There are no data to suggest that one agent is more efficacious than the others, but pembrolizumab should be reserved for patients with PD-L1 expression ≥1%. Prescribers and patients must be cognizant of the toxicity profile of these agents, as severe immune-related adverse events can occur with therapy. At this time, this practice pattern for immunotherapy in the first- and second-line can be considered the standard of care, but new data are likely to impact the role of immunotherapy as monotherapy or in combination in the near future.
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Advancing Immunotherapy in Metastatic Breast Cancer
Opinion statement
Despite many advances in the treatment of breast cancer, the development of metastatic disease remains an incurable and frequent cause of cancer death for women worldwide. An improved understanding of the role of host immunosurveillance in modulating breast cancer disease biology, as well as impressive survival benefits seen to checkpoint blockade in other malignancies have provided great hope for an expanding role of immunotherapies in breast cancer management. While these novel therapies are currently being investigated in clinical trials, signals of efficacy, and tolerability in early phase studies suggest these will eventually make their way into standard practice algorithms. Ongoing research has highlighted a high degree of intertumoural heterogeneity in tumour lymphocytic infiltrates, suggesting some tumours or subtypes are more immunogenic than others. Furthermore, tumour intrinsic mechanisms of immune evasion are beginning to be uncovered, potentially representing key therapeutic targets to use in combination with checkpoint blockade, exemplifying the emerging concept of personalised medicine approaches to immune therapies. Subsequently, different immunotherapeutic strategies may be required based on stratification by these factors—for the minority of tumours with a high level of pre-existing immunity, immune checkpoint blockade monotherapy may be sufficient. However, for the majority of tumours with lower levels of pre-existing immunity, combination approaches will likely be required to achieve maximal therapeutic effect. Results of ongoing clinical trials including combinations with chemotherapy, radiation therapy, and targeted therapies are eagerly awaited.
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Relation of total sugars, fructose and sucrose with incident type 2 diabetes: a systematic review and meta-analysis of prospective cohort studies [Research]
BACKGROUND:
Sugar-sweetened beverages are associated with type 2 diabetes. To assess whether this association holds for the fructose-containing sugars they contain, we conducted a systematic review and meta-analysis of prospective cohort studies.
METHODS:We searched MEDLINE, Embase, CINAHL and the Cochrane Library (through June 2016). We included prospective cohort studies that assessed the relation of fructose-containing sugars with incident type 2 diabetes. Two independent reviewers extracted relevant data and assessed risk of bias. We pooled risk ratios (RRs) using random effects meta-analyses. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.
RESULTS:Fiffeen prospective cohort studies (251 261 unique participants, 16 416 cases) met the eligibility criteria, comparing the highest intake (median 137, 35.2 and 78 g/d) with the lowest intake (median 65, 9.7 and 25.8 g/d) of total sugars, fructose and sucrose, respectively. Although there was no association of total sugars (RR 0.91, 95% confidence interval [CI] 0.76–1.09) or fructose (RR 1.04, 95% CI 0.84–1.29) with type 2 diabetes, sucrose was associated with a decreased risk of type 2 diabetes (RR 0.89, 95% CI 0.80–0.98). Our confidence in the estimates was limited by evidence of serious inconsistency between studies for total sugars and fructose, and serious imprecision in the pooled estimates for all 3 sugar categories.
INTERPRETATION:Current evidence does not allow us to conclude that fructose-containing sugars independent of food form are associated with increased risk of type 2 diabetes. Further research is likely to affect our estimates.
Trial registration:ClinicalTrials.gov, no. NCT01608620
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Non-surgical treatment of a relapsed cystic hygroma in an adult
Lymphatic malformations, also known as lymphangiomas or cystic hygromas, are benign masses that typically affect newborns and infants and involve the head and neck regions. They are, however, rare in adults and even rarer in the axillary region. Although surgery is considered to be the treatment of choice, we present a rare case of a recurrent cystic hygroma 32 years after the first surgical operation. Due to the cosmetic concerns and the risks of a surgical approach, non-surgical therapy with percutaneous sclerosants was performed, with a good outcome after a 2-year follow-up period.
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Incidental discovery of a large complicated arteriovenous haemangioma
Arteriovenous haemangiomas within the chest are rare and uncommonly documented. After a 60-year-old woman with a history of smoking underwent a routine chest X-ray revealing a right apical mass, further investigations led to the discovery of a large extrapulmonary arteriovenous haemangioma in the superior mediastinum. Additionally, this case became complicated when the hemangioma was found to not only be compressing adjacent major arteries and veins, but also invading into the spinal canal and displacing the spinal cord. With multidisciplinary planning, the arteriovenous haemangioma was embolised and successfully resected. Thus, we present a case of an arteriovenous haemangioma in the superior mediastinum and discuss the importance of the case.
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Traumatic phacocele: a rare but unique scenario
Description
The term phacocele is derived from a Greek word, where 'phaco' denotes lens and 'kele' meaning herniation. It is an unusual and very rare clinical condition.1
A 48-year-old male patient presented with sudden-onset diminution of vision, redness, pain in his left eye following blunt trauma 2 days ago. There was no significant ocular or systemic history. Visual acuity was perception of light positive with projection of rays accurate in left eye and 20/20 in right eye. On slit-lamp examination of the affected eye, there was a solid globular mass in the subconjunctival space located in the superonasal quadrant measuring 8x9 mm with smooth surface and rounded margins. There was an area of suspected scleral dehiscence, temporal to the mass lesion with uveal show (figure 1A). There was diffuse corneal oedema with descemet's folds. Anterior chamber detail was not clearly visible because of hyphaema (figure 1B). Intraocular pressure was 4 mm Hg....
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Angioscopy-guided selective aspiration thrombectomy for acute pulmonary thromboembolism
An 83-year-old woman with a history of pulmonary thromboembolism 10 years ago was referred for dyspnea. Anticoagulation therapy was terminated by her family doctor 3 years previously. On admission, D-dimer level was 16.6 µg/mL and arterial blood gas showed 88.1% on room air. Pulmonary arteriography (PAG) revealed some filling defects, mainly in the right interlobar artery (figure 1A). Non-obstructive angioscopy (NOA)1 showed two kinds of thrombi in the pulmonary arteries. At the translucent area, a massive, red, smooth thrombus was seen (figure 1B, video 1). Between the massive thrombus, floating, mobile, white-red, puff-like thrombi were demonstrated (figure 1C, video 2). As the thrombi entered the catheter spontaneously, aspiration was performed using a 20 mL syringe. Thrombi in the guiding catheter were collected by removing the guiding catheter. For the first trial, red thrombi were effectively aspirated (figure...
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Laryngocoele formation after ingestion of fish bone
Description
A 72-year-old man presented to the clinic with a 3-week history of anterior left neck pain. He described constant discomfort since eating fish a few weeks prior. He recalled pain at the time of eating, and felt he had ingested a fish bone.
There was no dysphagia, dyspnoea or haemoptysis on presentation. He had a medical history of type II diabetes mellitus, with no previous Ear, Nose and Throat issues.
Examination of the neck and oropharynx was normal. There were no palpable nodes or masses. Flexible nasendoscopy demonstrated a normal larynx. A lateral X-ray of the neck was arranged and showed no foreign body.
He was treated with simple analgesia and antacid, with a plan to review in 1 week.
He was reviewed and again examination and nasendoscopy were normal. CT scan revealed a traumatic laryngocoele at the left piriform sinus (figures 1 and 2).
...
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Severe medication-induced peripheral neuropathy treated with topical doxepin cream in a paediatric patient with leukaemia
A 17-year-old female with recently relapsed acute lymphoblastic leukaemia and a treatment course complicated by rhinocerebral mucormycosis infection developed severe peripheral neuropathy during the treatment for mucormycosis infection. This was felt to be a medication side effect. Her peripheral neuropathy was refractory to many well-established treatments, but ultimately responded dramatically and consistently to a novel therapy, topical doxepin cream (5%). This case report is the first published report of the application of topical doxepin cream for treatment of peripheral neuropathy in a paediatric patient.
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Systemic inflammatory response syndrome (SIRS) and a left bundle branch block (LBBB) due to nitrofurantoin
We present a case of a 74-year-old woman, who was on nitrofurantoin treatment for urinary tract infection (UTI), with fever and chills 7 hours after taking nitrofurantoin. She was hospitalised and evaluated for worsening UTI and sepsis. Initially, it appeared to be secondary to post-UTI sepsis because of possible resistant infection or conditions like pulmonary embolism or acute hepatitis. The patient also developed systemic inflammatory response syndrome, left bundle branch block (LBBB), thrombocytopaenia and transaminitis. Considering the side effects of nitrofurantoin, it was stopped. The patient showed improvement and recovered completely with symptomatic and supportive treatment. During follow-up visits with her primary care physician, thrombocytopaenia, transaminitisandLBBB were found to have been resolved.
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Actinomycosis presenting as an anterior abdominal mass after laparoscopic cholecystectomy
Abdominal actinomycosis is a rare disease caused by different anaerobic Actinomyces species. We report the case of a 55-year-old woman who presented with a painless, slow growing, left upper abdominal mass that developed after a laparoscopic cholecystectomy. A CT scan and MRI of the abdomen revealed a desmoid tumour of the left rectus abdominis muscle.
Surgical excision was performed with an uneventful postoperative course. The histological analysis of the specimen was inconsistent with a desmoid tumour and revealed an infection of Actinomyces israelii in the anterior abdominal wall that was confirmed with a microbiology culture. The surgical treatment was followed by a course of penicillin antibiotic therapy for 6 months. This treatment resulted in full recovery with no further complications. Although it is rare, the patient's history of laparoscopic cholecystectomy was identified as the likely source of infection.
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Pathological fracture of the femoral neck following septic coxitis and chronic osteomyelitis: a potential complication of Lemierres syndrome
We portray the case of a 16-year-old girl who was initially admitted to the paediatric emergency department with non-specific symptoms of a severe cold and was first treated symptomatically on an ambulatory basis. Within 6 days she developed the full clinical picture of Lemierre's syndrome with the extraordinary manifestation of involvement of her right hip. Despite an interdisciplinary coordinated treatment as well as surgical therapy, a full-blown sepsis evolved within a short time period and resulted in almost 2 months of intensive care. While the primary focus could be successfully controlled, a progressive avascular necrosis of the right proximal femur developed on the basis of a chronic osteomyelitis. This finally led to a pathological fracture of the femoral neck. After excluding the possibility of an enduring bacterial infection, the fracture was treated with a total hip replacement.
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Impella percutaneous left ventricular assist device for severe acute ischaemic mitral regurgitation as a bridge to surgery
Ischaemic papillary muscle rupture causing acute severe mitral regurgitation (MR) has a dramatic presentation and a very high mortality. Emergent surgical repair improves outcomes, which necessitates robust preoperative stabilisation. Here we discuss a patient with cardiogenic shock with an acute severe MR that was deemed very high risk for emergent valve replacement due to haemodynamic instability and respiratory failure. A percutaneous left ventricular assist device Impella 2.5 (Abiomed, Danvers, MA) drastically improved clinical status, and the patient underwent a successful surgical mitral valve replacement soon after placement of the temporary assist device. Our case highlights that percutaneous ventricular assist devices may help to stabilise patients with severe acute ischaemic MR, and it can serve as a bridge to surgery in high risk patients.
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Clostridium difficile extraintestinal abscess: a rare complication
Extraintestinal Clostridium difficile is rare. A 74-year-old man with a history of ulcerative colitis presented after a fall. Trauma work-up showed liver cirrhosis. Two days later he developed abdominal pain, distension, diarrhoea and leucocytosis. Stool tested positive for C. difficile. CT abdomen showed pancolitis with toxic megacolon. Total abdominal colectomy and ileostomy with a rectal stump was performed. He was discharged, but was readmitted with sepsis. CT abdomen showed a 10.4x7.2 cm fluid collection in the pelvis. C. difficile stool was negative. CT-guided abscess drainage grew C. difficile. Barium enema was negative for communication from the rectal stump to the abscess. The patient was treated with metronidazole for 2 weeks. In summary, extraintestinal C. difficile can develop from recent antibiotics use, gastrointestinal surgery and microperforations from toxic megacolon. We recommend abscess drainage, concomitant treatment with metronidazole and or vancomycin, and reimaging of abscess location 2–4 weeks after cessation of antibiotics.
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Native valve endocarditis caused by Lactococcus garvieae: an emerging human pathogen
A 57-year-old man presented with native mitral valve endocarditis caused by Lactococcus garvieae, a known animal pathogen that is increasingly being reported as a cause of human infections. The organism was cultured in four sets of blood cultures and identification was initially made by matrix-assisted laser desorption/ionisation—time of flight mass spectrometry and confirmed by 16S rDNA PCR of the blood culture isolate. He was successfully treated with 6 weeks of both amoxicillin and gentamicin and underwent valve replacement surgery after 4 weeks of antimicrobial treatment. The removed valve was sterile but L. garvieae DNA was detected on the valve using 16S rDNA PCR. The cause of the L. garvieae infection could not be ascertained but flexible sigmoidoscopy demonstrated colonic polyps, which have been linked to infection with this organism.
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Safe administration of S-1 after 5-fluorouracil-induced cardiotoxicity in a patient with colorectal cancer
Cardiotoxicity is a rare but challenging complication of 5-fluorouracil (5-FU) therapy. Compared with 5-FU, after application of S-1 lower plasma levels of the cardiotoxic metabolite alpha-fluoro-beta-alanine have been reported. Evidence for safe administration of S-1 following 5-FU cardiotoxicity is limited to a case report in an Asian patient. Herein we report the first case of S-1 application after 5-FU cardiotoxicity in a Caucasian patient.
A 67-year-old man with right-sided metastatic colorectal cancer and history of 5-FU cardiotoxicity had a progressive disease after 8-month therapy with irinotecan and bevacizumab. In consideration of known 5-FU cardiotoxicity, he was referred to our department for therapy counselling. We started a combination therapy with S-1, oxaliplatin and bevacizumab. The treatment was well tolerated without any cardiac problems.
Our report confirms the safety of S-1 in cases of 5-FU cardiotoxicity also in a Caucasian patient.
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Radiation-associated peritoneal angiosarcoma
Angiosarcomas account for only 1–2% of all soft tissue sarcomas, with the most common site of origin being in the head and neck region. Peritoneal angiosarcoma is an extremely rare tumour and few cases have been reported previously. Presentation of peritoneal angiosarcoma can be very variable, hence making diagnosis difficult. Herein, we review the current literature and describe a rare case of a patient who presented with haemorrhagic ascites, 17 years after radiotherapy for endometrial carcinoma and was subsequently diagnosed with peritoneal angiosarcoma. Due to extensive disease, surgery was not a viable option. She was started on palliative chemotherapy, but despite treatment, her condition deteriorated further and she eventually passed away. We highlight the diagnostic challenges and considerations in these patients as well as current treatment and management options available.
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Sesamoid osteonecrosis treated with radial extracorporeal shock wave therapy
Sesamoid osteonecrosis is a disabling condition resulting in severe forefoot pain, for which there are limited treatment options. We present a 52-year-old man with 1-year history of pain, aggravated by walking and playing tennis. On examination, pain was localised to plantar aspect of the first metatarsophalangeal joint. Imaging revealed evolving end-stage avascular necrosis of lateral sesamoid with early secondary degenerative changes. Previous exhaustive conservative treatment had been unsuccessful in alleviating his pain. As an alternative to surgery, radial extracorporeal shock wave therapy (rESWT) was proposed. Treatment protocol was 2000 pulses at frequency of 5 Hz, and pressure was varied from 1.2 to 1.8 bar according to patient tolerance. A total of eight sessions were delivered. At completion of treatment, the patient reported minimal discomfort to no pain and was able to return to playing tennis with no recurrence. We propose rESWT to be an effective novel conservative treatment for sesamoid osteonecrosis.
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Cardiac compression due to gastric volvulus: an unusual cause of chest pain
A 42-year-old man was admitted to coronary care for assessment with severe retrosternal chest pain. Echocardiography showed significant external compression of the left atrium. A subsequent CT scan revealed him to have a large hiatus hernia, with most of his stomach herniating into his thorax causing left atrial compression and gastric volvulus. He subsequently underwent successful emergency decompression of the gastric volvulus and repair of his hiatus hernia.
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A Syrian man with abdominal pain
A 32-year-old man presented with progressive abdominal pain, nausea and vomiting after swallowing a packet of dollar bills, his entire money savings, during his journey to Europe as a refugee. Subsequent imaging confirmed the presence of a foreign body in his stomach, which required surgical intervention to be removed. This is one of many cases that illustrate the hopeless circumstances people in the Middle-Eastern warzone are currently facing.
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'The dark pancreas: classic CT appearance of total pancreatic lipomatosis
Description
A 31-year-old male patient presented with a history of chronic abdominal pain and progressive loss of weight. Patient also had massive steatorrhea and had been a chronic alcoholic. There was no history of diabetes mellitus, tuberculosis or hypertension. Laboratory investigations revealed profound hypoproteinaemia. Patient underwent a contrast-enhanced CT of the abdomen. It demonstrated a striking 'dark' pancreas showing an attenuation of –88 Hounsfield units corresponding to fat (figure 1). No obvious enhancing solid component was seen. Careful review of the multiplanar CT reconstruction images confirmed the presence of dilated pancreatic duct with multiple intraductal calculi (figure 2). The CT findings were diagnostic of total pancreatic lipomatosis secondary to obstructed pancreatic ductal system by calculi/chronic calcific pancreatitis. Patient was managed conservatively using pancreatic enzyme replacement therapy.
Figure 1
Axial contrast-enhanced CT image shows the dark, hypoattenuating pancreatic parenchyma corresponding to fat. Note the...
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Caution advised with dapagliflozin in the setting of male urinary tract outlet obstruction
We describe an adverse outcome in a 70-year-old man with type 2 diabetes mellitus treated with sodium–glucose cotransporter type 2 (SGLT2) inhibitor dapagliflozin. SGLT2 inhibitors act in the proximal tubules to prevent glucose reabsorption and induce urinary glucose excretion, they have been associated with increased risk of urinary tract infection (UTI). Our patient presented to hospital with Escherichia coli septicaemia with positive urine and blood cultures on the background of two previous UTIs occurring post commencement of dapagliflozin in the community. Renal tract ultrasound in hospital revealed incomplete bladder emptying with evidence of urinary stasis, and a postvoid residual volume of 180 mL. His dapagliflozin was ceased, and he has had no further episodes of UTI. This case suggests there may be an increased risk of UTI in patients prescribed SGLT2 inhibitors who also have evidence of bladder outlet obstruction—caution is advised in the prescribing of SGLT2 inhibitors in this setting.
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Back pain and oedematous Schmorl node: a diagnostic dilemma
A 26-year-old female from India presented with progressive, unremitting low back pain for over 1 year. She had been treated unsuccessfully for left-sided sacroiliitis, pelvic floor dysfunction, ankylosing spondylitis and seronegative spondyloarthritis. MRI lumbar spine showed a Schmorl node with surrounding marrow oedema at L4, the relevance of which is not clear in literature. One year after initial presentation, a biopsy of this lesion revealed culture positive diagnosis of spinal tuberculosis. Despite advances in imaging, delayed diagnosis is not uncommon in spinal tuberculosis (TB). In our case, it was also attributed to an unknown early lesion: Schmorl node with surrounding oedema. Any association of this lesion with spinal TB has previously not been reported.
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She Didn’t Say Hello, and She Yawned
It was my second month as a neurology resident. So far, I had been to half a dozen stroke alerts, 2 of which had led to tPA administration. I felt ready for the next challenge, with an inflated sense of confidence from our noon lectures and my (limited) experience.
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Elderly Woman With Diffuse Abdominal Pain
A 73-year-old woman without underlying disease presented to our emergency department with diffuse abdominal pain for 3 days. Her initial vital signs showed a blood pressure of 91/59 mm Hg, pulse rate of 116 beats/min, and oral temperature of 38.5°C (101.3°F). Physical examination revealed distention of the abdomen, with diffuse muscle guarding. Laboratory testing revealed WBC count of 13,500 cells/μL and c-reactive protein level of 412 mg/L. Abdominal radiograph result was unremarkable. Contrast-enhanced computed tomography (CT) was performed (Figures 1 and 2).
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Adolescent Male With Syncope
An 18-year-old previously healthy man presented to the emergency department with 4 weeks of fatigue, a 20-pound weight loss, nonbloody, nonbilious vomiting, and a syncopal episode. He had no other significant symptoms. Vital signs were notable for a pulse rate of 78 beats/min and a blood pressure of 93/53 mm Hg. His physical examination result was unremarkable. Laboratory test results were remarkable for a sodium and potassium level of 132 and 4.7 mmol/L, respectively, with a normal glucose level.
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One Day, I’ll Be Like…
The phone rings; it's 11:30 pm, late for a 5-year-old but not that late for my father. It's 1980s Peru, where he's a general practitioner. They don't have much of an emergency medical services system, so when you are sick at night you call your doctor. He's got a nervous wife on the phone, telling him her husband is sick. I hear my dad call Laika, our pet boxer, to accompany him to the house call. This was an era when crime was rampant in Lima and our dog was his security while getting in and out of the houses when seeing patients at night.
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Middle-Aged Woman With Right Upper Quadrant Pain
A 50-year-old woman with a history of pseudotumor cerebri presented to the emergency department with worsening abdominal pain during 2 weeks. Surgical history included lumboperitoneal shunt, hernia repair, and cholecystectomy. Her pulse rate was 108 beats/min, but she was afebrile and well appearing. Laboratory analysis result was unremarkable. Examination revealed diffuse abdominal pain with rebound tenderness on palpation, most pronounced in the right upper quadrant.
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Adolescent With Chest Pain
A 16-year-old male adolescent with a history of short-chain acyl coenzyme A dehydrogenase deficiency and bicommissural aortic valve presented to the emergency department with 3 months of intermittent episodes of chest pain, emesis, and low-grade fevers. Physical examination demonstrated normal vital signs and unremarkable results aside from developmental delay. A chest radiograph demonstrated severe enlargement of the cardiac silhouette (Figure 1).
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Young Boy With Unilateral Facial Flushing
A 2-year-old previously healthy boy was referred to the emergency department (ED) by his pediatrician after an unusual pattern of facial flushing and sweating was observed after he had played outside earlier in the day (Figure 1). His skin color returned to normal within several minutes. In the ED, the child was happy and playful, with normal vital signs. He had anisocoria, with the left pupil larger than the right, which became more pronounced in dim lighting. He had no iris heterochromia and no ptosis.
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Classified 2017 Advertising Rates & Information
Ads and complete payments must be received in writing by the issue's deadline date. These deadlines apply to insertions, cancellations, and changes.
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Antibiotics First Versus Surgery for Appendicitis: A US Pilot Randomized Controlled Trial Allowing Outpatient Antibiotic Management: A Little Step Toward a Patient-Centered Approach and Rethinking the Management of Acute Appendicitis
We read with great interest the results of the randomized controlled trial by Talan et al.1 We congratulate the authors for performing such a well-organized study.
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Global Research Highlights
Editor's note: Annals has partnered with a small group of selected journals of international emergency medicine societies to share from each a highlighted research study, as selected monthly by their editors. Our goals are to increase awareness of our readership to research developments in the international emergency medicine literature, promote collaboration among the selected international emergency medicine journals, and support the improvement of emergency medicine world-wide, as described in the WAME statement at http://ift.tt/2dmKsCb.
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Correction
Correction to 'Trial to Examine Text Message–Based mHealth in Emergency Department Patients With Diabetes (TExT-MED): A Randomized Controlled Trial'
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Gaming for Emergency Physicians?
In the summer of 2016, 2 young men were playing the mobile telephone game Pokémon Go in Encinitas, CA, located just north of San Diego along the coast. Seeking to capture additional virtual Pokémon as part of the game, the 2 men paid no heed to signs saying "No Trespassing" and "Do Not Cross" as they bent their heads over their telephones. Soon, they fell more than 50 feet over a cliff and had to be transported to the emergency department (ED) of Scripps Memorial Hospital in La Jolla.
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Nonclinicians Get Crash Course in Bleeding Control
Nonclinicians are learning how to recognize potentially life-threatening bleeding, pack a wound, and tie a tourniquet to buy time until emergency responders arrive. Enthusiasts describe the training approach, called Stop the Bleed, as similar to teaching cardiopulmonary resuscitation (CPR) to the public, but with a Bleeding 101 focus.
http://ift.tt/2qe8CUW
Classified
COLORADO, Colorado Springs: Yes! There is a great job available in Colorado! Independent, democratic group is expanding and in need of a few BC/BE emergency physicians. For more information contact Bill Kimble, MD at kimbles01@hotmail.com.
http://ift.tt/2qJoWQP
MicroRNA-196b-5p regulates colorectal cancer cell migration and metastases through interaction of HOXB7 and GALNT5
Purpose: MicroRNA-196b-5p (miR-196b-5p) has been previously implicated in malignant transformation, however, its role in colorectal cancer (CRC) has not been fully explored. In the current study, we examine the clinical and biological relevance of miR-196b-5p, and the molecular pathways regulated by miR-196b-5p in CRC. <p>Experimental design: MiR-196b-5p expression was quantitated by qRT-PCR in two independent cohorts comprised of 292 CRC patients in total, to explore its biomarker potential. Transient and stable gain and loss of function experiments were conducted in a panel of CRC cell lines and mice, to evaluate the impact of miR-196b-5p on proliferation, chemo-sensitivity, migration/invasion and metastases formation in vitro and in vivo. The molecular pathways influenced by miR-196b-5p were characterized using whole transcriptome profiling, in-silico target prediction tools, luciferase-interaction assays, and pheno-copy/rescue gene knock-down experiments.</p> <p>Results: Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in two independent CRC patient cohorts (p<0.05, log-rank test). MiR-196b-5p inhibition led to significantly increased CRC cell migration/invasion and metastases formation in mice, whereas ectopic overexpression showed the opposite phenotype. Molecular profiling and target confirmation identified an interaction between miR-196b-5p and HOXB7 and GALNT5, which in turn regulate CRC cell migration.</p> <p>Conclusions: The association of low levels of miR-196b-5p and poor prognosis in CRC patients can be explained by its influence on cancer cell migration and metastases formation. MiR-196b-5p impacts CRC progression pathways through direct interaction with genes involved in cancer cell migration.
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Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression
Purpose: Lung cancer (LC) is the leading cause of cancer death in the US. The molecular events preceding the onset of disease are poorly understood and no effective tools exist to identify smokers with premalignant lesions (PMLs) that will progress to invasive cancer. Prior work identified molecular alterations in the smoke-exposed airway field of injury associated with LC. Here we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in LC chemoprevention.<br />Experimental Design: Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by mRNA-Seq from subjects with (n=50) and without (n=25) PMLs. Using surrogate variable and gene set enrichment analysis we identified genes, pathways, and LC-related gene sets differentially expressed between subjects with and without PMLs. A computational pipeline was developed to build and test a chemoprevention-relevant biomarker.<br />Results: We identified 280 genes in the airway field associated with the presence of PMLs. Among the up-regulated genes, oxidative phosphorylation was strongly enriched and immunohistochemistry and bioenergetics studies confirmed pathway findings in PMLs. The relationship to PMLs and squamous cell carcinomas (SCC) was also confirmed using published LC datasets. The biomarker performed well predicting the presence of PMLs (AUC=0.92, n=17), and changes in the biomarker score associated with progression/stability vs. regression of PMLs (AUC=0.75, n=51).<br />Conclusions: Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high-risk for PML progression and monitor outcome in chemoprevention trials.
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Multi-functional effects of a small-molecule STAT3 inhibitor on NASH and HCC in mice
Purpose: The incidence of hepatocellular carcinoma (HCC) is increasing in the United States and liver cancer is the second leading cause of cancer-related mortality worldwide. Non-alcoholic steatohepatitis (NASH) is becoming an important risk for HCC and most patients with HCC have underlying liver cirrhosis and compromised liver function, which limit treatment options. Thus, novel therapeutic strategies to prevent or treat HCC in the context of NASH and cirrhosis are urgently needed. <br /><br />Experimental Design: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in HCC tumors. STAT3 signaling plays a pivotal role in HCC survival, growth, angiogenesis and metastasis. We identified C188-9, a novel small-molecule STAT3 inhibitor using computer-aided rational drug design. In this study, we evaluated the therapeutic potential of C188-9 for HCC treatment and prevention. <br /><br />Results: C188-9 showed antitumor activity in vitro in three HCC cell lines. In mice with hepatocyte-specific deletion of Pten (HepPten- mice), C188-9 treatment blocked HCC tumor growth, reduced tumor development, and reduced liver steatosis, inflammation and bile ductular reactions, resulting in improvement of the pathological lesions of NASH. Remarkably, C188-9 also greatly reduced liver injury in these mice as measured by serum AST and ALT levels. Analysis of gene expression showed that C188-9 treatment of HepPten- mice resulted in inhibition of signaling pathways downstream of STAT3, STAT1, TREM-1, and Toll-like receptors. In contrast, C188-9 treatment increased liver specification and differentiation gene pathways. <br /><br />Conclusions: Our results suggest that C188-9 should be evaluated further for the treatment and/or prevention of HCC.
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Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade
Purpose: Radiotherapy (RT) is a highly effective anti-cancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity; however, the contribution and mechanisms of RT induced immune responses are unknown. <p>Experimental Design: The impact of low-dose fractionated RT (5 x 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing (NGS) of the T-cell receptor (TCR)-repertoire. A dual-tumor model was used, with fractionated RT delivered to a single tumor site to enable evaluation of the local and systemic response to treatment and ability to induce abscopal responses outside the radiation field.</p> <p>Results: We show that fractionated RT leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of pre-existing T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anti-cancer immunity following RT which can be overcome through combination with αPD-1 mAb leading to improved local and distal tumor control. Moreover, we show that effective clearance of tumor following combination therapy is dependent on both T-cells resident in the tumor at the time of RT and infiltrating T-cells.</p> <p>Conclusions: These data provide evidence that RT can enhance T-cell trafficking to locally-treated tumor sites and augment pre-existing anti-cancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy.
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MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer
Purpose: <br />The phase 2 MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC). <br /><br />Experimental Design: <br />MONARCH 1 was a phase 2 single arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS) and overall survival (OS).<br /><br />Results: <br />Patients (n=132) had a median of 3 (range 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12 month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI: 13.3, 27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%). <br /><br />Conclusions:<br /> <p>In this poor-prognosis, heavily pre-treated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single agent abemaciciclib was well tolerated and exhibited promising clinical activity.
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IGF1R Protein Expression Is Not Associated with Differential Benefit to Concurrent Trastuzumab in Early-Stage HER2+ Breast Cancer from the North Central Cancer Treatment Group (Alliance) Adjuvant Trastuzumab Trial N9831
Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial.
Methods: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years.
Results: Of 1,734 patients, 708 (41%) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs. 51, P = 0.007), estrogen receptor/progesterone receptor positivity (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R– tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R– tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42).
Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R– breast tumors. Clin Cancer Res; 1–9. ©2016 AACR.
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The myxobacterial metabolite Soraphen A inhibits HIV-1 by reducing virus production and altering virion composition [PublishAheadOfPrint]
Soraphen A is a myxobacterial metabolite that blocks the acetyl-CoA carboxylase of the host, and was previously identified as a novel HIV inhibitor. Here we report that Soraphen A acts by reducing virus production and altering the gp120 virion content, impacting entry capacity and infectivity. These effects are partially reversed by addition of palmitic acid, suggesting inhibition of HIV Env palmitoylation as one of the mechanisms of antiviral action.
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First Detection of a Fosfomycin Resistance Gene fosA7 in Salmonella enterica serovar Heidelberg Isolated from Broiler Chickens [PublishAheadOfPrint]
We previously described Salmonella Heidelberg harbouring a chromosomal gene cluster similar to the glutathione S-transferase gene, a putative fosA conferring resistance to fosfomycin. Here we show that this new gene named fosA7 confers resistance to fosfomycin. Introduction of fosA7 into fosfomycin susceptible Salmonella Enteritidis, resulted in a substantial increase in the fosfomycin MIC. This finding increases awareness of antibiotic resistance in Salmonella Heidelberg from broiler related to the food safety and public health.
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Impact of HIV-1 Integrase L74F/V75I Mutations from a Clinical Isolate on Resistance to Second-Generation Integrase Strand Transfer Inhibitors [PublishAheadOfPrint]
A novel HIV-1 integrase mutation pattern, L74F/V75I, which conferred resistance to first-generation integrase strand transfer inhibitors (INSTIs), was identified in a clinical case with virological failure under a raltegravir-based regimen. Addition of L74F/V75I to N155H or G140S/Q148H increased resistance levels to second-generation INSTIs, dolutegravir (>385-, 100-fold, respectively) and cabotegravir (153-, 197-fold, respectively). These findings are important for developing an accurate interpretation system of INSTI resistance and the rational design of next-generation INSTIs.
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Antibacterial and Antibiofilm Activities of a Novel Synthetic Cyclic Lipopeptide Against Cariogenic Streptococcus mutans UA159 [PublishAheadOfPrint]
Despite continuous efforts to control cariogenic dental biofilms, very few effective antimicrobial treatments exist. In this study, we characterized the activity of a novel synthetic cyclic lipopeptide 4 (CLP-4), derived from fusaricidin, against the cariogenic pathogen Streptococcus mutans UA159. We determined CLP-4's minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), spontaneous resistance frequency, and we performed time-kill assays. Additionally, we assessed CLP-4's potential to inhibit biofilm formation (MBIC) and eradicate pre-formed biofilms (MBEC). Our results demonstrate that CLP-4 has a strong antibacterial activity in vitro and is a potent bactericidal agent with low spontaneous resistance frequency. At a low concentration of 5 μg/ml, CLP-4 completely inhibited S. mutans UA159 biofilm formation and at 50 μg/ml reduced the viability of established biofilms by > 99.99%. We also assessed CLP-4's cytotoxicity and stability against proteolytic digestion. CLP-4 withstood trypsin or chymotrypsin digestion even after treatment for 24 h, and our toxicity studies showed that CLP-4 effective concentrations had negligible effects on hemolysis and the viability of human oral fibroblasts. In summary, our findings showed that CLP-4 is a potent antibacterial and antibiofilm agent with remarkable stability and low non-specific cytotoxicity. Hence, CLP-4 is a promising novel antimicrobial peptide with potential for clinical application in the prevention and treatment of dental caries.
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The tet39 determinant and the msrE-mphE genes in Acinetobacter plasmids are each part of discrete modules flanked by inversely-oriented pdif (XerC-XerD) sites [PublishAheadOfPrint]
The tet39 tetracycline resistance determinant and the macrolide resistance genes msrE and mphE were found in an 18.2 kb plasmid, pS30-1, recovered from a GC2 Acinetobacter baumannii isolate from Singapore, that conferred resistance to tetracycline and erythromycin. pS30-1 also contains mobA and mobC genes encoding MOBQ family proteins but attempts to mobilise pS30-1 utilising a co-resident conjugative repAci6 plasmid were unsuccessful. Eight pdif sites, consisting of inversely-oriented binding sites for the XerC and XerD recombinases separated by 6 bp, were detected in pS30-1. The tet39 determinant and the msrE-mphE gene pair are each surrounded by two pdif sites in inverse orientation. Identical regions in different contexts and many previously unnoticed pdif sites were found in a number of different plasmids in GenBank, showing that the tet39 and msrE-mphE dif modules are mobile. A putative toxin/antitoxin system, a gene encoding a serine recombinase and open reading frames of unknown function were also part of dif modules in pS30-1. In general, modules with internal XerC or XerD sites alternate. Two copies of ISAjo2-1 (94% identical to ISAjo2) in pS30-1 were inserted 5 bp from a XerC site and this appears to be the preferred insertion site for this IS group. Apparently, Acinetobacter plasmids exploit the Acinetobacter XerC-XerD recombinases to mobilise DNA units containing resistance and other genes, via an uncharacterised mechanism. The tet39 and msrE-mphE dif modules add to the oxa24 module and the oxa58 module redefined here, bringing the total resistance-gene-containing dif modules in Acinetobacter plasmids to four.
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Roles of ramR and tet(A) mutations in conferring tigecycline resistance in carbapenem-resistant Klebsiella pneumoniae clinical isolates [PublishAheadOfPrint]
Tigecycline is regarded as a last-resort treatment for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, but increasing numbers of tigecycline-resistant K. pneumoniae isolates have been reported. Tigecycline resistance mechanisms are underdetermined in CRKP. This study aimed to elucidate mechanisms underlying tigecycline resistance in 16 tigecycline- and carbapenem-resistant K. pneumoniae (TCRKP) isolates. Mutations in tigecycline resistance determinant genes (ramR, acrR, oqxR, tet(A), tet(L), tet(X), tet(M), rpsJ) were assessed by PCR amplicon sequencing, and mutations in ramR and tet(A) exhibited high prevalences individually (81%) and in combination (63%). Eight functional ramR mutation profiles reducing tigecycline sensitivity were verified by plasmid complementation of wild-type and mutant ramR. Using a site-specific mutant, the most frequent RamR mutation, A19V (60%), had no significant effect on tigecycline susceptibility and upregulation of ramA and acrA. Two tet(A) variants with double frameshift mutations, Type 1 and Type 2, were identified; Type 2 tet(A) is novel. Parent strain transformed with a plasmid carrying Type 1 or Type 2 tet(A) increased tigecycline MIC by 8-fold or 4-fold, respectively. Synergistic effects were observed in strains harboring deficient ramR and mutated tet(A), with an 8-fold increase in tigecycline MIC compared with strains harboring only mutated tet(A). Overall, mutations in the ramR and tet(A) efflux genes constituted the major tigecycline resistance mechanisms among the studied TCRKP isolates. The identification of strains exhibiting the combination of deficient ramR and widespread mutated tet(A) is concerning due to the possible dissemination of increased tigecycline resistance in K. pneumoniae.
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Posaconazole Induced Hypertension and Hypokalemia: In vivo 11{beta}-hydroxysteroid dehydrogenase Inhibition [PublishAheadOfPrint]
We describe a case of apparent mineralocorticoid excess (AME) secondary to posaconazole and suggest the biochemical mechanism. Clinical and laboratory investigation confirmed 11β-hydroxysteroid dehydrogenase inhibition and withholding therapy led to a resolution of all clinical and laboratory abnormalities. A lower dose of posaconazole was later restarted and avoided recurrence of this syndrome. Additional studies are necessary to determine the frequency of posaconazole induced AME and whether other azole antifungals can be associated with this phenomenon.
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Plasmodium falciparum and P. vivax demonstrate contrasting chloroquine resistance reversal phenotypes [PublishAheadOfPrint]
High-grade chloroquine (CQ) resistance has emerged in both P. falciparum and P. vivax. The aim of the present study was to investigate phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility.
Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay.
In P. falciparum, CQ IC50s were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2 fold), or PQ (1.8 fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs: VP (R2=0.951), (R2=0.852), L7 (R2=0.962), and PQ (R2=0.901), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s.
The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and potentially the likely mechanism of CQ resistance between these two species.
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5-Aminopyrazole-4-carboxamide based compounds prevent the growth of Cryptosporidium parvum [PublishAheadOfPrint]
Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) is a promising target for drug development against cryptosporidiosis. We report a series of low nanomolar CpCDPK1 5-aminopyrazole-4-carboxamide (AC) scaffold inhibitors that also potently inhibit C. parvum growth in vitro. Correlation between anti-CpCDPK1 and C. parvum growth inhibition, as previously reported for pyrazolopyrimidines, was not apparent. Nonetheless, lead AC-compounds exhibited a substantial reduction of parasite burden in the neonatal mouse cryptosporidiosis model when dosed at 25 mg/kg.
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Clonal dissemination of OXA-232 carbapenenase-producing Klebsiella pneumoniae in neonates [PublishAheadOfPrint]
Five OXA-232 carbapenemase-producing Klebsiella pneumoniae were isolated from neonates, belonging to the pandemic clone ST15, and co-produced blaCTX-M-15 and blaSHV-1 genes. All isolates were resistant to ertapenem (MIC>32μg/mL) and meropenem (4-8μg/mL), susceptible or intermediate to impenem (1-2μg/mL). The blaOXA-232 was located on a ColE-type transformable plasmid of 6,141 bp. To our best knowledge, this is the first report of OXA-232 carbapenemase among clinical isolates in China.
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A population pharmacokinetic model of gentamicin in paediatric oncology patients to facilitate personalised dosing [PublishAheadOfPrint]
To ensure safe and effective dosing of gentamicin in children therapeutic drug monitoring (TDM) is recommended. TDM utilising Bayesian forecasting software is recommended, but is unavailable as no population model exists that describes the pharmacokinetics of gentamicin in paediatric oncology patients. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalised dosing in paediatric oncology patients. A non-linear mixed effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination, best described gentamicin disposition. The final model included renal function (described by fat-free mass and post-menstrual age) and serum creatinine as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL: 5.77 L/h/70 kg; central volume of distribution: 21.6 L/70 kg, peripheral volume of distribution: 13.8 L/70 kg and intercompartmental clearance: 0.62 L/h/70kg. External evaluation suggested that current models developed in other paediatrics cohorts may not be suitable to use in paediatric oncology patients, as they showed a tendency to over-predict observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean squared error: 46.0% and mean relative prediction error: -3.40 %) and may therefore be useful to personalise gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model.
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Arr-cb, a rifampin resistance determinant found active or cryptic in Clostridium bolteae [PublishAheadOfPrint]
Clostridium bolteae, which belongs to the Clostridium clostridioforme complex is a member of the human gut microbiota. Recent analysis of seven genomes of C. bolteae revealed the presence of an arr-like gene. Among these strains only 90A7 was found to be resistant to rifampin in the absence of alteration in RpoB. Cloning of arr-cb from 90A7 in Escherichia coli combined with directed mutagenesis demonstrated that Arr-cb is functional but that a Q127->R variant present in 90A9 and 90B3 was inactive. qRT-PCR analysis indicated that arr-cb was silent in the four remaining strains due to a defective transcription. Thus, two independent mechanisms can lead to the crypticity of the likely intrinsic arr-cb gene of C. bolteae.
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Coadministration of Liposomal Amphotericin B and Contrast Medium Does Not Increase Risk of Kidney Injury [PublishAheadOfPrint]
Intravenous radiographic contrast medium and amphotericin B are commonly required in the care of patients with fungal infections. Both interventions have proposed nephrotoxicity through similar mechanisms. We systematically examined patients who received coadministration of liposomal amphotericin B (AmBisome; GE Healthcare) and intravenous contrast medium within a 24-hour period and compared them with patients who underwent non--contrast medium studies. We found 114 cases and 85 controls in our study period. Overall, no increased risk of renal injury was seen with coadministration of these 2 agents. Adjustment for age, baseline kidney function, and other clinical factors through propensity score adjustment did not change this result. Our observations suggest that, when clinically indicated, coadministration of contrast medium and amphotericin B liposomal does not present excess risk compared with amphotericin B liposomal alone.
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Heterocycle thiazole compounds exhibit antifungal activity through increase in the production of reactive oxygen species in Cryptococcus neoformans/Cryptococcus gattii species complex [PublishAheadOfPrint]
Human cryptococcosis can occur as a primary or opportunistic infection and develops as an acute, sub-acute, or chronic systemic infection, involving different organs of the host. Given the limited therapeutic options and the occasional resistance to fluconazole, there is a need to develop novel drugs for the treatment of cryptococcosis. In this report, we describe promising thiazoles 1, 2, 3, and 4 and explore their possible modes of action against Cryptococcus. To this end, we show evidence of interference in the Cryptococcus antioxidant system. The tested compounds exhibited MIC ranging from 0.25 to 2 μg/mL against C. neoformans H99 and KN99α strains. Interestingly, the knockout strains for cu-oxidase and sarcosine oxidase were resistant to thiazoles. MIC values, mainly, of 1, 2, and 4 against these mutants were higher than for the parental strain. After treatment of C. neoformans ATCC 24067 (=C. deneoformans), and C. gattii L27/01 (=C. deuterogattii) with thiazoles we verified an increase of intracellular ROS. Also, we verified the synergistic interaction among thiazoles and menadione, which generates superoxides, with FIC equal to 0.1874, 0.3024, 0.25, and 0.25 for the thiazoles 1, 2, 3, and 4, respectively. In addition, thiazoles exhibited antagonistic interaction with FeTPPS. Thus, in this work we showed that the action of these thiazoles is related to interference in the antioxidant system. These findings suggest that the oxidative stress may be primarily related to the accumulation of superoxide radicals.
http://ift.tt/2qPeR5s
Antimicrobial Resistance Risks of Cholera Prophylaxis for United Nations Peacekeepers [PublishAheadOfPrint]
More than five years after a United Nations peacekeeping battalion introduced cholera to Haiti, over 150,000 peacekeepers continue to be deployed annually from cholera endemic countries. The United Nations has thus far declined to provide antimicrobial chemoprophylaxis to peacekeepers, a policy based largely on concerns that the risks of drug resistance generation and spread would outweigh the potential benefits of preventing future cholera importations. In this study, we sought to better understand the relative benefits and risks of cholera chemoprophylaxis for peacekeepers in terms of antibiotic resistance.
Using a stochastic model to quantify the potential impact of chemoprophylaxis on importation and transmission of drug-resistant and drug-sensitive V. cholerae, we found that chemoprophylaxis would decrease the probability of cholera importation, but would increase the expected number of drug-resistant infections if an importation event were to occur. Despite this potential increase, we found that least 10 drug-sensitive infections would likely be averted per excess drug-resistant infection under a wide range of assumptions about the underlying prevalence of drug resistance and risk of acquired resistance.
Given these findings, policymakers should reconsider whether the potential resistance risks of providing antimicrobial chemoprophylaxis to peacekeepers are sufficient to outweigh the anticipated benefits.
http://ift.tt/2rN4sV6
Epidemic Emergence in the United States of Escherichia coli Sequence Type 131-H30, 2000-2009 [PublishAheadOfPrint]
The H30 subclone of Escherichia coli sequence type 131 (ST131) has become the leading antimicrobial-resistance E. coli lineage in the U.S., and often exhibits resistance to one or both of two key antimicrobial classes for treating Gram-negative infections, extended-spectrum cephalosporins (ESCs) and fluoroquinolones (FQs). However, the timing of and reasons for its recent emergence are inadequately defined. Accordingly, from E. coli clinical isolates collected systematically across the U.S. by the SENTRY Antimicrobial Surveillance Programs in 2000, 2003, 2006, and 2009, 234 isolates were selected randomly, stratified by year, within three resistance categories: (i) ESC-reduced susceptibility, regardless of FQ phenotype (hereafter, ESC-RS), (ii) FQ-resistant, ESC-susceptible (hereafter, FQ-R), and (iii) FQ-susceptible, ESC-susceptible (hereafter, FQ-S). Susceptibility profiles, phylogroup, ST, ST131 subclone, and virulence genotypes were determined, and temporal trends and between-variable associations were assessed statistically. From 2000 to 2006, concurrently with the emergence of ESC-RS and FQ-R strains, (virulence-associated) phylogroup B2's prevalence among such strains also rose dramatically, due entirely to rapid emergence of ST131, especially H30. By 2009, H30 was the dominant E. coli lineage overall (22%), accounting for a median of 43% of all single-agent and multidrug resistance (68% for ciprofloxacin). H30's emergence increased the net virulence gene content of resistant (especially FQ-R) isolates, giving stable overall virulence gene scores despite an approximately four-fold expansion of the historically-less-virulent resistant population. These findings define more precisely the timing and tempo of H30's emergence in the U.S., identify possible reasons for it, and suggest potential consequences, including more frequent and/or aggressive antimicrobial-resistant infections.
http://ift.tt/2qPjtIE
Potentiation of Antibiotic Activity by a Novel Cationic Peptide: Potency and Spectrum of Activity of SPR741 [PublishAheadOfPrint]
Novel approaches to the treatment of multi-drug resistant Gram-negative bacterial infections are urgently required. One approach is to potentiate the efficacy of existing antibiotics whose spectrum of activity is limited by the permeability barrier presented by the Gram-negative outer membrane. Cationic peptides derived from polymyxin B have been used to permeabilize the outer membrane, granting antibiotics that would otherwise be excluded access to their targets. We assessed the in vitro efficacy of combinations of SPR741 with conventional antibiotics against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Of 35 antibiotics tested, the MICs of eight were reduced 32- to 8,000-fold against E. coli and K. pneumoniae in the presence SPR741. The eight antibiotics - azithromycin, clarithromycin, erythromycin, fusidic acid, mupirocin, retapamulin, rifampicin, and telithromycin - had diverse targets and mechanisms of action. Against A. baumannii, similar potentiation was achieved with clarithromycin, erythromycin, fusidic acid, retapamulin and rifampicin. Susceptibility testing of the most effective antibiotic-SPR741 combinations was extended to 25 additional multi-drug resistant or clinical isolates of E. coli and K. pneumoniae, and 17 additional A. baumannii isolates, in order to rank the potentiated antibiotics. SPR741 was also able to potentiate antibiotics that are substrates of the AcrAB-TolC efflux pump in E. coli, effectively circumventing contribution of this pump to intrinsic antibiotic resistance. These studies support the further development of SPR741 in combination with conventional antibiotics for the treatment of Gram-negative bacterial infections.
http://ift.tt/2rNk2Qy
Differential Activity of the Oral Glucan Synthase Inhibitor SCY-078 against Wild-Type and Echinocandin-Resistant Strains of Candida spp. [PublishAheadOfPrint]
SCY-078 (formerly MK-3118) is a novel orally active inhibitor of fungal β- (1, 3)-glucan synthase (GS). SCY-078 is a derivative of enfumafungin and is structurally distinct from the echinocandin class of antifungal agents. We evaluated the in vitro activity of this compound against wild-type (WT) and echinocandin-resistant isolates containing mutations in the FKS genes of Candida spp. Against 36 Candida spp. FKS mutants tested, 30 (83.3%) were non-WT to 1 or more echinocandins and only 9 (25.0%) were non-WT (MIC, >WT-upper limit) to SCY-078. Among C. glabrata isolates carrying FKS alterations, 84.0% were non-WT to the echinocandins versus only 24.0% for SCY-078. In contrast to the echinocandin comparators, the activity of SCY-078 was minimally afected by the presence of FKS mutations suggesting that this agent may be useful in the treatment of Candida infections due to echinocandin-resistant strains.
http://ift.tt/2qP4jmK
The Changes in Rats with Sciatic Nerve Crush Injury Supplemented with Evening Primrose Oil: Behavioural, Morphologic, and Morphometric Analysis
Nerve crush injuries are commonly used models for axonotmesis to examine peripheral nerve regeneration. As evening primrose oil (EPO) is rich in omega-6 essential fatty acid component and gamma-linolenic acid, studies have shown the potential role of EPO in myelination. Seventy-two healthy adult Sprague-Dawley rats were classified into three groups: normal group, control group, and experimental group. The result indicates that there was significant difference in toe-spreading reflex between the normal and the control groups (, ) and the normal and the EPO groups (, ) and significant difference between EPO and the control groups (, ). Regeneration of axons and myelin in nerve fibre in the EPO-treated group developed better and faster than in the control group. In the control group, the shape of the axon was irregular with a thinner myelin sheath. In the experimental group, the shape of the axons, the thickness of the myelin sheath, and the diameter of the axons were almost the same as in the normal group. In conclusion, EPO supplementation may be beneficial as a therapeutic option for disturbances of nerve interaction.
http://ift.tt/2rbM4sG
Histopathological and Reproductive Evaluation in Male Rats Fed Jatropha curcas Seed Cake with or without Alkaline Hydrolysis and Subjected to Heat Treatment
Jatropha curcas cake, a by-product of biodiesel production, is rich in protein and has potential to be used in livestock feed; however, the presence of antinutritional factors and phorbol esters limits its use. Thus, this study investigated toxicological and reproductive effects in male Wistar rats after subchronic exposure to J. curcas cake subjected to detoxification procedures. Rats were divided into seven groups () and treated for 60 days. The control group received commercial feed, while experimental groups received a diet containing 5% J. curcas cake nonhydrolyzed or hydrolyzed with 5 M NaOH. The cakes were unwashed or washed with ethanol or water and were autoclaved at 121°C for 30 minutes. Alkaline hydrolysis combined with ethanol washing decreased the phorbol ester concentration in the cake by 98%. Histopathological findings included diffuse degeneration of the liver and edema around the pulmonary vessels in the nonhydrolyzed groups. In addition, nontreated females mated with males of nonhydrolyzed unwashed group showed a decreased number of live fetuses and an increased placental weight. There were no signs of toxicity in rats given hydrolyzed cakes washed and unwashed, indicating that alkaline hydrolysis associated with heat treatment is an efficient method for detoxification of the J. curcas cake.
http://ift.tt/2rKu85D
β1-adrenoceptor, but not β2-adrenoceptor, subtype regulates heart rate in type 2 diabetes rats in vivo
Abstract
Background
β-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific β1- and β2-adrenoceptor subtype contributions to chronotropic responses in type 2 diabetes in vivo, which are currently unknown.
Methods
Type 2 diabetic and non-diabetic rats were implanted with radio-telemeters to measure arterial blood pressure and derive heart rate under conscious conditions. Vascular access ports were implanted to inject isoproterenol (β1- and β2-adrenoceptor agonist, 0.1–300 μg kg−1) in the presence of atenolol (β1-adrenoceptor antagonist, 2000 μg kg−1) or nadolol (β1- and β2-adrenoceptor agonist, 4000 μg kg−1) to determine β-adrenoceptor subtype chronotropic contributions.
Results
Resting heart rate was reduced in diabetic rats (388 ± 62 vs. 290 ± 37 bpm non-diabetic vs. diabetic, P < 0.05, mean ± SD), which remained after atenolol or nadolol administration. Overall β-adrenoceptor chronotropic responsiveness was increased in diabetic rats (Δ heart rate at highest dose isoproterenol: 135 ± 66 vs. 205 ± 28 bpm, non-diabetic vs. diabetic, P < 0.05), a difference that diminished after β1-adrenoceptor blockade with atenolol (Δ heart rate at highest dose isoproterenol: 205 ± 37 vs. 195 ± 22 bpm, non-diabetic vs. diabetic, P < 0.05).
Conclusion
The β1-adrenoceptor is the main subtype to modulate chronotropic β-adrenoceptor responses in healthy, as well as diabetic rats. This study provides novel insights in the understanding of the pathological basis of dysregulation of heart rate in type 2 diabetes, which could be important for improving the current therapeutic strategies targeting the diabetic chronotropic incompetence.
This article is protected by copyright. All rights reserved
http://ift.tt/2qJoF0l
Reveal LINQ Versus Reveal XT Implantable Loop Recorders: Intra- and Post-Procedural Comparison
To compare the procedure, recovery, hospitalization times, and costs along with patient/parent satisfaction after newer-generation cardiac implantable loop recorder (Reveal LINQ; Medtronic Inc, Minneapolis, Minnesota) and previous-generation implantable loop recorder (Reveal XT; Medtronic Inc).
http://ift.tt/2rN3MyZ
Impact of Periconceptional Folic Acid Supplementation on Low Birth Weight and Small-for-Gestational-Age Infants in China: A Large Prospective Cohort Study
To explore the effects of maternal folic acid supplementation alone during pregnancy on the incidence of low birth weight (LBW) and small-for-gestational-age (SGA) infant status.
http://ift.tt/2qP6lU1
Regional Volume Characteristics of the Preterm Infant Receiving First Intention Continuous Positive Airway Pressure
To determine whether applying nasal continuous positive airway pressure (CPAP) using systematic changes in continuous distending pressure (CDP) results in a quasi-static pressure–volume relationship in very preterm infants receiving first intention CPAP in the first 12-18 hours of life.
http://ift.tt/2qOVXLY
Route of ondansetron administration and ventricular arrhythmias
Moeller et al published a large retrospective study that identified children who developed a ventricular tachyarrhythmia within 24 hours of receiving ondansetron.1 Although nearly 200 000 doses of ondansetron were administered in the cohort, only 7 patients experienced a ventricular tachyarrhythmia within 24 hours after ondansetron administration. All 7 patients had a baseline cardiac condition (eg, baseline conduction disorder) with a strong predisposition to arrhythmias. Two of the 7 had received concomitant QT-prolonging medications, and 3 had an electrolyte imbalance.
http://ift.tt/2rNpdjk
Rapid Cycling Genomic Selection in a Multi-parental Tropical Maize Population
Genomic selection (GS) increases genetic gain by reducing the length of the selection cycle, as has been exemplified in maize using rapid cycling recombination of bi-parental populations. However, no results of GS applied to maize multi-parental populations have been reported so far. This study is the first to show realized genetic gains of rapid cycling genomic selection (RCGS) for four recombination cycles in a multi-parental tropical maize population. Eighteen elite tropical maize lines were intercrossed twice and self-pollinated once to form the cycle 0 (C0) training population. One thousand ear-to-row C0 families were genotyped with 955,690 genotyping-by-sequencing SNP markers; their testcrosses were phenotyped at four optimal locations in Mexico to form the training population. Individuals from families with the best plant types, maturity, and grain yield were selected and intermated to form RCGS cycle 1 (C1). Predictions of the genotyped individuals forming cycle C1 were made, and the best predicted grain yielders were selected as parents of C2; this was repeated for more cycles (C2, C3, and C4), thereby achieving two cycles per year. Multi-environment trials of individuals from populations C0, C1, C2, C3, and C4 together with four benchmark checks were evaluated at two locations in Mexico. Results indicated that realized grain yield from C1 to C4 reached 0.225 ton ha-1 per cycle, which is equivalent to 0.100 ton ha-1 year-1 over a 4.5-year breeding period from the initial cross to the last cycle. Compared with the original 18 parents used to form cycle 0 (C0), genetic diversity narrowed only slightly during the last GS cycles (C3 and C4). Results indicate that in tropical maize multi-parental breeding populations, RCGS can be an effective breeding strategy for simultaneously conserving genetic diversity and achieving high genetic gains in a short period of time.
http://ift.tt/2rv0R1s
A Coding Variant in the Gene Bardet-Biedl Syndrome 4 (BBS4) Is Associated with a Novel Form of Canine Progressive Retinal Atrophy
Progressive retinal atrophy is a common cause of blindness in the dog and affects over 100 breeds. It is characterized by gradual vision loss that occurs due to the degeneration of photoreceptor cells in the retina. Similar to the human counterpart retinitis pigmentosa, the canine disorder is clinically and genetically heterogeneous and the underlying cause remains unknown for many cases. We use a positional candidate gene approach to identify putative variants in the Hungarian Puli breed using genotyping data of 14 family-based samples (CanineHD BeadChip array, Illumina) and whole genome sequencing data of two proband and two parental samples (Illumina HiSeq 2000). A single nonsense SNP in exon 2 of BBS4 (c.58A>T, p.Lys20*) was identified following filtering of high quality variants. This allele is highly associated (PCHISQ = 3.425e-14, n = 103) and segregates perfectly with progressive retinal atrophy in the Hungarian Puli. In humans, BBS4 is known to cause Bardet-Biedl syndrome that includes a retinitis pigmentosa phenotype. From the observed coding change we expect that no functional BBS4 can be produced in the affected dogs. We identified canine phenotypes comparable with Bbs4-null mice including obesity and spermatozoa flagella defects. Knockout mice fail to form spermatozoa flagella. In the affected Hungarian Puli spermatozoa flagella are present, however a large proportion of sperm are morphologically abnormal and <5% are motile. This suggests that BBS4 contributes to flagella motility but not formation in the dog. Our results suggest a promising opportunity for studying Bardet-Biedl syndrome in a large animal model.
http://ift.tt/2rv4vby
The Evolutionary Basis of Translational Accuracy in Plants
Mistranslation errors compromise fitness by wasting resources on nonfunctional proteins. In order to reduce the cost of mistranslations, natural selection chooses the most accurately-translated codons at sites that are particularly important for protein structure and function. We investigated the determinants underlying selection for translational accuracy in several species of plants belonging to three clades: the Brassicaceae, Fabidae and Poaceae. Although signatures of translational selection were found in genes from a wide range of species, the underlying factors varied in nature and intensity. Indeed, the degree of synonymous codon bias at evolutionarily-conserved sites varied among plant clades while remaining uniform within each clade. This is unlikely to solely reflect the diversity of tRNA pools because there is little correlation between synonymous codon bias and tRNA abundance, so other factors must affect codon choice and translational accuracy in plant genes. Accordingly, synonymous codon choice at a given site was affected not only by the selection pressure at that site but also its participation in protein domains or mRNA secondary structures. Although these effects were detected in all the species we analyzed, their impact on translation accuracy was distinct in evolutionarily-distant plant clades. The domain effect was found to enhance translational accuracy in dicot and monocot genes with a high GC content, but to oppose the selection of more accurate codons in monocot genes with a low GC content.
http://ift.tt/2qbpEDG
Development of a Medium Density Combined-Species SNP Array for Pacific and European Oysters (Crassostrea gigas and Ostrea edulis)
SNP arrays are enabling tools for high-resolution studies of the genetic basis of complex traits in farmed and wild animals. Oysters are of critical importance in many regions from both an ecological and economic perspective, and oyster aquaculture forms a key component of global food security. The aim of our study was to design a combined-species medium density SNP array for Pacific oyster (C. gigas) and European flat oyster (O. edulis), and to test the performance of this array on farmed and wild populations from multiple locations, with a focus on European populations. SNP discovery was carried out by whole genome sequencing of pooled genomic DNA samples from eight C. gigas populations, and RAD Sequencing of 11 geographically diverse O. edulis populations. Nearly 12 million candidate SNPs were discovered and filtered based on several criteria including preference for SNPs segregating in multiple populations and SNPs with monomorphic flanking regions. An Affymetrix Axiom® Custom Array was created and tested on a diverse set of samples (n = 219) showing ~ 27 K high quality SNPs for C. gigas and ~ 11 K high quality SNPs for O. edulis segregating in these populations. A high proportion of SNPs were segregating in each of the populations, and the array was used to detect population structure and levels of linkage disequilibrium. Further testing of the array on three C. gigas nuclear families (n = 165) revealed that the array can be used to clearly distinguish between families both based on identity-by-state clustering parental assignment software. This medium-density, combined-species array will be publicly available through Affymetrix, and will be applied for genome-wide association and evolutionary genetic studies, and for genomic selection in oyster breeding programs.
http://ift.tt/2rv7n8t
A study of FoxA1 expression in thyroid tumors
FoxA1 regulates a variety of tissues during embryogenesis and early life. In thyroid, FoxA1 expression has recently been shown in C cells and medullary thyroid carcinomas but not in follicular cells. FoxA1 has also been proposed as potential oncogene in anaplastic thyroid carcinomas. However, FoxA1 expression has not been extensively investigated in a spectrum of thyroid non-neoplastic lesions and tumors. A variety of thyroid tumors and lesions and their morphologic mimics were stained with monoclonal anti-FoxA1 antibody.
http://ift.tt/2qaYzRi
Lipoblasts in Spindle Cell and Pleomorphic Lipomas: a Close Scrutiny
The presence and frequency of lipoblasts (LPB) in spindle cell lipomas (SCL) and pleomorphic lipomas (PL) has never been studied in detail on histologically, immunohistochemically and molecular genetically validated set of tumors. The authors investigated this feature by reviewing 91 cases of SCL and 38 PL. When more than three unequivocal LPB were found, the case was regarded as positive for the presence of LPB. All positive cases were then stained with CD34 and Retinoblastoma (Rb) protein antibodies and tested by FISH for MDM2 and CDK4 amplifications and the FUS gene rearrangements.
http://ift.tt/2rKrAo2
Vaginal birth after caesarean: Views of women from countries with low VBAC rates
Publication date: Available online 22 May 2017
Source:Women and Birth
Author(s): Christina Nilsson, Joan Lalor, Cecily Begley, Margaret Carroll, Mechthild M. Gross, Susanne Grylka-Baeschlin, Ingela Lundgren, Andrea Matterne, Sandra Morano, Jane Nicoletti, Patricia Healy
Problem and backgroundVaginal birth after caesarean section is a safe option for the majority of women. Seeking women's views can be of help in understanding factors of importance for achieving vaginal birth in countries where the vaginal birth rates after caesarean is low.AimTo investigate women's views on important factors to improve the rate of vaginal birth after caesareanin countries where vaginal birth rates after previous caesarean are low.MethodsA qualitative study using content analysis. Data were gathered through focus groups and individual interviews with 51 women, in their native languages, in Germany, Ireland and Italy. The women were asked five questions about vaginal birth after caesarean. Data were translated to English, analysed together and finally validated in each country.FindingsImportant factors for the women were that all involved in caring for them were of the same opinion about vaginal birth after caesarean, that they experience shared decision-making with clinicians supportive of vaginal birth, receive correct information, are sufficiently prepared for a vaginal birth, and experience a culture that supports vaginal birth after caesarean.Discussion and conclusionWomen's decision-making about vaginal birth after caesarean in these countries involves a complex, multidimensional interplay of medical, psychosocial, cultural, personal and practical considerations. Further research is needed to explore if the information deficit women report negatively affects their ability to make informed choices, and to understand what matters most to women when making decisions about vaginal birth after a previous caesarean as a mode of birth.
http://ift.tt/2rvb4uU
Akt signaling is sustained by a CD44 splice isoform-mediated positive feedback loop
Tumor cells nearly invariably evolve sustained PI3K/Akt signaling as an effective means to circumvent apoptosis and maintain survival. However, for those tumor cells that do not acquire PI3K/Akt mutations to achieve this end the underlying mechanisms have remained obscure. Here we describe the discovery of a splice isoform-dependent positive feedback loop that is essential to sustain PI3K/Akt signaling in breast cancer. Splice isoform CD44s promoted expression of the hyaluronan synthase HAS2 by activating the Akt signaling cascade. The HAS2 product hyaluronan (HA) further stimulated CD44s-mediated Akt signaling, creating a feed-forward signaling circuit that promoted tumor cell survival. Mechanistically, we identified FOXO1 as a bona fide transcriptional repressor of HAS2. Akt-mediated phosphorylation of FOXO1 relieved its suppression of HAS2 transcription, with FOXO1 phosphorylation status maintained by operation of the positive feedback loop. In clinical specimens of breast cancer, we established that the expression of CD44s and HAS2 were positively correlated. Our results establish a positive feedback mechanism that sustains PI3K/Akt signaling in tumor cells, further illuminating the nearly universal role of this pathway in cancer cell survival.
http://ift.tt/2qe5vw9
VHL inactivation in precancerous kidney cells induces an inflammatory response via ER stress-activated IRE1{alpha} signaling
Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss-of-function in the development of ccRCC via inflammation remains poorly understood. VHL mutant cells exhibit metabolic abnormalities that can cause chronic endoplasmic reticulum (ER) stress and unfolded protein response (UPR). We hypothesize that unresolved ER stress induces the inflammatory responses observed in ccRCC. ER stress markers including BiP and XBP1s were significantly increased in cultured and primary VHL loss-of-function kidney cells. In epithelial cells, the kinase activity of IRE1α was required for the induction of NFκB and JNK and for the recruitment of macrophages. IRE1α kinase activity was also important for the development of fibrotic phenotype in conditional Vhlh knockout mice. Our results offer insights into the therapeutic potential against ccRCC development by relieving metabolic stress. Such cancer prevention strategy may be critical for high-risk cohorts such as the familial VHL disease patients.
http://ift.tt/2qJqj29
Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy
Inherent intermediate-to-low affinity T cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering re-instated Th1 function in tumor-infiltrating lymphocytes (TILs) that had been functionally disabled in the human renal cell carcinoma (RCC) environment without unleashing undesired Th2 cytokines or IL-10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFN-γ compared to T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T cell function makes it an attractive tool for ATT.
http://ift.tt/2qecHbH
Effect of aqueous extract of the leaves of Baccharis trimera on the proliferation of hepatocytes after partial hepatectomy in rats
Abstract Purpose: To evaluate the effect of aqueous extract of Baccharis trimera leaves on the proliferative capacity of the liver after partial hepatectomy (PH) in rats. Methods: Twenty Wistar rats weighing between 300 and 450g were divided into two groups: control (HP) and test (HP100-rats that received the aqueous extract of Baccharis trimera for four days at a dose of 100 mg / kg / day). On the fifth day, animals from both groups underwent resection of 70% of the liver. Twenty-four hours later, they were sacrificed and the remnant liver was removed and prepared for studied through PCNA immunohistochemistry. Data analysis for comparison between the two groups was made through the non-parametric statistical test Mann-Whitney test. Results: In all the animals studied was found most abundant nuclear immunostaining positive hepatocytes interlobular located in regions of the liver. Quantitative analysis of PCNA-positive cells revealed positivity rate significantly higher mean (p = 0.02) in HP100 group (77.1 ± 13.6) compared to the HP group (45.8 ± 12.9). Conclusion: DAdministration of aqueous extract of the leaves of Baccharis trimera 100 mg/kg of animal has a significant positive effect on liver regeneration in rats, 24 hours after hepatectomy (70%).
http://ift.tt/2q5cOek
Effects of hyperbaric oxygen and nerve growth factor on the long-term neural behavior of neonatal rats with hypoxic ischemic brain damage
Abstract Purpose: To evaluate the effects of HBO (Hyperbaric oxygen) and NGF (Nerve growth factor) on the long-term neural behavior of neonatal rats with HIBD (Neonatal hypoxic ischemic brain damage). Methods: The HIBD model was produced by ligating the right common carotid artery of 7 days old SD (Sprague-Dawley) rats followed by 8% O2 + 92% N2 for 2h. Totally 40 rats were randomly divided into 5 groups including sham-operated group, HIBD control group, HBO treated group, NGF treated group and NGF + HBO treated group. The learning and memory ability of these rats was evaluated by Morris water maze at 30 days after birth, and sensory motor function was assessed by experiments of foot error and limb placement at 42 days after birth. Results: The escape latency of HBO treated group, NGF treated group and NGF + HBO treated group was shorter than that of HIBD control group (p<0.01) and longer than that of sham-operated group. The piercing indexes of 3 treated groups were higher than that of HIBD control group (p<0.01). Conclusion: Hyperbaric oxygen and nerve growth factor treatments may improve learning and memory ability and sensory motor function in neonatal rats after hypoxic ischemic brain damage.
http://ift.tt/2qbkeZA
The effect of intradermal administration of inactive platelet-rich plasma on flap viability in rats
Abstract Purpose: To evaluate the effect of inactive form of platelet rich plasma (PRP) on the flap viability. Methods: Thirty six rats were used. Rats were divided into six groups then 9x3 cm random pattern skin flaps were elevated from dorsum of all rats. For precluding vascularization from the base, a silicone layer was placed under the flap in groups 2(only flap+silicone), 4(saline+silicone) and 6(PRP+silicone). In groups 1(only flap), 2(only flap+silicone) nothing was done except flap surgery. In groups 3(saline) and 4(saline+silicone), saline was applied intradermally , in groups 5(PRP) and 6(PRP+silicone), inactive form of PRP which obtained from different 16 rats was applied intradermally, into certain points of flaps immediately after surgery. After 7 days flap necrosis ratio was measured in all groups. Results: Mean necrosis rate in group 5(PRP) (16.05%) was statistically significantly lower than group 1(only flap) (31,93%) and group 3(saline) (30,43%) (p<0.001). Mean necrosis rate in group 6(PRP+silicone) (36.37%) was statistically significantly lower than group 2(only flap+silicone) (47.93%) and group 4(saline+silicone) (45.65%) (p<0.001). Conclusion: Intradermal inactive platelet rich plasma administration decreases flap necrosis so for skin application.
http://ift.tt/2rvmKhk
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
