bluuebunny/crossref_metadata_2025 huggingface dataset:
Component resolved diagnostics for hymenoptera venom allergy
Authors: Jakob Thilo , Müller Ulrich , Helbling Arthur , Spillner Edzard
Published: July 2017

Purpose of review

Component-resolved diagnostics makes use of defined allergen molecules to analyse IgE-mediated sensitizations at a molecular level. Here, we review recent studies on the use of component-resolved diagnostics in the field of Hymenoptera venom allergy (HVA) and discuss its benefits and limitations.

Recent findings

Component resolution in HVA has moved from single molecules to panels of allergens. Detection of specific immunoglobulin E (sIgE) to marker and cross-reactive venom allergens has been reported to facilitate the discrimination between primary sensitization and cross-reactivity and thus, to provide a better rationale for prescribing venom immunotherapy (VIT), particularly in patients sensitized to both honeybee and vespid venom. Characterization of IgE reactivity to a broad panel of venom allergens has allowed the identification of different sensitization profiles that in honeybee venom allergy were associated with increased risks for side effects or treatment failure of VIT. In contrast, component resolution so far has failed to provide reliable markers for the discrimination of sensitizations to venoms of different members of Vespidae.

Component-resolved diagnostics allows a better understanding of the complexity of sensitization and cross-reactivities in HVA. In addition, the enhanced resolution and precision may allow identification of biomarkers, which can be used for risk stratification in VIT. Knowledge about the molecular composition of different therapeutic preparations may enable the selection of appropriate preparations for VIT according to individual sensitization profiles, an approach consistent with the goals of personalized medicine.
Nonmedical Prescription Opioid Use for the Self-treatment of Pain in Young Adults: A National Shame
Authors: Passik Steven D.
Published: July 2017

Evans et al. (2017) have pointed out how frequently and pervasively nonmedical prescription opioid use is associated with severe pain in young adults, especially young white males. This is a subset of such nonmedical users at tremendous risk of overdose (indeed 1/3 of the study respondents had an overdose event), especially given their concomitant use of benzodiazepines. Avoiding further contributing to the catastrophic rise in overdoses requires access to comprehensive pain care for these young adults. If they were to require opioid therapy, it would have to be in the context of a highly complex and expert variety of such care. If we fail to make it available, we will fail to address the root cause of overdoses for a sizeable subset of nonmedical prescription opioid users.
Clonidine Increases the Likelihood That Abstinence Can Withstand Unstructured Time in Buprenorphine-maintained Outpatients
Authors: Kowalczyk William J. , Bertz Jeremiah W. , Moran Landhing M. , Phillips Karran A , Ghitza Udi E. , Epstein David H. , Preston Kenzie L.
Published: July 2017

Objective:

In a clinical trial examining daily clonidine as an adjunct to buprenorphine treatment for opioid dependence, we found that clonidine increased opioid abstinence and decoupled stress from craving. From a personalized-medicine perspective, the next step is to identify people for whom clonidine would be beneficial. To that end, using data from the same clinical trial, we examined the associations of daily-life activities with treatment success.

Methods:

Outpatients (N = 118) received clonidine (0.3 mg/d) or placebo during 18 weeks of buprenorphine treatment. Participants carried a smartphone that randomly prompted them 4 times per day to report their moods and activities. Using generalized linear mixed models, we assessed the likelihoods of different types of daily activity as a function of clonidine versus placebo, days of longest continuous opioid abstinence, and their interaction.

Results:

Participants in the buprenorphine-only (buprenorphine plus placebo) control group who engaged in more responsibilities (work and child/elder care) had longer streaks of abstinence, whereas those who engaged in more unstructured-time activities had shorter streaks of abstinence. Conversely, for participants in the buprenorphine-plus-clonidine group, longer streaks of abstinence were associated with higher frequencies of activities associated with “unstructured” time.

Conclusions:

The study replicates findings that engaging in responsibilities is related to positive treatment outcomes in standard opioid agonist therapy. The pattern of results also suggests that clonidine helped participants engage in unstructured-time activities with less risk of craving or use than they might otherwise have had.
Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers
Authors: Jonkman Kelly , Duma Andreas , Olofsen Erik , Henthorn Thomas , van Velzen Monique , Mooren René , Siebers Liesbeth , van den Beukel Jojanneke , Aarts Leon , Niesters Marieke , Dahan Albert
Published: July 2017

Background

Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability.

Methods

Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses.

Results

The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min–1 (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability.

Conclusions

We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.
Recent clinical trials in idiopathic inflammatory myopathies
Authors: Leclair Valérie , Lundberg Ingrid E.
Published: July 2017

Purpose of review

Idiopathic inflammatory myopathies (IIMs) are complex multisystemic autoimmune diseases. Glucocorticoids remain the cornerstone of treatment in IIM, and the benefit of additional immunosuppressors is still debated. A limited number of controlled clinical trials have been available to support treatment guidelines, but in the last year, several clinical trials have been published. In this review, the highlights of recently published and on-going clinical trials in IIM will be summarized and discussed.

Recent findings

Post hoc analyses of a large randomized controlled trial (RCT) suggested new predictive factors of response to rituximab in refractory IIM individuals. An international collaboration enabled the completion of a large RCT in early juvenile dermatomyositis that will orient first-line treatment in that population. New approaches are showing encouraging results in inclusion body myositis.

Recent advances in molecular mechanisms underlying IIM pathogenesis and the development of novel targeted therapies have influenced recent and on-going clinical research.
Quick Sequential Organ Failure Assessment and Systemic Inflammatory Response Syndrome Criteria as Predictors of Critical Care Intervention Among Patients With Suspected Infection*
Authors: Moskowitz Ari , Patel Parth V. , Grossestreuer Anne V. , Chase Maureen , Shapiro Nathan I. , Berg Katherine , Cocchi Michael N. , Holmberg Mathias J. , Donnino Michael W.
Published: July 2017

Objectives:

The Sepsis III clinical criteria for the diagnosis of sepsis rely on scores derived to predict inhospital mortality. In this study, we introduce the novel outcome of “received critical care intervention” and investigate the related predictive performance of both the quick Sequential Organ Failure Assessment and the Systemic Inflammatory Response Syndrome criteria.

Design:

This was a single-center, retrospective analysis of electronic health records.

Setting:

Tertiary care hospital in the United States.

Patients:

Patients with suspected infection who presented to the emergency department and were admitted to the hospital between January 2010 and December 2014.

Interventions:

Systemic Inflammatory Response Syndrome and quick Sequential Organ Failure Assessment scores were calculated, and their relationships to the receipt of critical care intervention and inhospital mortality were determined.

Measurement and Main Results:

A total of 24,164 patients were included of whom 6,693 (27.7%) were admitted to an ICU within 48 hours; 4,453 (66.5%) patients admitted to the ICU received a critical care intervention. Among those with quick Sequential Organ Failure Assessment less than 2, 13.4% received a critical care intervention and 3.5% died compared with 48.2% and 13.4%, respectively, for quick Sequential Organ Failure Assessment greater than or equal to 2. The area under the receiver operating characteristic was similar whether quick Sequential Organ Failure Assessment was used to predict receipt of critical care intervention or inhospital mortality (0.74 [95% CI, 0.73–0.74] vs 0.71 [0.69–0.72]). The area under the receiver operating characteristic of Systemic Inflammatory Response Syndrome for critical care intervention (0.69) and mortality (0.66) was lower than that for quick Sequential Organ Failure Assessment (p < 0.001 for both outcomes). The sensitivity of quick Sequential Organ Failure Assessment for predicting critical care intervention was 38%.

Conclusions:

Emergency department patients with suspected infection and low quick Sequential Organ Failure Assessment scores frequently receive critical care interventions. The misclassification of these patients as “low risk,” in combination with the low sensitivity of quick Sequential Organ Failure Assessment greater than or equal to 2, may diminish the clinical utility of the quick Sequential Organ Failure Assessment score for patients with suspected infection in the emergency department.
Elderly patients with multiple myeloma: towards a frailty approach?
Authors: Zweegman Sonja , Engelhardt Monika , Larocca Alessandra
Published: July 2017

Purpose of review

To describe how to better identify frail multiple myeloma patients and to treat them appropriately.

Recent findings

Proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, and immunomodulatory agents (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, have significantly improved the outcome of multiple myeloma patients in the last decade. However, both in clinical trials and in daily clinical practice, elderly multiple myeloma patients have shown lesser benefit. This is mainly due to less stringent use of proteasome inhibitors and IMiDs, increased toxicity, and subsequent early discontinuation of therapy in elderly.

Multiple myeloma typically affects elderly patients. Approximately one-third of patients are older than 75 years at diagnosis. Moreover, at least 30% are frail, both due to disease-related symptoms and (age-related) decline in physical capacity, presence of comorbidities, frailty, polypharmacy, nutritional status, and cognitive impairment. Treatment regimens that are investigated in clinical trials for transplant-ineligible patients have largely been investigated in fit, rather than frail patients, the latter being typically excluded or highly underrepresented therein. Data on the feasibility and efficacy of current standards of care are therefore lacking in frail patients. Preliminary data suggest a higher toxicity and discontinuation rate, loss of efficacy, and impaired quality of life in frail patients. Geriatric assessment helps to identify frail patients according to their functional and cognitive status. Both the International Myeloma Working Group (IMWG)-frailty index and Revised Myeloma Comorbidity Index constitute recently proposed algorithms that easily identify intermediate-fit and frail patients. Ongoing and future clinical trials, specifically designed for frail patients, will hopefully define frailty-directed treatment selection.
Bullous Erythema Nodosum Leprosum as the First Manifestation of Multibacillary Leprosy: A Rare Phenomenon
Authors: Bakshi Neha , Rao Seema , Batra Rohit
Published: July 2017

Erythema nodosum leprosum (ENL) may uncommonly present before treatment in patients with multibacillary leprosy. Atypical manifestations are known in ENL and may be clinically misleading. Such wide variations in the clinical presentation of leprosy in reaction make histopathology an important tool for supporting clinical diagnosis. We report bullous ENL presenting as the first manifestation of leprosy in a 30-year-old Indian man diagnosed using histopathology.
Metastatic Cutaneous Paraganglioma: A Case Report and Review of the Literature
Authors: de Leon Dianne , Walton Kara , Sokumbi Olayemi
Published: July 2017

Paragangliomas are rare neoplasms that arise from chromaffin cells of the sympathetic and parasympathetic nervous system. These tumors are often cured by surgical resection but the risk for metastatic disease exists, particularly for extra-adrenal paragangliomas. The behavior of these tumors is unpredictable, and clinical and histopathological features associated with malignancy have not been determined. The most common sites of metastases include local and distant lymph nodes, bone, liver, and lung. Cutaneous metastases are exceedingly rare with only 2 reported cases, both of which presented on the scalp. Here we describe a 78-year-old woman with cutaneous metastatic paraganglioma presenting as a forehead nodule, which developed 15 years after her initial diagnosis of paraganglioma.
Folliculotropic Metastatic Melanoma: A Case Report and Review of the Literature
Authors: McKinnon Elizabeth L. , West Kelly L. , Ball Russell A. , Wright Nathan , Barnhill Raymond L.
Published: July 2017

Folliculotropic metastasis of cutaneous melanoma is rare, with only 5 published case reports in the English language literature since it was first described in 2009. We report a 41-year-old man with a primary cutaneous melanoma of the right upper preauricular region with metastatic spread to the parotid gland and pulmonary lymph nodes. Excision of the primary lesion was performed and immunotherapy was initiated. Sixteen months later, the patient presented with 2 new lesions of the left forehead and left neck. Histopathological examination was consistent with folliculotropic dermal deposits of metastatic melanoma. Deeper sectioning into the blocks revealed only sparse perifollicular pigment deposition and rare dermal melanocytes—a potential diagnostic pitfall had this been seen in the initial sections. This case represents the sixth and youngest patient to date with folliculotropic metastatic melanoma. This entity often presents in patients with advanced disease, including increased Breslow thickness and/or multiple metastases to lymph nodes, internal organs, or both. The folliculotropic metastases tend to be small and are often multiple. The precise relationship between folliculotropic primary melanoma and folliculotropic metastasis is unclear. In one reported case and in our patient, the primary tumor was noted to have a “folliculocentric” pattern. Because of the latter finding, the differential diagnosis includes multiple primary folliculotropic melanomas. Thus, clinical correlation and knowledge concerning the evolution of disease in the patient are critical. This case highlights a rare and unusual pattern of metastatic melanoma and potential problems in differential diagnosis.
Anterior compartment prolapse: what's new?
Authors: Lang Patrick , Whiteside James L.
Published: July 2017

Purpose of review

The purpose of this review is to summarize the treatment options for anterior compartment prolapse, describe the role that apical suspension plays in the correction of anterior vaginal wall prolapse, and assess the risks and benefits of biologic and synthetic graft use in anterior compartment repair.

Recent findings

In 2016, The Cochrane Review published a review of 37 trials including 4023 participants finding that compared to native tissue repair, the use of synthetic mesh resulted in reduced symptomatic prolapse recurrence, anatomic recurrence, and repeat prolapse surgery. There was insufficient evidence regarding quality of life improvement or the use of biologic grafts. Of note the differences between native tissue and mesh kit repairs were not large.

A strong consideration should be on the correction of apical prolapse when present; isolated anterior wall repairs should be pursued with caution. The surgeon may consider the use of augmenting materials in their repair of anterior vaginal wall prolapse, although the available evidence is not strongly supportive of their use given potential risks.
Lasers for pelvic floor dysfunctions: is there evidence?
Authors: Lang Patrick , Karram Mickey
Published: July 2017

Purpose of review

The purpose of this review is to discuss the available energy sources used in the vaginal canal that are currently being promoted for certain pelvic floor conditions and explore the body of peer-reviewed literature supporting their use.

Recent findings

The majority of research has focused on the use of fractional CO2 laser treatment for genitourinary syndrome of menopause (GSM). Most of these studies are nonrandomized prospective studies, but their data consistently shows an improvement in symptoms without significant side effects.

Vaginal laser treatment for GSM is of particular interest to gynecologists as it provides patients with a history of estrogen receptor positive breast cancer, thromboembolic event, or other contraindication to hormone therapy, an effective treatment option. Currently, we are in the early stages of scientific investigation into the use of lasers in the treatment of pelvic floor dysfunction, but the emerging data is encouraging. The existing data is limited to mostly observational studies with additional quality randomized controlled trials and sham studies needed to ensure that physicians are providing the optimum evidence-based treatments to their patients. At the present time there is insufficient data to promote these therapies for stress incontinence, vaginal tightening, or other pelvic floor abnormalities.
Management of benign ovarian lesions in girls: a trend toward fewer oophorectomies
Authors: Gonzalez Dani O. , Minneci Peter C. , Deans Katherine J.
Published: July 2017

Purpose of review

The management of benign ovarian lesions in girls is currently a controversial topic in the pediatric surgical literature. The purpose of this review is to highlight the epidemiology of benign ovarian masses, outline preoperative risk stratification strategies, review the indications and importance of ovary-sparing surgery (OSS), and discuss the impact of management algorithms.

Recent findings

Efforts across the United States and Canada to promote OSS have improved awareness about the role and safety of OSS for the management of benign ovarian masses in pediatric and adolescent girls. Preoperative risk stratification techniques by a multidisciplinary team can improve the preoperative identification of lesions with a high likelihood of benign disease.

Avoiding oophorectomy may be associated with a number of benefits to individual patients and the overall population. The implementation of a management algorithm to guide the treatment of pediatric and adolescent girls with ovarian lesions can reduce the rate of inappropriate oophorectomies.
Bipolar Disorder and Early Emotional Trauma: A Critical Literature Review on Indicators of Prevalence Rates and Clinical Outcomes
Authors: Dualibe Aline Limiéri , Osório Flávia L.
Published: July 2017

Learning objectives

After participating in this activity, learners should be better able to:

• Evaluate the prevalence of early emotional trauma in patients with bipolar disorder (BD)

• Assess the impact of these traumas on patients and on their development of BD

Objectives

We performed a systematic literature review to (1) evaluate the prevalence of early emotional trauma (EET) in patients with bipolar disorder (BD) and the impact of these traumas on the development of the disorder, and (2) integrate the findings of our review with those previously reported by Fisher and Hosang, Daruy-Filho and colleagues, and Maniglio.

Methods

The literature search was performed on PubMed, SciELO, and PsycINFO databases using the keywords bipolar disorder, early trauma, physical abuse, emotional abuse, sexual abuse, maltreatment, adversity, and neglect.

Results

Twenty-eight articles were selected and analyzed. Taken together, the articles described a high prevalence of EET in BD, consisting mainly of emotional neglect/abuse (approximately 40%), particularly when compared to healthy subjects. The review also identified substantial evidence regarding an association between the presence of EET, early disease onset, rapid cycling, comorbidity with anxiety/stress disorders, and cannabis use.

Conclusion

The integration of the current findings with the identified studies reveals that (1) the methodological limitations noted by Daruy-Filho and colleagues have been largely resolved in more recent studies and (2) the presence of EET in patients with BD is associated with worse clinical outcomes, particularly early disease onset, presence of clinical or psychiatric comorbidities, suicide, and presence of psychotic episodes/symptoms. The review shows that patients with BD experience more traumatic situations than controls and that emotional trauma is the most frequent type of trauma in this group.
Video-Assisted Thoracoscopic versus Robotic-Assisted Thoracoscopic Thymectomy
Authors: Fok Matthew , Bashir Mohamad , Harky Amer , Sladden David , DiMartino Mariano , Elsyed Hazim , Howard Callum , Knipe Maxwell , Shackcloth Michael J.
Published: July 2017

Objective

Minimally invasive thoracic surgical procedures, performed with or without the assistance of a robot, have gained popularity over the last decade. They have increasingly become the choice of intervention for a number of thoracic surgical operations. Minimally invasive surgery decreases postoperative pain, hospital stay and leads to a faster recovery in comparison with conventional open methods. Minimally invasive techniques to perform a thymectomy include video-assisted thoracoscopic surgery (VATS) or robotic-assisted thoracoscopic surgery (RATS). In this study, we aim to systematically review and interrogate the literature on minimally invasive thymectomy and draw a meta-analysis on the outcomes between the two approaches.

Methods

An extensive electronic health database search was performed on all articles published from inception to May 2015 for studies describing outcomes in VATS and RATS thymectomy.

Results

A total of 350 patients were included in this study, for which 182 and 168 patients underwent RATS and VATS thymectomy, respectively. There were no recorded in-hospital deaths for either procedure. There was no statistical difference in conversion to open, length of hospital stay, or postoperative pneumonia. Operational times for RATS thymectomy were longer.

Conclusions

The VATS and RATS thymectomy offer good and safe operative and perioperative outcomes. There is little difference between the two groups. However, there is poor evidence basis for the long-term outcomes in minimally invasive procedures for thymectomy. It is imperative that future studies evaluate oncological outcomes both short and long term as well as those related to safety.
Minimally Invasive Access Aortic Arch Surgery
Authors: Goebel Nora , Bonte Daniel , Salehi-Gilani Schahriar , Nagib Ragi , Ursulescu Adrian , Franke Ulrich F. W.
Published: July 2017

Objective

Median sternotomy is still the standard approach for aortic arch surgery. Minimally invasive techniques promise faster recovery with shorter hospital stay due to thoracic stability, reduced pain, and superior cosmetic results. However, safety is a concern in complex aortic surgery. The aim of our study was to demonstrate that aortic arch surgery via partial upper sternotomy is viable, safe, and equivalent to standard procedure both in terms of its safety and the risk of major adverse cardiac and cerebrovascular events.

Methods

We interrogated our prospectively collected database and identified a total of 21 nonemergent patients operated on at our center between October 2008 and February 2015. Indication for operation was aneurysmatic disease in 18 and aortic dissection in 3 patients. Data were analyzed for in-hospital mortality, stroke, bleeding complications, and acute kidney injury.

Results

Mean ± standard deviation age of patients was 69.3 ± 14.4 years, 57.1% were female, and mean ± standard deviation logistic EuroSCORE was 17.0 ± 7.2%. Surgery on the aortic arch comprised proximal arch in 9, hemiarch in 9, and total arch replacement plus frozen elephant trunk in 3 patients. Concomitant procedures included aortic root repair in 10, aortic root replacement in 2, and aortic valve replacement in 3 patients. We lost one patient because of septic shock, no stroke occurred, but a transient neurologic deficit in three and a postoperative delirium in four patients. Re-exploration for bleeding was necessary in two patients, and one patient had acute kidney injury.

Conclusions

Minimally invasive aortic arch surgery via partial upper sternotomy does not increase the risk of morbidity or mortality. Thus, in experienced hands, it is viable, safe, and therefore favorable and as a result should be offered to more patients.
Endovascular Repair of Peripheral Arterial Disease
Authors: Korkmaz Kemal , Selcuk Gedik Hikmet , Baran Budak Ali , Gunaydin Serdar , Cagli Kerim
Published: July 2017

Objective

One thousand consecutive patients who underwent endovascular repair in an 8-year period were studied retrospectively to evaluate technical success, freedom from reinterventions, early clinical outcome, and risk factors for restenosis/occlusion.

Methods

Mean ± SD Rutherford class was 3.29 ± 0.8. A total of 755 patients have claudication, 423 from rest pain, and 569 from ischemic ulceration.

Results

A total of 552 men and 448 women (mean ± SD = 69.84 ± 8 years; range = 19–89 years) underwent endovascular repair. A total of 698 patients received local anesthesia and 302 general anesthesia. A total of 447 patients received percutaneous transluminal angioplasty, 650 stents were placed; 231 atherectomies were performed and 171 patients received hybrid approach. The procedure was successful in 847 patients (84%). There was no early death. There were 151 early occlusions (95 underwent surgery, 56 received stents), 121 dissections (39 underwent surgery, 56 received stents and 26 medical treatment), 32 hematoma, and 13 early leaks. Mean ± SD Rutherford class improved to 3.02 ± 0.9. Freedom from reintervention rate at 8 years was 76%. A total of 63 patients underwent surgery and 59 cellular therapy. A total of 134 finger, 142 below-knee, and 29 above-knee amputations were reported.

Conclusions

Endovascular interventions can be performed with a satisfactory technical success and low complication rates; however, nonfatal complications and catheter-based reinterventions are frequent.
Qualitative Hormonal Profiling of the Lacrimal Drainage System: Potential Insights into the Etiopathogenesis of Primary Acquired Nasolacrimal Duct Obstruction
Authors: Ali Mohammad Javed , Schicht Martin , Paulsen Friedrich
Published: July 2017

Purpose:

To investigate the presence and distribution patterns of hormone receptors in the lacrimal drainage system in normal and diseased states.

Methods:

The study was performed on cadaveric and clinical samples of the lacrimal drainage system. Immunohistochemical labeling was performed for assessing the presence and distribution of receptors of estrogen alpha, estrogen beta, aromatase (CYP19), testosterone, progesterone, oxytocin, prolactin, and somatostatins 1 to 5 (SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5). The immunohistochemistry stains were scored as positive or negative, and the distribution patterns in the canaliculus, lacrimal sac, and nasolacrimal duct were assessed.

Results:

There was a strong expression of estrogen alpha, estrogen beta, and oxytocin, but this showed variations in distribution patterns. Testosterone and progesterone expressions were more localized to the basement membrane of the epithelium in postmenopausal females. While SSTR2 and SSTR4 expressed only on the villus surfaces of superficial epithelial cells; oxytocin, aromatase, and prolactin additionally expressed in the subepithelial lamina propria and submucosal glands. Diseased samples from primary acquired nasolacrimal duct obstruction showed dramatic reduction or absence of the receptor expression patterns of all the hormones with the exception of epithelial immunoreactivity with prolactin.

Conclusions:

This study provides a proof of principle for the presence of multiple hormone receptors and hypothesizes their possible links in the etiopathogenesis of primary acquired nasolacrimal duct obstructions.
Bulleyaconitine A preferably reduces tetrodotoxin-sensitive sodium current in uninjured dorsal root ganglion neurons of neuropathic rats probably via inhibition of protein kinase C
Authors: Xie Man-Xiu , Pang Rui-Ping , Yang Jie , Shen Kai-Feng , Xu Jing , Zhong Xiong-Xiong , Wang Shao-Kun , Zhang Xiao-Long , Liu Yan-Qing , Liu Xian-Guo
Published: July 2017

Oral Bulleyaconitine A (BLA) is effective for treating neuropathic pain in human patients, but the underlying mechanism is poorly understood. Here, we tested whether BLA blocked voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons. Compelling evidence shows that voltage-gated sodium channels are upregulated in uninjured DRG neurons but downregulated in injured ones following peripheral nerve injury. We found that BLA preferably inhibited Na+ currents in uninjured DRG neurons in neuropathic rats. Compared to sham rats, IC50 values for resting and inactivated Na+ currents were 113 and 74 times lower in injured and uninjured neurons of L4-6 DRGs in spared nerve injury (SNI) rats (4.55 and 0.56 nM) and were 688 and 518 times lower in the uninjured L4 and L6 DRG neurons of L5 spinal nerve ligation (L5-SNL) rats. The use-dependent blockage of BLA on Na+ currents was more potent in neuropathic rats compared to sham rats. Bulleyaconitine A facilitated the inactivation of Na+ channels in each group. IC50 values for resting and inactivated tetrodotoxin-sensitive (TTX-S) channels were 1855 and 1843 times lower than those for TTX-resistant channels in the uninjured neurons of L5 spinal nerve ligation rats. The upregulation of protein kinase C was associated with the preferable effect of BLA on TTX-S Na+ channels in the uninjured DRG neurons. Local application of BLA onto L4-6 DRGs at 0.1 to 10 nM dose-dependently alleviated the mechanical allodynia and thermal hyperalgesia in L5 spinal nerve ligation model. Thus, preferable blockage of TTX-S Na+ channels in uninjured DRG neurons may contribute to BLA's antineuropathic pain effect.
Nervous system delivery of antilysophosphatidic acid antibody by nasal application attenuates mechanical allodynia after traumatic brain injury in rats
Authors: Eisenried Andreas , Meidahl Anders C.N. , Klukinov Michael , Tzabazis Alexander Z. , Sabbadini Roger A. , Clark J. David , Yeomans David C.
Published: July 2017

Lysophosphatidic acid (LPA) is a bioactive lipid that impacts neurological outcomes after neurotrauma by inhibiting neuroregeneration, promoting inflammation, and contributing to behavioral deficits. Blocking LPA signaling with a novel anti-LPA monoclonal antibody (mAb) is neuroprotective after traumatic brain injury (TBI) if given to injured animals whose blood–brain barrier (BBB) has been compromised. It is hypothesized that the anti-LPA mAb could improve chronic pain initiated by TBI. However, poor brain penetration after systemic application of the antibody makes access to the central nervous system (CNS) problematic in situations where the BBB is intact. Our experiments investigated whether intranasal delivery of the anti-LPA mAb could bypass the BBB, allowing for direct entry of the antibody to certain areas of the CNS. When the humanized anti-LPA mAb, LT3114, was intranasally applied to injured rats within 30 minutes after mild TBI using the central lateral percussion model, enzyme-linked immunospecific assay and immunohistochemistry demonstrated antibody uptake to several areas in the CNS, including the area of cortical injury, the corpus callosum, cerebellum, and the subventricular region. Compared with control rats that received LT3114 but no TBI, TBI rats demonstrated significantly higher concentrations of intranasally administered LT3114 antibody in some tissues. In behavioral studies, a significant attenuation of mechanical allodynia after TBI was observed in the anti-LPA treatment group (P = 0.0079), when compared with vehicle controls within 14 days after TBI. These results suggest that intranasal application of the anti-LPA antibody directly accesses CNS sites involved in TBI-related pain and that this access attenuates pain sequelae to the neurotrauma.
Cyclin-dependent kinase 5 modulates the P2X2a receptor channel gating through phosphorylation of C-terminal threonine 372
Authors: Coddou Claudio , Sandoval Rodrigo , Castro Patricio , Lazcano Pablo , Hevia Maria José , Rokic Milos , Hall Bradford , Terse Anita , Gonzalez-Billault Christian , Kulkarni Ashok B. , Stojilkovic Stanko S. , Utreras Elias
Published: July 2017

The purinergic P2X2 receptor (P2X2R) is an adenosine triphosphate–gated ion channel widely expressed in the nervous system. Here, we identified a putative cyclin-dependent kinase 5 (Cdk5) phosphorylation site in the full-size variant P2X2aR (372TPKH375), which is absent in the splice variant P2X2bR. We therefore investigated the effects of Cdk5 and its neuronal activator, p35, on P2X2aR function. We found an interaction between P2X2aR and Cdk5/p35 by co-immunofluorescence and co-immunoprecipitation in HEK293 cells. We also found that threonine phosphorylation was significantly increased in HEK293 cells co-expressing P2X2aR and p35 as compared to cells expressing only P2X2aR. Moreover, P2X2aR-derived peptides encompassing the Cdk5 consensus motif were phosphorylated by Cdk5/p35. Whole-cell patch-clamp recordings indicated a delay in development of use-dependent desensitization (UDD) of P2X2aR but not of P2X2bR in HEK293 cells co-expressing P2X2aR and p35. In Xenopus oocytes, P2X2aRs showed a slower UDD than in HEK293 cells and Cdk5 activation prevented this effect. A similar effect was found in P2X2a/3R heteromeric currents in HEK293 cells. The P2X2aR-T372A mutant was resistant to UDD. In endogenous cells, we observed similar distribution between P2X2R and Cdk5/p35 by co-localization using immunofluorescence in primary culture of nociceptive neurons. Moreover, co-immunoprecipitation experiments showed an interaction between Cdk5 and P2X2R in mouse trigeminal ganglia. Finally, endogenous P2X2aR-mediated currents in PC12 cells and P2X2/3R mediated increases of intracellular Ca2+ in trigeminal neurons were Cdk5 dependent, since inhibition with roscovitine accelerated the desensitization kinetics of these responses. These results indicate that the P2X2aR is a novel target for Cdk5-mediated phosphorylation, which might play important physiological roles including pain signaling.
Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis
Authors: Sakai Kent , Sanders Kristen M. , Youssef Marina R. , Yanushefski Kevin M. , Jensen Liselotte E. , Yosipovitch Gil , Akiyama Tasuku
Published: July 2017

Psoriasis is often accompanied by itch, but the mechanisms behind this symptom remain elusive. Dynamic changes in epidermal innervation have been observed under chronic itch conditions. Therefore, we investigated whether epidermal innervation is altered in the imiquimod-induced psoriasis mouse model, whether blockade of neurotrophic growth factor signaling can reduce these changes, and whether this system can impact psoriatic itch. Over the 7-day time course of imiquimod treatment, the density of epidermal nonpeptidergic nerves significantly increased, whereas the density of peptidergic nerves significantly decreased. The nonpeptidergic epidermal nerves expressed glial cell line–derived neurotrophic factor (GDNF) family receptor GFRα-1 and GFRα-2, the ligand-binding domains for GDNF and neurturin (NRTN). The NRTN mRNA expression was elevated in the skin of imiquimod-treated mice, whereas the GDNF mRNA expression was decreased. Treatment of imiquimod-challenged mice with an NRTN-neutralizing antibody significantly reduced nonpeptidergic nerve density as well as spontaneous scratching. These results indicate that NRTN contributes to an increase in the epidermal density of nonpeptidergic nerves in the imiquimod-induced psoriasis model, and this increase may be a factor in chronic itch for these mice. Therefore, inhibition of NRTN could be a potential treatment for chronic itch in psoriasis.
Sexual Offender Treatment Readiness, Responsivity, and Change: Linkages to Treatment Completion and Recidivism
Authors: Sowden Justina N. , Olver Mark E.
Published: July 2017

This study examined the interrelationship of treatment readiness, responsivity variables, and treatment change to sexual offender treatment outcome, featuring the Treatment Readiness, Responsivity, and Gain Scale: Short Version (TRRG:SV). The sample was composed of 185 Canadian federal offenders who attended a high-intensity sexual offender treatment program and were followed up an average of 9.3 years postrelease. Men with higher levels of education, employment history, and cognitive ability and who were married or equivalent, did not have a serious mental illness or intellectual disability, and were not actuarially high risk tended to show higher levels of treatment engagement across the TRRG:SV subscales. Significant pre–post changes, denoting improvement, were observed on the TRRG:SV. In turn, positive treatment engagement assessed by the TRRG:SV was associated with increased risk-relevant treatment change, decreased program attrition, and reductions in sexual and violent recidivism, even after controlling for baseline risk. The role of attention to responsivity variables and treatment readiness to promote client engagement and maximize therapeutic benefit is underscored.
The current status of biomarkers for the diagnosis of nosocomial pneumonias
Authors: Salluh Jorge I.F. , Souza-Dantas Vicente C. , Póvoa Pedro
Published: July 2017

Purpose of review

Nosocomial pneumonia is a frequent and severe nosocomial infection divided in two distinct groups: hospital-acquired pneumonia and ventilator-associated pneumonia (VAP). In this context, the VAP is notoriously difficult to diagnose clinically, resulting from the lack of a ‘gold standard’ method of diagnosis.

Recent findings

The use of biomarkers may potentially improve the early diagnosis of infections allowing earlier and better identification and treatment. An exhausting list of biomarkers has been studied and although far from perfect, procalcitonin (PCT) and C-reactive protein (CRP) are the most studied biomarkers used in clinical practice. Data coming from literature suggests the use of PCT for VAP prognosis and as a based algorithm tool for the reduction of duration of pneumonia therapy, as well as, the use of the CRP dynamics to the early prediction of VAP and the response to the antibiotics.

The evidence for the use of biomarkers to diagnose nosocomial pneumonia as a stand-alone tool is low to moderate. Improved performance for both PCT and CRP can be obtained by using them in association with clinical features or scoring systems but prospective studies are still needed to validate this hypothesis.
What is new in the prevention of nosocomial pneumonia in the ICU?
Authors: Klompas Michael
Published: July 2017

Purpose of review

To summarize and contextualize recent evidence on preventing ventilator-associated pneumonia (VAP).

Recent findings

Many centers continue to report dramatic decreases in VAP rates after implementing ventilator bundles. Interpreting these reports is complicated, however, by the subjectivity and lack of specificity of VAP definitions. More objective data suggest VAP rates may not have meaningfully changed over the past decade. If so, this compels us to re-examine and revise the prevention bundles we have been using to prevent VAP. New analyses suggest that most hospitals’ ventilator bundles include a mix of helpful and potentially harmful elements. Spontaneous awakening trials, spontaneous breathing trials, head-of-bed elevation, and thromboprophylaxis appear beneficial. Oral chlorhexidine and stress ulcer prophylaxis may be harmful. Subglottic secretion drainage, probiotics, and novel endotracheal cuff designs do not clearly improve objective outcomes. Selective digestive decontamination by contrast appears to lower VAP and mortality rates. Effective implementation is as important as choosing the right bundle components. Best practices include engaging and educating staff, creating structures that facilitate bundle adherence, and providing regular feedback on process measure performance and outcome rates.

VAP rates may still be elevated despite multiple reports to the contrary. Recent evidence suggests new ways to optimize the selection of ventilator bundle components and their implementation.
The evaluation of critically ill transplant patients with infectious diarrhea
Authors: Florescu Diana F.
Published: July 2017

Purpose of review

The review summarizes the epidemiology, risk factors, clinical presentation, diagnosis and management of the most important etiologic agents of infectious diarrhea in critically ill transplant recipients.

Recent findings

Diarrhea, frequently caused by infectious pathogens, can cause significant morbidity and mortality in transplant recipients. Diarrhea can lead to severe dehydration, acute renal failure, medication toxicity, rejection, graft-versus-host disease and impairs patients’ quality of life. Opportunistic infectious pathogens can pose significant diagnostic and therapeutic challenges in immunocompromised hosts.

In transplant recipients, it is vital to differentiate infectious from noninfectious diarrhea to adequately manage their therapeutic approach. Supportive measures and reduction in immunosuppression are essential for the treatment management.
Efficacy and Safety of Proton Pump Inhibitors in the Long-Term Aspirin Users: A Meta-Analysis of Randomized Controlled Trials
Authors: Dahal Khagendra , Sharma Sharan P. , Kaur Jaspreet , Anderson Billie J. , Singh Gurpinder
Published: July 2017

Background:

Long-term aspirin use in cardiovascular disease prevention may result in gastrointestinal bleeding. Although proton pump inhibitors (PPI) have been shown to reduce the risks of peptic ulcers and dyspeptic symptoms in long-term aspirin users in the randomized controlled trials, there are safety concerns about the long-term use of PPI.

Study Question:

What is the safety and efficacy of PPI in patients using aspirin in long term for prevention of cardiovascular diseases and stroke?

Methods:

We searched MEDLINE, EMBASE, CENTRAL, CINAHL, ProQuest, and relevant references from inception through February 2015, and used random-effects model for meta-analysis.

Results:

A total of 10 publications from 9 studies (n = 6382) were included in the meta-analysis. Compared with control, PPI reduced the risks of peptic ulcers [risk ratio (RR): 0.19; 95% confidence interval: 0.13–0.26; P < 0.00001], gastric ulcers [0.24 (0.16–0.35); P < 0.00001], duodenal ulcers [0.12 (0.05–0.29); P < 0.00001], bleeding ulcers [0.22 (0.10–0.51); P = 0.0004], and erosive esophagitis [0.14 (0.07–0.28); P < 0.00001]. PPI increased the resolution of epigastric pain [1.13 (1.03–1.25); P = 0.01], heartburn [1.24 (1.18–1.31); P < 0.00001], and regurgitation [1.26 (1.13–1.40); P < 0.0001], but did not increase the risks of all-cause mortality [1.72 (0.61–4.87); P = 0.31], cardiovascular mortality [1.80 (0.59–5.44); P = 0.30], nonfatal myocardial infarction/ischemia [0.56 (0.22–1.41); P = 0.22], ischemic stroke/transient ischemic attack [1.09 (0.34–3.53); P = 0.89] and other adverse events.

Conclusions:

The PPI seems to be effective in preventing peptic ulcers and erosive esophagitis and in resolution of dyspeptic symptoms without increasing adverse events, cardiac risks or mortality in long-term aspirin users.
Comparison of 3-Factor Versus 4-Factor Prothrombin Complex Concentrate With Regard to Warfarin Reversal, Blood Product Use, and Costs
Authors: DeAngelo Jessica , Jarrell Daniel , Cosgrove Richard , Camamo James , Edwards Christopher , Patanwala Asad E.
Published: July 2017

Background:

Prothrombin complex concentrates (PCCs) are drug products containing varying amounts of vitamin K-dependent coagulation factors II, VII, IX, and X. The evidence comparing 3-factor PCC (3-PCC) versus 4-factor PCC (4-PCC) for warfarin reversal is conflicting. It has been hypothesized that 3-PCC may be less effective than 4-PCC because of relatively lower factor VII content.

Study Question:

The primary objective of this study was to compare international normalized ratio (INR) reversal between 3-PCC and 4-factor PCC (4-PCC) in warfarin-treated patients. The secondary objectives include comparing blood product use, total reversal costs, and cost-effectiveness between the groups.

Study Design:

This was a retrospective cohort study conducted in 2 affiliated, academic institutions in the United States. Consecutive adult patients who received 3-PCC or 4-PCC for warfarin reversal were included.

Measures and Outcomes:

The primary outcome was adequate INR reversal defined as a final INR ≤1.5. Secondary outcomes were the utilization of plasma, red blood cells and platelets, reversal costs, and the cost-effectiveness ratio.

Results:

There were 89 patients who were included in the overall cohort (3-PCC = 57, 4-PCC = 32). Adequate INR reversal occurred less commonly with 3-PCC (45.6%) compared with 4-PCC (87.5%) (P < 0.001). There was no significant difference in the proportion of patients who received plasma (32% vs. 28%, P = 0.813), red blood cells (37% vs. 47%, P = 0.377), or platelets (16% vs. 28%, P = 0.180) between the 3-PCC and 4-PCC groups, respectively. The median reversal cost of 3-PCC ($3663) was lower than 4-PCC ($5105) (P = 0.001). The cost-effective ratio favored 4-PCC ($5105/87.5% = $5834) compared with 3-PCC ($3663/45.6% = $8033).

Conclusions:

Four-PCC was more effective than 3-PCC with regard to INR reversal in patients taking warfarin, but blood product use was similar. Although 4-PCC is associated with increased reversal costs, it may be cost-effective in terms of INR reversal.