Prevention of stricture recurrence following urethral internal urethrotomy: routine repeated dilations or active surveillance?
Strictures of the urethra are the most common cause of obstructed micturition in younger men and there is frequent recurrence after initial treatment. Currently, routine repeated dilations, including intermittent self-catheterisation (ISC) are prescribed by urologists to prevent urethral stricture recurrence. There is, however, no high level evidence available supporting the effectiveness of practicing these painful techniques. Balancing efficacy, adverse effects and costs, we hypothesize that active surveillance is a better option for preventing stricture recurrence as compared with routine repeated dilations. However, well designed, adequately powered multi-center trials with comprehensive evaluation are urgently needed to confirm our hypothesis.&nbsp.


Inflammasomes NLRP3 and AIM2 in peri-implantitis: A cross-sectional study.
Inflammasome components NLRP3 and AIM2 contribute to inflammation development by the activation of caspase-1 and IL-1β. They have not been yet evaluated in samples from patients with active peri-implantitis. Thus, the aim of the present study is to analyze the expression of inflammasomes NLRP3 and AIM2 and subsequent caspase 1 and IL-1β assessing the microenvironment of leukocyte subsets in samples from patients with active peri-implantitis. Biopsies were collected from 33 implants in 21 patients being treated for peri-implantitis. Biopsies from gingival tissues from 15 patients with healthy periodontium were also collected for control. These tissues were evaluated through conventional histological stainings. Then, immunohistochemical detection was performed to analyze NLRP3, AIM2, caspase-1, and IL-1β and markers of different leukocyte subsets. PCR for inflammasomes and related genes was also done. This manuscript reveals a high immunohistochemical and mRNA expression of NLRP3 and AIM2 inflammasomes, caspase-1, and IL-1β in biopsies collected from human peri-implantitis. The expression of the tested markers was significantly correlated with the increase in inflammatory infiltrate, probing depth, presence of biofilm, and bleeding on probing. In these peri-implantitis lesions, the area of biopsy tissue occupied by inflammatory infiltrate was intense while the area occupied by collagen was significantly lower. In comparison with periodontal healthy tissues, the inflammatory infiltrate was statistically significantly higher in the peri-implantitis biopsies and was mainly composed of plasma cells, followed by T and B lymphocytes. In human peri-implantitis, chronic inflammation can be explained in part by the action of IL-1β/caspase 1 induced through NLRP3 and AIM2 inflammasome activation.


Internal jugular vein thrombosis associated with hemodialysis catheters.
To determine the prevalence of internal jugular vein thrombosis among patients undergoing hemodialysis in whom tunneled dialysis catheters were placed by interventional radiologists and to evaluate potential risk factors for thrombosis, such as the number of catheters inserted per patient through the right internal jugular vein, catheter type and material, total catheter days, and catheter-associated infection. Ultrasonographic (US) evaluation of the right internal jugular vein was performed by interventional radiologists in 143 patients with a history of dialysis catheter placement. The examination focused on the detection of right internal jugular vein thrombosis, with or without occlusion. Total catheter days, catheter type, and catheter-related complications, most notably infection, were evaluated with database analysis for possible association with subsequent development of thrombosis. Statistical analysis of potential risk factors was performed with logistic regression models and chi2 tests. Evidence of right internal jugular vein thrombosis was present in 25.9% of the patients enrolled in the study. Among the veins with thrombosis, 62% were occluded. Only the mean number of catheters placed in the right internal jugular vein per patient was significant below the level of P =.20; therefore, a multivariate logistic regression model was not used. Prevalence of internal jugular thrombosis, both complete and incomplete, was higher in the study population than previously reported. The risk factors that were analyzed demonstrated no statistically significant association with development of thrombosis.


Ceftaroline fosamil: a cephalosporin with activity against methicillin-resistant Staphylococcus aureus.
Ceftaroline is a cephalosporin with expanded gram-positive activity recently approved for clinical uses by the US Food and Drug Administration. This article provides an overview of the in vitro and in vivo activities, mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of ceftaroline. Relevant information was identified through a search of PubMed (1990-April 2011), EMBASE (1990-April 2011), International Pharmaceutical Abstracts (1970-April 2011), and Google Scholar using the key words ceftaroline, PPI-0903, PPI-0903M, T-91825, and TAK-599. A review of the reference lists of identified articles, a search of the US Food and Drug Administration Web site, and posters and abstracts from scientific meetings yielded additional publications. In vitro, ceftaroline exhibits activity against most aerobic gram-positive isolates, common aerobic gram-negative respiratory pathogens, and some gram-positive anaerobes. The MIC range for most Staphylococcus aureus isolates, including vancomycin-resistant strains was between ≤0.008 and 4 μg/mL. In Phase III studies (CANVAS 1 and CANVAS 2), ceftaroline was found to be noninferior to vancomycin + aztreonam for the treatment of complicated skin and skin-structure infections, with a clinical cure rate of 91.6% among clinically evaluable patients (ceftaroline versus vancomycin + aztreonam: difference, -1.1; 95% CI, -4.2 to 2.0; P = NS). Ceftaroline's efficacy has also been assessed for the treatment of community-acquired pneumonia in 2 Phase III studies (FOCUS 1 and FOCUS 2) and was equivalent to ceftriaxone, with cure rates of 84.3% and 77.7%, respectively, among clinically evaluable patients in the combined analysis (ceftaroline versus ceftriaxone: difference, 6.7; 95% CI, 1.6 to 11.8). The recommended dosage for patients 18 years and older is 600 mg IV every 12 hours. Dosage adjustment is necessary in patients with renal impairment (creatinine clearance ≤50 mL/min). The pharmacokinetic properties of ceftaroline in patients with hepatic impairments are currently unavailable. Ceftaroline appeared to be well tolerated generally. The most frequently (>3%) reported adverse events were nausea, headaches, diarrhea, pruritus, rash, and insomnia; all were usually mild to moderate, self-limiting, and of little clinical significance. Ceftaroline is a cephalosporin with broad gram-positive activity, including Methicillin-resistant S aureus and vancomycin-resistant S aureus. Its gram-negative activity includes common respiratory pathogens and members of the Enterobacteriaceae. Clinical trials have reported that ceftaroline was noninferior to ceftriaxone, and vancomycin + aztreonam for the treatment of community-acquired pneumonia and complicated skin and skin-structure infections, respectively.


An Open Discussion of the Impact of OpenNotes on Clinical Ethics: A Justification for Harm-Based Exclusions from Clinical Ethics Documentation.
The OpenNotes (ON) mandate in the 21st Century Cures Act requires that patients or their legally authorized representatives be able to access their medical information in their electronic medical record (EMR) in real time. Ethics notes fall under the domain of this policy. We argue that ethics notes are unique from other clinical documentation in a number of ways: they lack best-practice guidelines, are written in the context of common misconceptions surrounding the purpose of ethics consultation, and often answer questions of a different nature than other documentation. Thus, we believe the clinical ethics community would benefit from clarification on when the withholding of ethics notes is justified. We provide recommendations for excluding information from ethics documentation based on the likelihood and magnitude of harm that may occur with particular disclosures and suggest approaches to decrease the potential harms that may occur. We define and explain six types of reasons to exclude information from ethics notes based on significant harms that are not addressed in the ON policy: (1) harmful revelations from a protected chart note; (2) negative emotional effects on patients or families; (3) the purpose of the consultation is undermined by harmful consequences; (4) avoidable negative impact on interpersonal dynamics; (5) inappropriate labeling or disclosure of medical, social, or financial information; and (6) inclusion of biasing or otherwise unfair information. We also suggest approaches to mitigate harm when excluding, including, reframing, or delaying release of information that is perceived to be relevant to an ethics case. Overall, we hope our analysis and recommendations will initiate a much-needed discussion about the impact of the ON mandate on clinical ethics documentation.


Implementation of an inhaled nitric oxide protocol decreases direct cost associated with its use.
The objective of this study was to determine whether the implementation of an inhaled nitric oxide protocol (INO) in a pediatric ICU (PICU) would reduce cost associated with its use without negatively affecting patient outcomes. This is a retrospective cohort study of 76 subjects who required INO therapy in the PICU during the study period. A nitric oxide setup and weaning protocol was implemented in the PICU. The medical records of subjects who had received INO 18 months after protocol implementation, as well as the medical records of subjects who had received INO in the 18 months before protocol implementation, were reviewed. Length of time on INO, cost of INO per subject, mortality, stay, and ventilator hours were recorded. There were 38 subjects in the pre-protocol group and 38 subjects in the post-protocol group. There was a statistically significant decrease in the median per subject cost of INO between the pre- and post-protocol groups (P < .01). There was no statistically significant difference in the median duration of INO use (P = .06), median PICU (P = .42) or hospital (P = .58) stay, median duration of mechanical ventilation (P = .79) or percent mortality (P = .28) between the 2 groups. Implementation of an INO setup and weaning protocol in a PICU reduces the cost associated with its use without a statistically significant difference in mortality. In an era of increased awareness regarding healthcare spending, implementation of evidence-based protocols can provide a way to ensure the judicious utilization of medical resources.


Poland's syndrome and Wilms tumor: an unusual association.
Poland's syndrome, a rare congenital disorder with pectoralis muscular girdle defect, have been reported in association with lymphoreticular malignancies in the past. Childhood solid tumors in association with this congenital anomaly have not been reported so far. We describe this rare association of Poland's syndrome and Wilms tumor. Due to the possibility of increased risk of leukemogenesis in patients with Poland's syndrome, chemo-radiation therapy of Wilms tumor in our patient may increase the risk of secondary leukemia. Therapeutic modification of primary cancer in these patients may be necessary with careful long-term follow-up for early detection and treatment of secondary cancer.


Evidence for oxidative stress in the hepatic mitochondria of bile duct ligated rats.
Lipid peroxidation increased both in the liver homogenates and in the hepatic mitochondrial fraction of bile duct ligated (BDL)-rats. Although mitochondrial superoxide dismutase (SOD) activity did not change in the liver, glutathione (GSH) levels and glutathione peroxidase (GSH-Px) activity decreased in hepatic mitochondrial fraction of BDL-rats as compared to sham-operated rats. In addition, GSH-Px and glutathione transferase (GST) activities decreased but SOD activity remained unchanged in the post-mitochondrial fraction of the liver from BDL-rats. However, erythrocyte lipid peroxide and GSH levels did not change in BDL-rats. In conclusion, our results show that the disturbance of oxidant-antioxidant balance especially in mitochondria may be responsible for cholestatic liver injury in BDL-rats.


Alpha-ketoglutarate inhibits glutamine degradation and enhances protein synthesis in intestinal porcine epithelial cells.
α-Ketoglutarate (AKG) is a key intermediate in glutamine metabolism. Emerging evidence shows beneficial effects of AKG on clinical and experimental nutrition, particularly with respect to intestinal growth and integrity. However, the underlying mechanisms are unknown. Intestinal porcine epithelial cells (IPEC-1) were used to test the hypothesis that AKG inhibits glutamine degradation and enhances protein synthesis. IPEC-1 cells were cultured for 3 days in Dulbecco's modified Eagle's-F12 Ham medium (DMEM-F12) containing 0, 0.2, 0.5 or 2 mM of AKG. At the end of the 3-day culture, cells were used to determine L-[U-14C]glutamine utilization, protein concentration, protein synthesis, and the total and phosphorylated levels of the mammalian target of the rapamycin (mTOR), ribosomal protein S6 kinase-1 (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein-1 (4E-BP1). Compared with 0 mM of AKG (control), 0.2 and 0.5 mM of AKG dose-dependently reduced (P<0.05) glutamine degradation and the production of glutamate, alanine and aspartate in IPEC-1 cells. Addition of 0.5 and 2 mM of AKG to culture medium enhanced protein synthesis (P<0.05) by 78 and 101% without affecting protein degradation, compared to the control group. Rapamycin (50 nM; a potent inhibitor of mTOR) attenuated the stimulatory effect of AKG on protein synthesis. Consistent with these metabolic data, the addition of 0.5 or 2 mM of AKG to culture medium increased (P<0.05) the phosphorylated levels of mTOR, S6k1 and 4E-BP1 proteins. Collectively, these results indicate that AKG can spare glutamine and activate the mTOR signaling pathway to stimulate protein synthesis in intestinal epithelial cells.


[The non perception of obesity can be an obstacle to the role of mothers in taking care of their children].
The goal of this study is to review articles in the scientific literature investigating the role of mothers, fathers and relatives in the treatment of obesity of their children. A search for original articles was conducted in the BIREME (BVS), PUBMED (MEDLINE) and Scielo platforms from 2004 to 2010, using the key words "the role of parents" and "childhood obesity," "the role of parents" and "child obesity treatment," "the mother's role" and "childhood obesity," "the mothers role" and "child obesity treatment." Twenty papers were selected and divided into two thematic categories. It was revealed that there are implications of the role of family, namely the father or mother, on the obesity of children, and more specifically related to the role of mothers. The conclusion drawn is that the role of parents and relatives is fundamental in promoting healthy behavior and lifestyles. Distorted maternal perception leads to excess weight being perceived as normal and this may prejudice treatment of child obesity. Acknowledging that the children are overweight most probably promotes greater acceptance of the need for treatment, in addition to being the necessary impetus for seeking professional assistance.


The significance of epidermal growth factor receptor uncommon mutations in non-small cell lung cancer: A systematic review and critical appraisal.
Uncommon epidermal growth factor receptor (EGFR) mutations collectively account for 10% of EGFR mutations, harboring heterogeneous molecular alterations within exons 18-21 with clinically variable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced Non-Small Cell Lung Cancer (NSCLC) patients. In addition, with the introduction of different NGS gene approach an improvement of EGFR mutations detection was reported. Today, no specific studies have prospectively evaluated uncommon sensitizing mutations in detail and no firm standard of care has been established in the first-line setting. The aim of this comprehensive review is to critically consider the clinical role of uncommon EGFR mutations highlighting the results of several in vitro and in vivo studies, which singly evaluated the sensitivity of uncommon mutations to currently European of Medicines Agency (EMA)-approved EGFR TKIs in cell lines, xenograft models and humans, in order to obtain a practical guide for refining the clinical decision-making process.


OPTN/SRTR 2011 Annual Data Report: kidney.
A shortage of kidneys for transplant remains a major problem for patients with end-stage renal disease. The number of candidates on the waiting list continues to increase each year, while organ donation numbers remain flat. Thus, transplant rates for adult wait-listed candidates continue to decrease. However, pretransplant mortality rates also show a decreasing trend. Many kidneys recovered for transplant are discarded, and discard rates are increasing. Living donation rates have been essentially unchanged for the past decade, despite introduction of desensitization, non-directed donations, and kidney paired donation programs. For both living and deceased donor recipients, early posttransplant results have shown ongoing improvement, driven by decreases in rates of graft failure and return to dialysis. Immunosuppressive drug use has changed little, except for the Food and Drug Administration approval of belatacept in 2011, the first approval of a maintenance immunosuppressive drug in more than a decade. Pediatric kidney transplant candidates receive priority under the Share 35 policy. The number of pediatric transplants peaked in 2005, and decreased to a low of 760 in 2011. Graft survival and short-term renal function continue to improve for pediatric recipients. Postransplant lymphoproliferative disorder is an important concern, occurring in about one-third of pediatric recipients.


Do cervical epidural injections provide long-term relief in neck and upper extremity pain? A systematic review.
The high prevalence of chronic persistent neck pain not only leads to disability but also has a significant economic, societal, and health impact. Among multiple modalities of treatments prescribed in the management of neck and upper extremity pain, surgical, interventional and conservative modalities have been described. Cervical epidural injections are also common modalities of treatments provided in managing neck and upper extremity pain. They are administered by either an interlaminar approach or transforaminal approach. To determine the long-term efficacy of cervical interlaminar and transforaminal epidural injections in the treatment of cervical disc herniation, spinal stenosis, discogenic pain without facet joint pain, and post surgery syndrome. The literature search was performed from 1966 to October 2014 utilizing data from PubMed, Cochrane Library, US National Guideline Clearinghouse, previous systematic reviews, and cross-references. The evidence was assessed based on best evidence synthesis with Level I to Level V. There were 7 manuscripts meeting inclusion criteria. Of these, 4 assessed the role of interlaminar epidural injections for managing disc herniation or radiculitis, and 3 assessed these injections for managing central spinal stenosis, discogenic pain without facet joint pain, and post surgery syndrome. There were 4 high quality manuscripts. A qualitative synthesis of evidence showed there is Level II evidence for each etiology category. The evidence is based on one relevant, high quality trial supporting the efficacy of cervical interlaminar epidural injections for each particular etiology. There were no randomized trials available assessing the efficacy of cervical transforaminal epidural injections. Paucity of available literature, specifically conditions other than disc herniation. This systematic review with qualitative best evidence synthesis shows Level II evidence for the efficacy of cervical interlaminar epidural injections with local anesthetic with or without steroids, based on at least one high-quality relevant randomized control trial in each category for disc herniation, discogenic pain without facet joint pain, central spinal stenosis, and post surgery syndrome.


What is the predictive value of MRI for the occurrence of knee replacement surgery in knee osteoarthritis?
Knee osteoarthritis is associated with structural changes in the joint. Despite its many drawbacks, radiography is the current standard for evaluating joint structure in trials of potential disease-modifying osteoarthritis drugs. MRI is a non-invasive alternative that provides comprehensive imaging of the whole joint. Frequently used MRI measurements in knee osteoarthritis are cartilage volume and thickness; others include synovitis, synovial fluid effusions, bone marrow lesions (BML) and meniscal damage. Joint replacement is considered a clinically relevant outcome in knee osteoarthritis; however, its utility in clinical trials is limited. An alternative is virtual knee replacement on the basis of symptoms and structural damage. MRI may prove to be a good alternative to radiography in definitions of knee replacement. One of the MRI parameters that predicts knee replacement is medial compartment cartilage volume/thickness, which correlates with radiographic joint space width, is sensitive to change, and predicts outcomes in a continuous manner. Other MRI parameters include BML and meniscal lesions. MRI appears to be a viable alternative to radiography for the evaluation of structural changes in knee osteoarthritis and prediction of joint replacement.


Oestrogen, atherosclerosis and cardiovascular disease in women: Epidemiological studies on menopause and hormone replacement therapy.
What part menopause and hormone replacement therapy (HRT) play in the risk of cardiovascular disease in women after middle-age is still debated. The associations between menopause, HRT and cardiovascular disease as well as atherosclerosis were examined in a large cohort study. Our results suggest menopause has an unfavorable association with several cardiovascular risk factors, structural characteristics of the large arteries, on atherosclerosis and on coronary heart disease. HRT was shown to protect women from development of atherosclerosis in the lower extremities and in the common carotid artery. This suggests that the mechanisms underlying this protection include inhibition of the atherosclerotic process. Our analyses of a randomised, placebo-controlled study could not confirm the effect on HRT on atherosclerosis of the common carotid artery. As findings from large randomised trials do not confirm the benefit of estrogen therapy for prevention of cardiovascular disease no definite conclusions can be drawn, and HRT should not be recommended for this purpose in clinical practice.


Effect of forms of collagen linked to polyurethane on endothelial cell growth.
Collagen has been widely coated or grafted onto polymer surfaces to improve the biocompatibility of materials. To better support the growth of endothelial cells on polyurethane (PU), collagen was grafted to the carboxyl group enriched PU through 1,2-bis(2,3-epoxypropoxy)ethane linking. Our results demonstrated that collagen in various conditions may result in different forms being grafted to the PU substrate, which subsequently affected the growth of endothelial cells. Collagen predialyzed against physiological phosphate buffered saline (PBS) could be reconstituted into native type fibrils with a bigger diameter at 37 degrees C than could collagen neutralized by titration with NaOH. At low temperature, titrated collagen formed floss-like fibrils packed in a ball with cobblestone-like morphology. The amount of collagen grafted was related to the condition of the collagen used, which in consequence affected the diameter of the collagen fibril formed and the growth of endothelial cells. In conclusion, reconstituted collagen fibrils formed from collagen in PBS at 37 degrees C grafted in the highest amounts to an epoxy-PU substrate and that optimally supported the growth of endothelial cells. Such prepared materials may be potentially good vascular bioprosthetic materials and may provide a wide range of biological applications.


Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats.
While human observational studies and animal studies report a neuroprotective role for estrogen therapy in stroke, the multicenter placebo-controlled Women's Health Initiative (WHI) study concluded that hormone therapy increased the risk for stroke in postmenopausal women. The present study therefore tested the hypothesis that estrogen replacement would increase the severity of a stroke-like injury in females when this replacement occurs after a prolonged hypoestrogenic period, such as the menopause or reproductive senescence, but not when given to females that were normally cycling immediately prior to the hormone replacement. Two groups of female rats were used: multiparous females with normal but lengthened estrus cycles (mature adults), and older multiparous females currently in a persistent acyclic state (reproductive senescent). Animals were either used intact, or were bilaterally ovariectomized and immediately replaced with a 17beta-estradiol pellet or control pellet. Animals were subject to a forelimb placing test (a test for sensorimotor deficit) and thereafter to middle cerebral artery occlusion (MCAo) by stereotaxic injection of the vasoconstrictive peptide endothelin-1, adjacent to the MCA. One week after stroke, behavioral tests were performed again. Cortical and striatal infarct volume, measured from brain slices, was significantly greater in intact reproductive senescent females as compared to intact mature adults. Furthermore, estrogen treatment to ovariectomized mature adult females significantly reduced the cortical infarct volume. Paradoxically, estrogen treatment to ovariectomized reproductive senescent females significantly increased cortical and striatal infarct volumes as compared to control pellet replaced senescent females. Significant post-stroke behavioral deficit was observed in all groups on the side contralateral to the lesion, while senescent females also exhibited deficits on the ipsilateral side, in the cross-midline forelimb placement test. Using an animal model that approximates the natural ovarian aging process, these findings strongly support the hypothesis that the effectiveness of estrogen therapy in protecting brain health may depend critically on the time of initiation with respect to a female's reproductive status.


Selective inhibition of distracting input.
We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience.


Considering the effect of stem-loop reverse transcription and real-time PCR analysis of blood and saliva specific microRNA markers upon mixed body fluid stains.
Forensic RNA analysis is gathering pace with reports of messenger RNA analysis being used in case work, and with microRNA being increasingly researched. Such techniques address a fundamental issue in body fluid identification, namely increased specificity over existing chemical tests, and the incorporation of additional body fluids such as vaginal material. The use of RNA analysis will be of particular value to sex offences, where there can be a mixture of multiple body fluids from different people. The aim of this study was to determine whether microRNA based body fluid identification tests can be applied to mixed body fluid samples. Blood and saliva were acquired from volunteers and underwent total RNA extraction. Mixed samples were prepared using a range of ratios from 1:1 to 10:1. Each mixed sample then underwent a blood-saliva differentiation test developed in-house, which includes stem-loop reverse transcription and real-time PCR analysis. Aliquots following mixture preparation also underwent standard STR analysis, utilising Quantiplex and Next Generation Multiplex kits. Data relating to the development of an in-house blood-saliva differentiation test is presented, in which it has been demonstrated that such a test has a lower limit of detection than the enzymatic equivalent. It has been shown that not only is it possible to determine the presence of more than one body fluid, it is also possible to determine the major body fluid contributor as well as the minor contributor.


Gene expression profiling of gastric mucosa in mice lacking CCK and gastrin receptors.
The stomach produces acid, which may play an important role in the regulation of bone homeostasis. The aim of this study was to reveal signaling pathways in the gastric mucosa that involve the acid secretion and possibly the bone metabolism in CCK1 and/or CCK2 receptor knockout (KO) mice. Gastric acid secretion was impaired and the ECL cell signaling pathway was inhibited in CCK2 receptor KO mice but not in CCK1 receptor KO mice. However, in CCK1+2 receptor double KO mice the acid secretion in response to pylorus ligation-induced vagal stimulation and the ECL cell pathway were partially normalized, which was associated with an up-regulated pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1). The basal part of the gastric mucosa expressed parathyroid hormone-like hormone (PTHLH) in a subpopulation of likely ECL cells (and possibly other cells) and vitamin D3 1α hydroxylase probably in trefoil peptide2-immunoreactive cells. In conclusion, mice lacking CCK receptors exhibited a functional shift from the gastrin-CCK pathways to the neuronal pathway in control of the ECL cells and eventually the acid secretion. Taking the present data together with previous findings, we suggest a possible link between gastric PTHLH and vitamin D and bone metabolism.


Genetic Causes of Functional Adrenocortical Adenomas.
Aldosterone and cortisol, the main mineralocorticoid and glucocorticoid hormones in humans, are produced in the adrenal cortex, which is composed of three concentric zones with specific functional characteristics. Adrenocortical adenomas (ACAs) can lead to the autonomous secretion of aldosterone responsible for primary aldosteronism, the most frequent form of secondary arterial hypertension. In the case of cortisol production, ACAs lead to overt or subclinical Cushing syndrome. Genetic analysis driven by next-generation sequencing technology has enabled the discovery, during the past 7 years, of the genetic causes of a large subset of ACAs. In particular, somatic mutations in genes regulating intracellular ionic homeostasis and membrane potential have been identified in aldosterone-producing adenomas. These mutations all promote increased intracellular calcium concentrations, with activation of calcium signaling, the main trigger for aldosterone production. In cortisol-producing adenomas, recurrent somatic mutations in PRKACA (coding for the cyclic adenosine monophosphate-dependent protein kinase catalytic subunit α) affect cyclic adenosine monophosphate-dependent protein kinase A signaling, leading to activation of cortisol biosynthesis. In addition to these specific pathways, the Wnt/β-catenin pathway appears to play an important role in adrenal tumorigenesis, because β-catenin mutations have been identified in both aldosterone- and cortisol-producing adenomas. This, together with different intermediate states of aldosterone and cortisol cosecretion, raises the possibility that the two conditions share a certain degree of genetic susceptibility. Alternatively, different hits might be responsible for the diseases, with one hit leading to adrenocortical cell proliferation and nodule formation and the second specifying the hormonal secretory pattern.


Salvage surgery of the limb with severe pseudoamniotic band syndrome: case report and literature review.
Pseudoamniotic band syndrome is a rare iatrogenic complication of twin-to-twin transfusion syndrome treated with foetoscopic procedures. We report a severe pseudoamniotic band syndrome in the recipient monochorionic diamniotic twin pregnancy with twin-to-twin transfusion syndrome following a selective foeticide procedure. A male newborn with a severe circumferential amniotic band in the left leg was treated by single-stage excision of the ring and arterio-venous decompression. No complications were encountered. A microsurgical approach to improve the circulation together with ring excision may be useful in some cases.


A distinctive cutaneous reaction pattern indicative of infection by reactive arthropathy-associated microbial pathogens: the superantigen ID reaction.
The two major cutaneous expressions of infective states are infections of the skin by viable organisms and immunological responses to nonviable microbial antigens or, in the case of molecular mimickry, their human analogues. These immunological responses are designated as cutaneous id reactions, and manifest a histomorphology similar to that seen at the primary infective site. This study presents the clinical and histological findings in 16 patients who developed skin eruptions associated with extracutaneous or systemic infections. There was a striking female predominance; patients ranged in age from 10 to 78 years. The majority of cases manifested skin lesions which clinically resembled Sweet's syndrome, erythema multiforme and/or erythema nodosum. Fever, arthralgia, oligoarthritis, mucosal ulcers of the mouth and/ or genital tract and uveitis were additional features in some cases. Isolated clinical presentations included a petechial rash in a stocking and glove distribution, papular dermatitis, a morbilliform eruption and annular erythema. Among the medical and family histories were atopy and stigmata associated with connective tissue disease (CTD). Two patients were ingesting drugs with known immune dysregulating properties. Skin biopsies showed focal lymphocytic interface dermatitis, a diffuse interstitial histiocytic infiltrate, and a mononuclear cell predominant vascular reaction which in some cases represented vasculitis by virtue of manifesting concomitant luminal or mural fibrin deposition. Eosinophils, eczematous alterations, and papillary dermal edema were identified in a minority of cases. All patients had evidence of a prior or concurrent infection, based on either positive IgM serology for specific microbes or cultures. Among the implicated pathogens were cytomegalovirus, parvovirus B19, streptococcus, mycoplasma, klebsiella, and Borrelia burgdorferi. All of these organisms are among those associated with reactive arthritis, a phenomenon that was seen in some cases. The histology suggested florid cell mediated immunity (CMI), which the authors attributed to the superantigen properties held by the aforesaid pathogens. Skin lesions and constitutional symptoms resolved quickly with antimicrobial therapy in 7 of 9 cases causally linked to bacteria. Spontaneous resolution occurred in 5 of 6 virally mediated eruptions. The other 4 patients were given topical steroids or prednisone; these included 1 patient with Borrelia burgdorferi infection and 1 patient with radiographic evidence of pneumonia who was never cultured, 1 patient with parvovirus B19 infection, and 1 patient with pneumococcal pneumonia and concomitant sarcoidosis. It is the authors' belief that the eruptions seen in these patients may in part reflect a genetic or iatrogenic predisposition to respond excessively to certain infectious triggers.


Stress and social behaviors of maternally deprived captive giraffes (Giraffa camelopardalis).
Maternal deprivation can cause long-term behavioral changes in captive mammals. Studies regarding captive ungulates have also indicated behavioral shifts in the presence of the animal keeping staff; however, little is known about these effects in captive giraffes (Giraffa camelopardalis). To examine this, we observed a population of reticulated giraffes composed of maternally raised and maternally deprived individuals by direct and camera observations at Binder Park Zoo, Battle Creek, Michigan. We conducted observations using a unique ethogram with special regard for behaviors that might indicate stress or anti-social tendencies. Several variables can interact to create behavioral changes; to account for this, our study design examined the interactive effects of observation technique, raising style, and temperature on giraffe behavior. The results of these observations showed a significant increase in the rate of stereotypic and antisocial behaviors resulting from the interaction of observation technique and raising style. Stereotypic behaviors in particular showed a marked increased during cooler temperatures among giraffes of all raising style. Likewise, raising style, observation technique, and their interaction significantly impacted the time spent rubbing the enclosure. The findings of this study suggest that captive giraffe behavior can be a complex response to multiple factors and studies only examining single factors might oversimplify behavioral shifts.


An Updated Analysis of Clinical Outcome Measures Across Patients From the UK Medical Cannabis Registry.
Introduction: There is a growing body of literature supporting the efficacy of cannabis-based medicinal products (CBMPs). Despite an increase in prescribing globally, there is a paucity of high-quality clinical data on the efficacy of CBMPs for many conditions. This study aims to detail the changes in health-related quality of life (HRQoL) and associated clinical safety in patients prescribed CBMPs for any clinical indication from the UK Medical Cannabis Registry (UKMCR). Methods: An uncontrolled prospective case series of the UKMCR was analyzed. Primary outcomes included change from baseline in patient-reported outcome measures collected across all patients (the Generalized Anxiety Disorder Scale [GAD-7], EQ-5D-5L, and Sleep Quality Scale [SQS]) at 1, 3, and 6 months. Secondary outcomes included the self-reported incidence and severity of adverse events. Statistical significance was defined as p<0.050. Results: Three hundred twelve patients were included in the final analysis, with a mean age of 44.8. The most common primary diagnoses were chronic pain of undefined etiology (n=102, 32.7%), neuropathic pain (n=43, 13.8%), and fibromyalgia (n=31, 9.9%). Before enrolment, 112 (35.9%) patients consumed cannabis daily. The median cannabidiol and (-)-trans-Δ9-tetrahydrocannabinol doses prescribed at baseline were 20.0 mg (0.0-510.0 mg) and 3.0 mg (0.0-660.0 mg), respectively. Statistically significant improvements were observed in GAD-7, EQ-5D-5L Index, EQ-5D Visual Analog Scale and SQS scores at 1, 3, and 6 months (p<0.050). There were 94 (30.1%) reported adverse events, of which nausea (n=12, 3.8%), dry mouth (n=10, 3.2%), dizziness (n=7, 2.2%), and somnolence (n=7, 2.2%) were the most common. Conclusion: This study demonstrated CBMP treatment to be associated with a relatively low incidence of severe adverse events in the medium-term. Positive changes following treatment were observed in general, as well as anxiety and sleep-specific, HRQoL outcomes. Randomized controlled trials are still awaited to assess causation; however, real-world evidence can help inform current clinical practice, future trials, and is an important component of pharmacovigilance.


Simultaneous saccharification and fermentation of Kanlow switchgrass pretreated by hydrothermolysis using Kluyveromyces marxianus IMB4.
A thermotolerant yeast strain named Kluyveromyces marxianus IMB4 was used in a simultaneous saccharification and fermentation (SSF) process using Kanlow switchgrass as a feedstock. Switchgrass was pretreated using hydrothermolysis at 200 degrees C for 10 min. After pretreatment, insoluble solids were separated from the liquid prehydrolyzate by filtration and washed with deionized water to remove soluble sugars and inhibitors. Insoluble solids were then hydrolyzed using a commercial cellulase preparation and the released glucose was fermented to ethanol by K. marxianus IMB4 in an SSF process. SSF temperature was 37, 41, or 45 degrees C and pH was 4.8 or 5.5. SSF was conducted for 7 days. Results were compared with a control of Saccharomyces cerevisiae D(5)A at 37 degrees C and pH 4.8. Fermentation by IMB4 at 45 and 41 degrees C ceased after 3 and 4 days, respectively, when a pH 4.8 citrate buffer was used. Fermentation continued for all 7 days using IMB4 at 37 degrees C and the control. When pH 5.5 citrate buffer was used, fermentation ceased after 96 h using IMB4 at 45 degrees C, and ethanol yield was greater than when pH 4.8 citrate buffer was used (78% theoretical). Ethanol yield using IMB4 at 45 degrees C, pH 5.5 was greater than the control after 48, 72, and 96 h (P < 0.05).


Immunology knowledge as one of the basic sciences that forms the foundations to developing sound clinicians.
The aim of this study was to (1) generate a valid questionnaire to determine immunology knowledge, (2) compare immunology knowledge across 3 different cohorts of chiropractic students that had already studied immunology, (3) examine the attitudes of chiropractic students to the study of immunology, and (4) examine whether students' attitudes affected their knowledge levels. Factor analysis was used to refine an immunology knowledge and perceptions questionnaire that was generated by a group of experts that was then completed by 90 students. Immunology knowledge level of each of the cohorts was compared using a 1-way analysis of variance. Kappa statistics were used to measure agreement between 2 statements, and logistic regression was used to determine whether students' attitudes were associated with their knowledge levels. There was a significant difference in the immunology knowledge levels across the 3 year groups (F[2, 87] = 4.78, p = .011). Fifth-year students (n = 26) demonstrated 25% less immunology knowledge than third-year students (n = 35; p = .005). Of 90 students, 64 agreed that immunology knowledge was important to chiropractors, and 53 agreed that immunology knowledge was important for the average person. No relationship existed between their value of immunology knowledge and their score on the multiple-choice questions. Third-year students' immunology knowledge was significantly higher than that of the fifth-year students. Students value immunology knowledge, but this does not translate to retention of this knowledge. The validated questionnaire is a useful tool for assessing immunology knowledge retention for undergraduate students.


Binding of [3H]Ro 11-2465. Possible identification of a subclass of [3H]imipramine binding sites.
Ro 11-2465 is a cyanide derivative of imipramine. In cerebral cortex homogenates, [3H] Ro 11-2465 displays a binding profile similar to that of [3H]imipramine. Agents compete with binding of [3H]Ro 11-2465 in an order of potency similar to their ability to block serotonin uptake, and raphe lesions greatly decrease the binding of [3H]Ro 11-2465. These observations suggest that the sites labeled by [3H]Ro 11-2465 are presynaptic. The binding of [3H]Ro 11-2465 is sodium ion-dependent, as are both the binding of [3H] imipramine and the serotonin uptake mechanism. In the presence of sodium ions, binding of [3H]Ro 11-2465 to brain tissue or platelets at 4 degrees is apparently irreversible. Binding is not displaced by high concentrations of the displacing agent desipramine or by repeated washing. However, by either removing sodium or increasing the assay temperature to 23 degrees, the ligand dissociates from the tissue. In tissue where [3H]Ro 11-2465 is irreversibly bound to receptor at 4 degrees, subsequent [3H]imipramine binding is decreased by about 50%. At temperatures greater than 23 degrees, [3H]Ro 11-2465 binding displays a temperature dependency similar to that of [3H]imipramine; that is, when temperatures are raised from 23 degrees to 30 degrees or 37 degrees there is no change in the Bmax, but the affinity of the ligand for the receptor is decreased. These data suggest that [3H]Ro 11-2465 binds to a discrete population of [3H]imipramine binding sites, comprising about one-half of the total [3H] imipramine binding sites.


Identification of potential genes in upper tract urothelial carcinoma using next-generation sequencing with bioinformatics and in vitro analyses.
We aimed to identify prognostic biomarkers of upper tract urothelial carcinomas (UTUCs), including microRNAs (miRNAs) and genes which account for only 5% to 10% of all urothelial carcinomas (UCs). In Taiwan, this figure is markedly higher, where it can reach up to 30% of UC cases. Using next-generation sequencing (NGS), we analyzed two pairs of renal pelvis tumors and adjacent normal urothelial tissues to screen miRNAs and messenger RNAs. By combining bioinformatics analysis from miRmap, Gene Expression Omnibus (GEO), and Oncomine and Ingenuity® Pathway Analysis databases, we identified candidate genes. To search for upstream miRNAs with exact target binding sites, we used miRmap, TargetScan, and miRDB to enforce evidence. Then, we clarified gene and protein expression through an in vitro study using western blot analysis and quantitative real-time reverse transcriptase-PCR. Interactions between selected target genes obtained using the NGS and miRmap methods were assessed through a Venn diagram analysis. Six potential genes, namely, PDE5A, RECK, ZEB2, NCALD, PLCXD3 and CYBRD1 showed significant differences. Further analysis of gene expression from the GEO dataset indicated lower expression of PDE5A, RECK, ZEB2, and CYBRD1 in bladder cancer tissue than in normal bladder mucosa, which indicated that PDE5A, RECK, ZEB2, and CYBRD1 may act as tumor suppressors in UTUC. In addition, we compared the expression of these genes in various UC cell lines (RT4, BFTC905, J82, T24, UMUC3, 5637, BFTC 909, UMUC14) and found decreased expression of PDE5A in muscle-invasive UC cells compared with the RT4 cell line. Furthermore, by using paired UTUC and normal tissues from 20 patients, lower PDE5A expression was also demonstrated in tumor specimens. Our findings suggest these candidate genes may play some roles in UTUC progression. We propose that these markers may be potential targets clarified by in vitro and in vivo experiments. PDE5A also potentially presents tumor suppressor genes, as identified by comparing the expression between normal and tumor specimens.


The role of phototherapy in cutaneous T-cell lymphoma.
Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin's lymphoma characterized by the malignant proliferation of T lymphocytes in the skin. Phototherapy has been proven an effective treatment modality for CTCL, in particular early stage disease (patch and plaque). Specifically, broadband ultraviolet B (BB-UVB), psoralen and ultraviolet A (PUVA), and more recently narrowband UVB (NB-UVB) are the skin-directed phototherapies typically utilized. Phototherapy poses the risk of sunburn, photoaging and photocarcinogenesis. Combination therapies with IFN-alpha, retinoids (acitretin and isotretinoin) and rexinoid (bexarotene) are adjunctive systemic therapies that facilitate enhanced therapeutic response and often allow for lower doses of phototherapy. Extracorporeal photopheresis (ECP) has also been shown to be effective in more advanced stage disease.


Pediatric low-grade glioma: State-of-the-art and ongoing challenges.
The most common childhood central nervous system (CNS) tumor is pediatric low-grade glioma (pLGG), representing 30%-40% of all CNS tumors in children. Although there is high associated morbidity, tumor-related mortality is relatively rare. pLGG is now conceptualized as a chronic disease, underscoring the importance of functional outcomes and quality-of-life measures. A wealth of data has emerged about these tumors, including a better understanding of their natural history and their molecular drivers, paving the way for the use of targeted inhibitors. While these treatments have heralded tremendous promise, challenges remain about how to best optimize their use, and the long-term toxicities associated with these inhibitors remain unknown. The International Pediatric Low-Grade Glioma Coalition (iPLGGc) is a global group of physicians and scientists with expertise in pLGG focused on addressing key pLGG issues. Here, the iPLGGc provides an overview of the current state-of-the-art in pLGG, including epidemiology, histology, molecular landscape, treatment paradigms, survival outcomes, functional outcomes, imaging response, and ongoing challenges. This paper also serves as an introduction to 3 other pLGG manuscripts on (1) pLGG preclinical models, (2) consensus framework for conducting early-phase clinical trials in pLGG, and (3) pLGG resistance, rebound, and recurrence.


Structural requirements for the procoagulant activity of nucleic acids.
Nucleic acids, especially extracellular RNA, are exposed following tissue- or vessel damage and have previously been shown to activate the intrinsic blood coagulation pathway in vitro and in vivo. Yet, no information on structural requirements for the procoagulant activity of nucleic acids is available. A comparison of linear and hairpin-forming RNA- and DNA-oligomers revealed that all tested oligomers forming a stable hairpin structure were protected from degradation in human plasma. In contrast to linear nucleic acids, hairpin forming compounds demonstrated highest procoagulant activities based on the analysis of clotting time in human plasma and in a prekallikrein activation assay. Moreover, the procoagulant activities of the DNA-oligomers correlated well with their binding affinity to high molecular weight kininogen, whereas the binding affinity of all tested oligomers to prekallikrein was low. Furthermore, four DNA-aptamers directed against thrombin, activated protein C, vascular endothelial growth factor and nucleolin as well as the naturally occurring small nucleolar RNA U6snRNA were identified as effective cofactors for prekallikrein auto-activation. Together, we conclude that hairpin-forming nucleic acids are most effective in promoting procoagulant activities, largely mediated by their specific binding to kininogen. Thus, in vivo application of therapeutic nucleic acids like aptamers might have undesired prothrombotic or proinflammatory side effects.


Ulipristal acetate decreases transforming growth factor β3 serum and tumor tissue concentrations in patients with uterine fibroids.
To evaluate and compare transforming growth factor β3 (TGF-β3) serum concentration in patients with uterine fibroids (UFs) without hormone treatment, treated with ulipristal acetate (UPA), and controls; to evaluate TGF-β3 concentrations in UF tissue in patients without hormone treatment and those treated with UPA; and to evaluate the correlations of age and body mass index (BMI) with TGF-β3 serum and UF tissue levels between the groups. Retrospective cohort study. University teaching hospital. A total of 141 patients divided into three groups: UFs non-UPA, UFs, and UPA, controls. Medical history and examination, genital ultrasound scan, blood and tissue sampling, and measurement of TGF-β3 serum and tissue concentrations. Evaluation of the impact of UPA (3 months treatment), age and BMI on TGF-β3 serum and UF tissue levels. The values of TGF-β3 serum and tissue concentrations statistically significantly differed between the non-UPA and UPA groups. The mean TGF-β3 serum concentrations were non-UPA group 32.24 ± 34.55 pg/mL, UPA group 10.88 ± 7.15 pg/mL, and controls 11.97 ± 10.30 pg/mL. The mean TGF-β3 tissue concentrations were non-UPA group 171.29 ± 91.81 pg/mg and UPA group 99.99 ± 60.63 pg/mg. Statistically significantly lower mean TGF-β3 serum and tissue concentrations were observed in patients treated with UPA. No statistically significant correlations between TGF-β3 concentrations and age or BMI were found. Reduction of serum and tissue TGF-β3 concentrations in UFs may be an important component of the effect of UPA on UF biology. Further research in this area is necessary.


Contrasting effects of vasopressin on baroreflex inhibition of lumbar sympathetic nerve activity.
Baroreflex inhibition of lumbar sympathetic nerve activity (LSNA) during intravenous infusions of phenylephrine and vasopressin is contrasted in rats and rabbits. In rabbits, vasopressin caused smaller increases in arterial pressure and greater inhibition of LSNA than phenylephrine. In Sprague-Dawley rats, however, both vasopressin and phenylephrine caused equivalent increases in arterial pressure and reflex reductions in LSNA. The inhibition of LSNA was mediated through the arterial baroreceptors in both species because it was abolished by sinoaortic denervation. In rats, the possibility that a high level of endogenous vasopressin may have prevented the demonstration of a facilitated baroreflex with the infusion of exogenous vasopressin is unlikely since vasopressin also did not facilitate the reflex in Brattleboro rats, which lack circulating vasopressin. Further, Sprague-Dawley rats were responsive to exogenous vasopressin since infusion of increasing doses of vasopressin caused significant increases in urinary osmolality as well as progressive increments in arterial pressure. The results indicate that intravenous vasopressin given for a period of 6 min facilitates the reflex inhibition of LSNA mediated through arterial baroreceptors in rabbits, but not in rats. Vasopressin given for a period of up to 45 min to rats also fails to facilitate baroreflexes, emphasizing the difference from rabbits. In rabbits, this facilitation appears to involve a central mechanism.


Cardiac dysfunction in survivors of sepsis: a scoping review.
Sepsis is associated with an increased risk of adverse cardiovascular events in a magnitude comparable to other major cardiovascular risk factors. Sepsis is one of the most common reasons for intensive care admission and survivors often have significant functional limitations following discharge. However, it is not clear to what extent chronic cardiovascular dysfunction might mediate these functional impairments, or how we might screen and manage these patients at risk of chronic cardiovascular disease. We conducted a scoping review to map existing evidence and identify research gaps relating to cardiovascular dysfunction following sepsis. We conducted a systematic search of MEDLINE, Embase and CINAHL databases using a concept, context, population (CoCoPop) framework. Studies examining cardiovascular outcomes or symptoms following an episode of sepsis in adults were included. Data were mapped based on the population assessed, cardiovascular outcomes examined, inclusion of objective measures of cardiac dysfunction such as biomarkers or cardiovascular imaging, or whether cardiovascular symptoms or patient-reported functional outcomes measures were recorded. We identified 11 210 articles of which 70 were eligible for full text review and 28 were included in final analysis. Across our dataset, a wide range of incident cardiovascular outcomes were reported in the literature including incidence of congestive heart failure (13/28), arrhythmia (6/28), myocardial infarction (24/28) or cardiovascular death or all-cause mortality (20/28). Only 39% (11/28) of articles reported objective measures of cardiovascular function and only one article related cardiovascular function to functional impairment via patient-reported outcome measures. There are significant gaps in our understanding of cardiac dysfunction following sepsis . While the research highlights the strong association of sepsis with a variety of adverse cardiovascular outcomes, further prospective work is required to understand the mechanisms that mediate this phenomenon and how we can best identify and manage patients at risk.


Platelet concentrations and platelet-associated IgG in greyhounds.
Greyhounds have lower platelet concentrations (PC) than dogs of other breeds have. No underlying cause has been investigated. We hypothesized that Greyhounds have lower mean PC because of breed variation, not immune-mediated causes. Our secondary hypothesis was that PC is dependent on the method of analysis. Sixty privately owned Greyhounds in Kansas. Blood samples were collected into evacuated glass tubes containing ethylenediamine tetraacetic acid (EDTA). Blood smears were evaluated for platelet clumps. All 60 samples had PC determined by manual, impedance, and buffy coat analyzer methods. Results of the 60 samples were compared with results of samples with (n = 25) and without (n = 35) clumps, and with control dogs. Platelets were assayed for the presence of surface-associated antigen (PSAIgG) by direct immunofluorescence. The mean PC was below that of the control dogs for the impedance method (P < .001). No significant difference in PC was detected between analysis methods or between samples with or without platelet clumps. Three of 60 (5%) of the Greyhounds had PC between 50,000 and 100,000/microL with impedance analysis; no samples had < 100,000/microL via buffy coat analysis. PSAIgG was not identified in any samples. The mean Greyhound PC for the impedance method was below the reference interval for control dogs but was not significantly different from PC determined by other methods. An immune-mediated cause for the lower PC was unlikely because no samples had PSAIgG. The decreased PC is most consistent with breed variation. As only 0-5% of samples, depending on analysis method, had PC < 100,000/microL, a Greyhound with a PC < 100,000/microL is not necessarily consistent with breed variation, thus diagnostic testing is indicated.


Plant-derived vaccines and other therapeutics produced in contained systems.
The use of contained plant systems for the production of biopharmaceuticals represents a powerful alternative to current methods, combining the benefits of whole-plant systems and cell cultures. In vitro contained production systems include plant cell suspensions, hairy root cultures, novel plants grown in contained conditions and microalgae. These systems show intrinsic advantages, such as control over growth conditions, production in compliance with good manufacturing practice and avoidance of political resistance to the release of genetically modified field crops. At present, one of the two plant-produced vaccine-related products that have gone all the way through production and regulatory hurdles derives from tobacco cell suspensions, and the second is a human therapeutic enzyme, which is expected to reach commercial development soon and derives from carrot suspension cells. In the future, several other products from contained systems are expected to reach the clinical trial stage.


Developing a strategy to promote the generation and effective use of population health research for NSW Health: 2011-2015.
The Population Health Division of the NSW Department of Health has developed a 5-year strategy to improve the effectiveness of its resource investment in population health research. This paper describes the development of the strategy, Promoting the generation and effective use of population health research in NSW: a Strategy for NSW Health 2011-2015. A review of Australian and international strategic research documents and stakeholder interviews was conducted to support the development of the strategy. The findings from these two processes influenced the structure of the document and supported the inclusion of strategies and actions to assist with identifying research priorities, improving communication, enhancing networks and partnerships, supporting workforce development initiatives, providing research infrastructure, enhancing research and the use of research evidence and streamlining research governance and ethics processes. Small group discussions and a detailed review of literature were conducted to refine the thinking around four of the more complex aspects of the strategy. Finally, a broad consultation process was used to test the face validity of the proposed strategy content.


Meta-analysis for pathway enrichment analysis when combining multiple genomic studies.
Many pathway analysis (or gene set enrichment analysis) methods have been developed to identify enriched pathways under different biological states within a genomic study. As more and more microarray datasets accumulate, meta-analysis methods have also been developed to integrate information among multiple studies. Currently, most meta-analysis methods for combining genomic studies focus on biomarker detection and meta-analysis for pathway analysis has not been systematically pursued. We investigated two approaches of meta-analysis for pathway enrichment (MAPE) by combining statistical significance across studies at the gene level (MAPE_G) or at the pathway level (MAPE_P). Simulation results showed increased statistical power of meta-analysis approaches compared to a single study analysis and showed complementary advantages of MAPE_G and MAPE_P under different scenarios. We also developed an integrated method (MAPE_I) that incorporates advantages of both approaches. Comprehensive simulations and applications to real data on drug response of breast cancer cell lines and lung cancer tissues were evaluated to compare the performance of three MAPE variations. MAPE_P has the advantage of not requiring gene matching across studies. When MAPE_G and MAPE_P show complementary advantages, the hybrid version of MAPE_I is generally recommended. http://www.biostat.pitt.edu/bioinfo/ email@example.com Supplementary data are available at Bioinformatics online.


Silk worm Bm1 SINE RNA increases following cellular insults.
The effect of cell stresses upon the expression of the Bm1 short interspersed element (SINE) family in cultured silk worm cells is examined. Primer extension analysis shows that Bm1 repeats are transcribed by RNA polymerase III (Pol III) into cytoplasmic RNAs. Five consecutive T residues, which would normally terminate Pol III transcription, occur within the Bm1 consensus and are included within cDNA sequences representing these transcripts. In analogy to mammalian SINEs, the level of the Bm1 transcripts increases in response to either heat shock, inhibiting protein synthesis by cycloheximide or viral infection. The lifetime of Bm1 RNA increases following cell insults so that post-transcriptional events partially account for stress induced increases in its abundance. In the case of heat shock, the increase in Bm1 RNA follows the transient increase in hsp70 mRNA indicating that this response is temporally regulated to occur later in heat shock recovery. These results support the proposal that SINE RNAs serve a role in the cell stress response that predates the divergence of insects and mammals implying that SINEs are essentially a class of cell stress genes.


Long-range persistence of temperature records induced by long-term climatic phenomena.
The occurrence of persistence in climatic systems has been investigated by analyzing 1167 surface temperature records, covering 110 years, in the whole United States. Due to the nonlinear and nonstationary character of temperature time series, the seasonal cycle suffers from both phase and amplitude modulations, which are not properly removed by the classical definition of the temperature anomaly. In order to properly filter out the seasonal component and the monotonic trends, we define the temperature anomaly in a different way by using the empirical mode decomposition (EMD). The essence of this method is to empirically identify the intrinsic oscillatory modes from the temperature records according to their characteristic time scale. The original signal is thus decomposed into a collection of a finite small number of intrinsic mode functions (IMFs), having its own time scale and representing oscillations experiencing amplitude and phase modulations, and a residue, describing the mean trend. The sum of all the IMF components as well as the residue reconstructs the original signal. Partial reconstruction can be achieved by selectively choosing IMFs in order to remove trivial trends and noise. The EMD description in terms of time-dependent amplitude and phase functions overcomes one of the major limitation of the Fourier analysis, namely, a correct description of nonlinearities and nonstationarities. By using the EMD definition of temperature anomalies we found persistence of fluctuations with a different degree according to the geographical location, on time scales in the range 3-15 years. The spatial distribution of the detrended fluctuation analysis exponent, used to quantify the degree of memory, indicates that the long-term persistence could be related to to the presence of climatic regions, which are more sensitive to climatic phenomena such as the El Niño southern oscillation.


Sphingomyelinase has an insulin-like effect on glucose transporter translocation in adipocytes.
Rat epididymal adipocytes were incubated with 0, 0.1, and 1 mU sphingomyelinase/ml for 30 or 60 min, and glucose uptake and GLUT-1 and GLUT-4 translocation were assessed. Adipocytes exposed to 1 mU sphingomyelinase/ml exhibited a 173% increase in glucose uptake. Sphingomyelinase had no effect on the abundance of GLUT-1 in the plasma membrane of adipocytes. In contrast, 1 mU sphingomyelinase/ml increased plasma membrane content of GLUT-4 by 120% and produced a simultaneous decrease in GLUT-4 abundance in the low-density microsomal fraction. Sphingomyelinase had no effect on tyrosine phosphorylation of either the insulin receptor beta-subunit or the insulin receptor substrate-1, a signaling molecule in the insulin signaling pathway. It is concluded that the incubation of adipocytes with sphingomyelinase results in insulin-like translocation of GLUT-4 to the plasma membrane and that this translocation does not occur via the activation of the initial components of the insulin signaling pathway.


Defect transfer from nanoparticles to nanowires.
Metal-seeded growth of one-dimensional (1D) semiconductor nanostructures is still a very active field of research, despite the huge progress which has been made in understanding this fundamental phenomenon. Liquid growth promoters allow control of the aspect ratio, diameter, and structure of 1D crystals via external parameters, such as precursor feedstock, temperature, and operating pressure. However the transfer of crystallographic information from a catalytic nanoparticle seed to a growing nanowire has not been described in the literature. Here we define the theoretical requirements for transferring defects from nanoparticle seeds to growing semiconductor nanowires and describe why Ag nanoparticles are ideal candidates for this purpose. We detail in this paper the influence of solid Ag growth seeds on the crystal quality of Ge nanowires, synthesized using a supercritical fluid growth process. Significantly, under certain reaction conditions {111} stacking faults in the Ag seeds can be directly transferred to a high percentage of <112>-oriented Ge nanowires, in the form of radial twins in the semiconductor crystals. Defect transfer from nanoparticles to nanowires could open up the possibility of engineering 1D nanostructures with new and tunable physical properties and morphologies.


Quality improvement primer part 3: Evaluating and sustaining a quality improvement project in the emergency department.
Quality improvement (QI) and patient safety are two areas that have grown into important operational and academic fields in recent years in health care, including in emergency medicine (EM). This is the third and final article in a series designed as a QI primer for EM clinicians. In the first two articles we used a fictional case study of a team trying to decrease the time to antibiotic therapy for patients with sepsis who were admitted through their emergency department. We introduced concepts of strategic planning, including stakeholder engagement and root cause analysis tools, and presented the Model for Improvement and Plan-Do-Study-Act (PDSA) cycles as the backbone of the execution of a QI project. This article will focus on the measurement and evaluation of QI projects, including run charts, as well as methods that can be used to ensure the sustainability of change management projects.


[Role of chemokines in the pathogenesis of chronic synovitis during rheumatoid arthritis].
Chemokines play a central role in the pathogenesis of rheumatoid arthritis (RA) synovitis which is characterised by new blood vessel formation, thickening of the lining layer and infiltration of immune cells. The inflammatory infiltrate is generated by a series of events which include the recruitment of leukocytes from the blood stream into the tissue, their local retention and activation to effector cells. All these processes are finely regulated by the interplay of different cell adhesion molecules (CAMs) and chemoattractant factors called chemokines (CK). CK are a superfamily of small proteins that play a crucial role in immune and inflammatory reactions. These chemoattractant cytokines share structural similarities including four conserved cysteine residues which form disulphide bonds in the tertiary structure of the proteins. CK mediate their effects by binding specific receptors (CK-R) characterised by a domain structure which spans the cell membrane seven times and signal through heterotrimeric GPT-binding proteins. Activation of the CK network results in an amplification of the inflammatory cascade and consequently in the progressive destruction of RA joints. The recognition of the central role of CK in inflammation has paved the way to the development of new agents capable of interfering with CK and CK-R. This review will focus in particular on the role of CK in regulating leukocyte trafficking in RA joints.


The effect of incremental distal gastric myotomy lengths on EGJ distensibility during POEM for achalasia.
During peroral esophageal myotomy (POEM) for the treatment of achalasia, the optimal distal gastric myotomy length is unknown. In this study, we used a functional lumen imaging probe (FLIP) to intraoperatively measure the effect of variable distal myotomy lengths on esophagogastric junction (EGJ) distensibility. EGJ distensibility index (DI) (minimum cross-sectional area divided by intrabag pressure) was measured with FLIP after each operative step. Each patient's myotomy was performed in four increments from proximal to distal: (1) an esophageal myotomy (from 6 cm proximal to the EGJ to 1 cm proximal to it), (2) a myotomy ablating the lower esophageal sphincter (LES) complex (from 1 cm proximal to the EGJ to 1 cm distal to it), (3) an initial gastric extension (from 1 cm distal to the EGJ to 2 cm distal), and (4) a final gastric extension (from 2 cm distal to the EGJ to 3 cm distal). Measurements were taken in 16 achalasia patients during POEM. POEM resulted in an overall increase in DI (pre 1.2 vs. post 7.2 mm(2)/mmHg, p < .001). Initial creation of the submucosal tunnel resulted in a threefold increase in DI (1.2 vs. 3.6 mm(2)/mmHg, p < .001). When the myotomy was then performed in a stepwise fashion from proximal to distal, the initial esophageal myotomy component had no effect on DI. Subsequent myotomy extension across the LES complex resulted in an increase in DI, as did the initial gastric myotomy extension (to 2 cm distal to the EGJ). The final gastric myotomy extension (to 3 cm distal) had no further effect. During POEM, creation of the submucosal tunnel prior to myotomy resulted in a marked improvement in EGJ physiology. Myotomy extension across the LES complex and to 2 cm onto the gastric wall resulted in the normalization of EGJ distensibility, whereas subsequent extension to 3 cm distal to the EGJ did not increase compliance further.


Intake of ruminant trans-fatty acids, assessed by diet history interview, and changes in measured body size, shape and composition.
Studies have suggested that total intake of trans-fatty acids (TFA) is positively associated with changes in body weight and waist circumference, whereas intake of TFA from ruminant dairy and meat products (R-TFA) has not been associated with weight gain. However, these previous studies are limited by self-reported measures of body weight and waist circumference or by a cross-sectional design. The objective of the present study was to investigate if R-TFA intake was associated with subsequent changes in anthropometry (body weight, waist and hip circumference) measured by technicians and body composition (body fat percentage). A 6-year follow-up study. Information on dietary intake was collected through diet history interviews, and anthropometric and bioelectrical impedance measurements were obtained by trained technicians at baseline (1987-1988) and at follow-up (1993-1994). Multiple regression with cubic spline modelling was used to analyse the data. Copenhagen County, Denmark. Two hundred and sixty-seven men and women aged 35-65 years from the Danish MONICA (MONItoring of trends and determinants in CArdiovascular diseases) cohort. The median R-TFA intake was 1.3 g/d (5th, 95th percentile: 0.4, 2.7 g/d) or 0.6% of the total energy intake (5th, 95th percentile: 0.2, 1.1%). No significant associations were observed between R-TFA intake and changes in body weight, waist and hip circumference or body fat percentage. R-TFA intake within the range present in the Danish population was not significantly associated with subsequent changes in body size, shape or composition and the 95% confidence intervals indicate that any relevant associations are unlikely to have produced these observations.


[Ozone therapy of migraine].
Application of ozone therapy was based on the notions of a significant role of lipid peroxidation in the pathogenesis of migraine attacks. A therapy was performed in form of intravenous infusions of the ozonized physiologic solutions with ozone, concentration 1200 micrograms/l; a therapy course included 8-9 procedures. 68 patients with migraine attacks, followed by the pronounced autonomic changes, that developed in the frequency range from 5-6 times a year to 2-3 times a week were examined. 40 patients formed a study group and 28 individuals control one (in a control group the physiologic solution was used without ozone). The intensity of a headache, the expression of an anxiety, the state of the vessels of the brain and some biochemical indices were determined. Positive dynamics of the disease was 25% higher in the study group than made up a those in the controls (p < 0.05). In 58% of the patients the attacks were absent during 3-5 months after ozone therapy; less intensity of headache was observed after their relapse. Improvements in the patients coincides with changes in biochemical parameters.


[Co-occurrence of physical and psychological violence among dating adolescents in Recife, Brazil: prevalence and associated factors].
The scope of this study was to assess the prevalence of physical and psychological violence among dating adolescents from Recife, Brazil, to identify associated factors and the co-occurrence of both types of violence. 302 adolescents aged between 15 and 19 years in public and private schools who were in a relationship in the last year filled out the questionnaire. Univariate and multivariate logistic regression statistical analysis were performed and the sample weight and the complex sample design were entered. The prevalence was 19.9% of physical violence 82.8% of psychological violence and 18.9% for the co-occurrence of both. Adolescents who have experienced violence in the community and who were in dating relationships of more than one year duration were more likely to perpetrate psychological violence. For the co-occurrence of physical and psychological violence, the variables that increased the chance of perpetration were suffering physical violence from the father, violence among siblings, physical violence and the perpetration of verbal violence in previous relationships. The conclusion reached is that psychological violence and the co-occurrence of physical and psychological violence have a distinct dynamics from physical violence in dating relationships.


[Effects of changes in mitochondrial permeability transition of medullary neurons on arterial pressure in rats].
In acute experiments on anaesthetized with urethane normotensive rats we studied effects of modulating the mitochondrial permeability transition (MPT) of the neurons in the medullary cardiovascular nuclei - nucleus of the tractus solitarius (NTS), paramedian reticular nucleus (PMn), n.ambiguus (AMB), and lateral reticular nucleus (LRN) on the systemic arterial pressure level (SAP). An increase in the MPT with injections of an inductor for MPT phenylarsine oxide (10(-12) M - 10(-8) M) into the medullary nuclei under exploration has been shown to induce the lowering in the SAP level in a dose-dependent manner. A decrease in the MPT of the medullary neurons with either cyclosporine A or melatonin (10(-12) M - 10(-10) M) resulted in hypertensive responses of the SAP. Effects of phenylarsine oxide injections into the medullary nuclei were attenuated after preliminary intravenous administration of L-arginine. The data obtained give evidence that functional activity of the medullary cardiovascular neurons and their effects depend to a large extent on the functional state of their mitochondria.


SIVagm infection in wild African green monkeys from South Africa: epidemiology, natural history, and evolutionary considerations.
Pathogenesis studies of SIV infection have not been performed to date in wild monkeys due to difficulty in collecting and storing samples on site and the lack of analytical reagents covering the extensive SIV diversity. We performed a large scale study of molecular epidemiology and natural history of SIVagm infection in 225 free-ranging AGMs from multiple locations in South Africa. SIV prevalence (established by sequencing pol, env, and gag) varied dramatically between infant/juvenile (7%) and adult animals (68%) (p<0.0001), and between adult females (78%) and males (57%). Phylogenetic analyses revealed an extensive genetic diversity, including frequent recombination events. Some AGMs harbored epidemiologically linked viruses. Viruses infecting AGMs in the Free State, which are separated from those on the coastal side by the Drakensberg Mountains, formed a separate cluster in the phylogenetic trees; this observation supports a long standing presence of SIV in AGMs, at least from the time of their speciation to their Plio-Pleistocene migration. Specific primers/probes were synthesized based on the pol sequence data and viral loads (VLs) were quantified. VLs were of 10(4)-10(6) RNA copies/ml, in the range of those observed in experimentally-infected monkeys, validating the experimental approaches in natural hosts. VLs were significantly higher (10(7)-10(8) RNA copies/ml) in 10 AGMs diagnosed as acutely infected based on SIV seronegativity (Fiebig II), which suggests a very active transmission of SIVagm in the wild. Neither cytokine levels (as biomarkers of immune activation) nor sCD14 levels (a biomarker of microbial translocation) were different between SIV-infected and SIV-uninfected monkeys. This complex algorithm combining sequencing and phylogeny, VL quantification, serology, and testing of surrogate markers of microbial translocation and immune activation permits a systematic investigation of the epidemiology, viral diversity and natural history of SIV infection in wild African natural hosts.


Origins of Cerebral Edema: Implications for Spaceflight-Associated Neuro-Ocular Syndrome.
Spaceflight-associated neuro-ocular syndrome (SANS) was first described in 2011 and is associated with structural ocular changes found to occur in astronauts after long-duration missions. Despite multiple insufficient potential terrestrial models, an understanding of the etiology has yet to be described. A systematic review was conducted on literature published about the pathophysiology of cerebral edema. Databases searched include PubMed, Scopus, and the Texas Medical Center Online Library. This information was then applied to create theories on mechanisms on SANS etiology. Cerebral edema occurs through 2 general mechanisms: redistribution of ions and water intracellularly and displacement of ions and water from the vascular compartment to the brain parenchyma. These processes occur through interconnected endocrine and inflammatory pathways and involve mediators such as cytokines, matrix metalloproteases, nitric oxide, and free radicals. The pathways ultimately lead to a violation of cellular membrane ionic gradients and blood-brain barrier degradation. By applying the principles of cerebral edema pathophysiology to the optic disc edema (ODE) see in SANS, several theories regarding its etiology can be formed. Venous stasis may lead to ODE through venous and capillary distension and leak, as well as relative hypoxia and insufficient ATP substrate delivery causing axoplasmic flow stasis and local oxidative stress. Using the pathophysiology of cerebral edema as a model, hypotheses can be inferred as to the etiology of ODE in SANS. Further studies are needed to determine the presence and contribution of local vascular stasis and resulting inflammation and oxidative stress to the pathophysiology of SANS.


Distorted food pyramid in kids programmes: a content analysis of television advertising watched in Switzerland.
In the light of increasing childhood obesity, the role of food advertisements relayed on television (TV) is of high interest. There is evidence of food commercials having an impact on children's food preferences, choices, consumption and obesity. We describe the product categories advertised during kids programmes, the type of food promoted and the characteristics of food commercials targeting children. A content analysis of the commercials aired during the kids programmes of six Swiss, one German and one Italian stations was conducted. The commercials were collected over a 6-month period in 2006. Overall, 1365 h of kids programme were recorded and 11 613 advertisements were found: 3061 commercials (26.4%) for food, 2696 (23.3%) promoting toys, followed by those of media, cleaning products and cosmetics. Regarding the broadcast food advertisements, 55% were for fast food restaurants or candies. The results of the content analysis suggest that food advertising contributes to the obesity problem: every fourth advertisement is for food, half of them for products high in sugar and fat and hardly any for fruit or vegetables. Long-term exposure to this distortion of the pyramid of recommended food should be considered in the discussion of legal restrictions for food advertising targeting children.


Right place, right time: the evolving role of herpesvirus infection as a "second hit" in idiopathic pulmonary fibrosis.
Over the course of the past decade, increasing evidence has implicated alveolar epithelial cell injury and dysfunction in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Genetic factors, cigarette smoking, and other environmental exposures have been identified as potential factors leading to a population of vulnerable alveolar epithelial cells. In addition, molecular techniques have demonstrated herpesviruses are commonly detectable in the lungs of patients with IPF, raising suspicion that, in the setting of a vulnerable alveolar epithelium, lytic (or latent) herpesvirus infection may act as a "second hit" leading to the development of pulmonary fibrosis. Intriguingly, in vivo modeling has shown that herpesvirus infection induces or worsens lung fibrosis when combined with immunodeficiency or other injurious stimuli. Here, we discuss potential mechanisms through which herpesvirus infection may contribute to the pathogenesis of IPF. Ultimately, antiviral therapy may hold promise for halting the progression of this deadly disease.


Nitrogen dioxide exposure attenuates cigarette smoke-induced cytokine production in mice.
Cigarette smoke is the most important cause for the development of chronic obstructive pulmonary disease (COPD). Since only a minority of smokers and some nonsmokers develop COPD, other factors must be involved as well. NO2 is an important air pollutant associated with respiratory symptoms in humans and emphysema development in animal models. We hypothesized that combined exposure to NO2 and cigarette smoke will enhance pulmonary inflammation and emphysema development. Mice were exposed to 20 ppm NO2 for 17 h/day, to 24 puffs of cigarette smoke 2 times per day, to their combination, or to control air for 5 days/wk during 4 wk. Following the last NO2 exposure and within 24 h after the last smoke exposure the mice were sacrificed. Lungs were removed and analyzed for several inflammatory parameters and emphysema. Cigarette smoke exposure increased eosinophil numbers and levels of tumor necrosis factor (TNF)-alpha, KC, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6. NO2 exposure increased goblet cells, eosinophils, and the levels of IL-6, while it decreased the levels of IL-10. Four weeks of NO2, cigarette smoke, or their combination was not sufficient to induce significant emphysema, nor did it lead to increased numbers of lymphocytes, neutrophils, or macrophages in lung tissue. Instead, NO2 exposure attenuated the smoke-induced increases in levels of TNF-alpha, KC, and MCP-1. These dampening effects of NO2 may be due to modulating effects of NO2 on cytokine production by macrophages and epithelial cells, which have been reported earlier. The next step is to translate these findings of combined, controlled exposure in animals to the human situation.


Light-induced losses and dark recovery rates of guanosine 3',5'-cyclic monophosphate in rod outer segments of intact amphibian photoreceptors.
We used an apparatus in which pieces of dark-adapted amphibian retinas (Rana pipiens, Bufo marinus) obtained under infrared illumination were exposed to precise intervals of 500-nm illuminations, and then frozen by contact of their outer segment surface with a liquid helium-cooled copper mirror. Sections of the frozen outer segment layer were obtained in a cryostat and then assayed for total extractable cyclic 3',5'-guanosine monophosphate (cGMP). Significant losses of cGMP with respect to the dark level were evident as early as 60 ms after light onset. With dim subsecond illuminations these losses were surprisingly large, which suggests a previously underestimated magnification in the cGMP cascade, or a transient substantial inhibition of guanylate cyclase activity in combination with increased cyclic GMP phosphodiesterase activity. Within the subsecond period, significant losses that were proportional to light intensity (2-log-unit range) and duration (60-550 ms) were generally not evident. However, losses significantly proportional to these factors became evident with durations of 1 s or longer. When pieces of retina were first illuminated (10 or 60 ms), then held in darkness for increasing periods before freezing, we observed a continuous loss of cGMP during the early postillumination dark period, followed by a recovery of the total cGMP level. The times for recovery to the preillumination level appear to be significantly longer than times reported for the recovery of the photoreceptor membrane potential after similar light exposures.


Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.
Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.


Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years.
We assessed the risk of second brain tumors in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Four hundred and twenty-six patients (United Kingdom residents) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. They were followed up for 5749 person-years. The cumulative incidence of second intracranial tumors and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and the National Health Service Central Register (previously OPCS) to record death and the potential causes. Eleven patients developed a second brain tumor, including five meningiomas, four high grade astrocytomas, one meningeal sarcoma, and one primitive neuroectodermal tumor. The cumulative risk of second brain tumors was 2.0% [95% confidence interval (CI), 0.9-4.4%] at 10 yr and 2.4% (95% CI, 1.2-5.0%) at 20 yr, measured from the date of radiotherapy. The relative risk of second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3-16.7). The relative risk was 7.0 for neuroepithelial and 24.3 for meningeal tumors. The relative risks were 24.2 (95% CI, 4.8-43.5), 2.9 (95% CI, 0-8.5), and 28.6 (95% CI, 0.6-56.6) during the intervals 5-9, 10-19, and more than 20 yr after radiotherapy (four cases occurred >20 yr after treatment). There was no evidence of excess risk of second systemic malignancy. An additional 10-yr update confirmed our previous report of an increased risk of second brain tumors in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 yr remains low and should not preclude the use of radiotherapy as an effective treatment option. However, an increased risk of second brain tumors continues beyond 20 and 30 yr after treatment.


Epipodial Tentacle Gene Expression and Predetermined Resilience to Summer Mortality in the Commercially Important Greenlip Abalone, Haliotis laevigata.
"Summer mortality" is a phenomenon that occurs during warm water temperature spikes that results in the mass mortality of many ecologically and economically important mollusks such as abalone. This study aimed to determine whether the baseline gene expression of abalone before a laboratory-induced summer mortality event was associated with resilience to summer mortality. Tentacle transcriptomes of 35 greenlip abalone (Haliotis laevigata) were sequenced prior to the animals being exposed to an increase in water temperature-simulating conditions which have previously resulted in summer mortality. Abalone derived from three source locations with different environmental conditions were categorized as susceptible or resistant to summer mortality depending on whether they died or survived after the water temperature was increased. We detected two genes showing significantly higher expression in resilient abalone relative to susceptible abalone prior to the laboratory-induced summer mortality event. One of these genes was annotated through the NCBI non-redundant protein database using BLASTX to an anemone (Exaiptasia pallida) Transposon Ty3-G Gag Pol polyprotein. Distinct gene expression signatures were also found between resilient and susceptible abalone depending on the population origin, which may suggest divergence in local adaptation mechanisms for resilience. Many of these genes have been suggested to be involved in antioxidant and immune-related functions. The identification of these genes and their functional roles have enhanced our understanding of processes that may contribute to summer mortality in abalone. Our study supports the hypothesis that prestress gene expression signatures are indicative of the likelihood of summer mortality.


Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins.
Leptin activates its cognate receptor (LR) to regulate body weight and metabolically costly processes, such as reproduction and immune responses. Despite such benevolent pleiotropy, leptin-mediated signaling has been implicated in autoimmune diseases and breast cancer, thereby rejuvenating interest in leptin antagonism. We present comparative biochemical and structural studies of the LR ectodomain (LRecto) in complex with wild-type and antagonist leptin variants. We show that high-affinity binding of leptin to the cytokine receptor homology 2 domain of LRecto primes interactions with the Ig-domain (LRIg) of another leptin-bound LRecto to establish a quaternary assembly. In contrast, antagonist leptin variants carrying mutations at the LRIg binding site only enable binary complexes with LRecto. Acetylation of free cysteines in LRecto also abrogates quaternary complexes, suggesting a functional role for intrareceptor disulfides. We propose a revised conceptual framework for LR activation whereby leptin activates predimerized LR at the cell surface to seed higher order complexes with 4:4 stoichiometry.


The effects of co-administration of 3,4-methylenedioxymethamphetamine ("ecstasy") or para-methoxyamphetamine and moclobemide at elevated ambient temperatures on striatal 5-HT, body temperature and behavior in rats.
We have recently demonstrated that co-administration of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") with the reversible monoamine oxidase type A (MAO-A) inhibitor moclobemide at an ambient temperature of 22 degrees C significantly increases striatal 5-HT outflow and 5-HT-mediated behaviors. In the present study, using microdialysis, we examined the effects of co-administration of MDMA or para-methoxyamphetamine (PMA) with moclobemide on striatal 5-HT outflow at the elevated ambient temperatures of 30 degrees C. Samples were collected every 30 min for 4 h and analyzed by high-performance liquid chromatography assay with electrochemical detection (HPLC-ED). 5-HT-mediated effects on body temperature and behavior were also recorded. Rats were treated with either saline or 20 mg/kg (i.p.) moclobemide, followed by 10 mg/kg (i.p.) MDMA, 10 mg/kg (i.p.) PMA or saline 60 min later. Both MDMA and PMA produced significant increases in 5-HT outflow (370% peak and 309% peak, respectively, P<0.05). MDMA and PMA significantly increased body temperature (+2.0 degrees C and +2.1 degrees C, respectively, P<0.01) and drug-related behaviors (P<0.05). When MDMA or PMA was co-administered with moclobemide, additional significant increases were seen in 5-HT outflow (850% peak, P<0.01 and 1450% peak, P<0.001, respectively) and only MDMA showed additional significant increase in body temperature (+5.0 degrees C, P<0.001). No additional increases were seen in behavioral activity. When moclobemide was co-administered with MDMA, sustained increases in body temperature were recorded that were significantly higher than with MDMA alone and such increases were not observed in our previous study at normal room temperature. Our results suggest greater risk of MDMA-induced adverse effects on body temperature regulation, compared with PMA, when used in combination with moclobemide at elevated ambient temperatures.


WHO IS 'BEHAVIORAL'? COGNITIVE ABILITY AND ANOMALOUS PREFERENCES.
In this paper, we ask whether variation in preference anomalies is related to variation in cognitive ability. Evidence from a new laboratory study of Chilean high-school students with similar schooling backgrounds shows that small-stakes risk aversion and short-run discounting are less common among those with higher standardized test scores. The relationship with test scores survives controls for parental education and wealth. We find some evidence that elementary-school GPA is predictive of preferences measured at the end of high school. Two laboratory interventions provide suggestive evidence of a possible causal impact of cognitive resources on expressed preferences. (JEL: J24, D14, C91).