Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Background: Concise methodological directions for administration of serial cardiopulmonary exercise testing (CPET) are needed for testing of patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Maximal CPET is used to evaluate the coordinated metabolic, muscular, respiratory and cardiac contributions to energy production in patients with ME/CFS. In this patient population, CPET also elicits a robust post-exertional symptom flare (termed, post-exertional malaise); a cardinal symptom of the disease. CPET measures are highly reliable and reproducible in both healthy and diseased populations. However, evidence to date indicates that ME/CFS patients are uniquely unable to reproduce CPET measures during a second test, despite giving maximal effort during both tests, due to the effects of PEM on energy production. Methodology: To document and assess functional impairment due to the effects of post-exertional malaise in ME/CFS, a 2-day CPET procedure (2-day CPET) has been used to first measure baseline functional capacity (CPET1) and provoke post-exertional malaise, then assess changes in CPET variables 24 h later with a second CPET to assess the effects of post-exertional malaise on functional capacity. The second CPET measures changes in energy production and physiological function, objectively documenting the effects of post-exertional malaise. Use of CPET as a standardized stressor to induce post-exertional malaise and quantify impairment associated with post-exertional malaise has been employed to examine ME/CFS pathology in several studies. This article discusses the results of those studies, as well as the standardized techniques and procedures for use of the 2-day CPET in ME/CFS patients, and potentially other fatiguing illnesses. Conclusions: Basic concepts of CPET are summarized, and special considerations for performing CPET on ME/CFS patients are detailed to ensure a valid outcome. The 2-day CPET methodology is outlined, and the utility of the procedure is discussed for assessment of functional capacity and exertion intolerance in ME/CFS.


Retrospective study of placenta accreta, placenta increta and placenta percreta in Peripartum hysterectomy specimens.
Abnormal placentations such as placenta accreta, placenta increta and placenta percreta are important causes of hemorrhage after delivery causing maternal morbidity and mortality. Risk factors for abnormal placentation are prior caesarean section, placenta previa and pre-eclampsia. There is a need for reliable antenatal diagnosis for these serious conditions. If these pregnancies can be identified, antepartum, site and time of delivery as well as the surgical approach can be planned ahead; this decreases the incidence of maternal mortality due to massive hemorrhage. (1) To study the incidence of abnormal placentation in emergency peripartum hysterectomy specimen. (2) To evaluate various risk factors associated with abnormal placentation. Retrospective cross-section study done in patients with abnormal placentation leading to emergency peripartum hysterectomy during a course of eight-year period. We received total of 18 emergency hysterectomy specimens during eight-year period of which placenta accreta accounts 55.5 percent (10/18), placenta increta upto 38.8 percent (7/18) and placenta percreta 5.5 percent (1/18). Analysis of result with parity shows uniparous women up to 22.2 percent (4/18), and multiparous women 77.7 percent (14/18). Risk factor analysis shows previous caesarean section in 55.5 percent (10/18), placenta previa in 33.3 percent (6/18) and pre-eclampsia in 11.1 percent (2/18). In our study, among abnormal placentation, incidence of placenta accreta accounts for 55.5 percent and it is more common in multiparous women than uniparous women. Among risk factors in our study, previous caesarean section is commonly associated with abnormal placentation followed by a placenta previa and pre-eclampsia.


Evaluation of a rapid serological test for the determination of Mycobacterium bovis infection in badgers (Meles meles) found dead.
Between October 2005 and May 2006, a total of 727 badgers found dead in Wales were reported, and 550 were delivered to the Regional Laboratories of the Veterinary Laboratories Agency (VLA). Of the 459 carcasses suitable for examination, 55 were deemed to be infected with Mycobacterium bovis on the basis of culture, spoligotyping, and variable-number tandem repeat typing. Acid-fast bacteria were observed histologically in a further six badgers, but these bacteria were not confirmed as M. bovis by culture. A rapid serological test (BrockTB Stat-Pak) performed on thoracic blood showed a sensitivity of 35% and a specificity of 99%. Presence of M. bovis infection was 45 times more likely to be confirmed postmortem by culture in BrockTB Stat-Pak-reactive animals than in seronegative ones. Using visible carcass lesions as a marker of bovine tuberculosis (bTB) infection had a similar sensitivity (38%) but was significantly less specific (84%) than serology. The overall accuracy of the antibody detection was 93% (346 correct results from 374 tests), whereas the accuracy of regarding visible lesions as a marker for bTB infection was 78% (354 correct from 453 carcasses examined). Culture remains the gold standard method for detecting M. bovis infection in badgers. However, where resources are limited and/or an instant result is preferred, the BrockTB Stat-Pak could be used in field surveillance efforts to identify animals which should be examined further by only submitting test-negative animals to more detailed postmortem examination and culture.


Prediction of sludge bulking using the knowledge-leverage-based fuzzy neural network.
One of the most important steps and the main bottleneck of the activated sludge wastewater treatment process (WWTP) is the secondary clarification, where sludge bulking is still a widespread problem. In this paper, an intelligent method, based on a knowledge-leverage-based fuzzy neural network (KL-FNN), is developed to predict sludge bulking online. This proposed KL-FNN can make full use of the data and the existing knowledge from the operation of WWTP. Meanwhile, a transfer learning mechanism is applied to adjust the parameters of the proposed method to improve the predicting accuracy. Finally, this proposed method is applied to a real wastewater treatment plant for predicting the sludge bulking risk, and then for predicting the sludge bulking. The experimental results indicate that the proposed prediction method can be used as a tool to achieve better performance and adaptability than the existing methods in terms of predicting accuracy for sludge bulking.


Avoiding routine postoperative voiding cystourethrogram: Predicting radiologic success for endoscopically treated vesicoureteral reflux.
Variability in the success rates for the endoscopic correction of vesicoureteral reflux (VUR) has prompted a debate regarding the use of routine postoperative voiding cystourethrogram (VCUG). This study examines the predictive performance of intraoperative mound morphology (IMM) and the presence of a postoperative ultrasound mound (PUM) on radiologic success, as well as investigates the role of using these two predictive factors as a composite tool to predict VUR resolution after endoscopic treatment. This retrospective study included children with primary VUR who underwent endoscopic correction with a double hydrodistension-implantation technique (HIT) and dextranomer/hyaluronic acid copolymer. IMM was assessed intraoperatively. The presence of a PUM and VUR resolution were assessed by postoperative ultrasound (US) and VCUG, respectively. Radiologic success was defined as VUR resolution. A total of 70 children (97 ureters) were included in the study. The overall radiologic success rate was 83.5%. There was no statistically significant association between radiologic success and IMM (85.2% with excellent and 87.5% with "other" morphology; p=0.81). The sensitivity and specificity of PUM for radiologic success in this study was 98% and 71%, respectively, while the sensitivity and specificity of the combined prediction model were 81.9% and 85.7%, respectively. We objectively demonstrated that IMM was a poor predictor of radiologic success and should be used with caution. In addition, the performance of a combined prediction model was inferior to the presence of a PUM alone. As such, selective use of postoperative VCUG may be guided solely by the presence of a PUM.


Long-term administration of valproic acid in the treatment of affective symptoms in people with mental retardation.
We report the results of an open trial of valproic acid in the treatment of affective symptoms in people with mental retardation. The study population consisted of 209 people with mental retardation who were serially referred to a tertiary-care medical center for the evaluation of behavioral symptoms. Criteria for treatment included the presence of three of the four following symptoms: irritability, sleep disturbance, aggressive or self-injurious behavior, and behavioral cycling. Twenty-one patients met enrollment criteria and were studied prospectively for a 2-year period. Two patients were lost to follow-up. One patient experienced severe drug side effects. Eighteen patients completed the study. Fourteen patients (78%) responded favorably to treatment and were maintained on valproic acid for the 2 years of the study (p < 0.001). Medications prescribed at the time of enrollment were usually discontinued, including neuroleptic medication in 9 of 10 patients and in all patients (N = 3) who were receiving phenobarbital. A history of epilepsy or a suspicion of seizures was strongly associated with a favorable response to valproic acid (p < 0.005). The results of this study suggest that people with mental retardation and concurrent affective disorders can be recognized by a cluster of developmentally appropriate symptoms such as those listed above. In addition, affective symptoms can be successfully treated with valproate with reductions in neuroleptic and barbiturate anticonvulsant medication. Further study of the comparative benefit of valproate and carbamazepine in this population is warranted.


Children at risk: A comparison of child pedestrian traffic collisions in Santiago, Chile, and Seoul, South Korea.
We examine and compare pedestrian-vehicle collisions and injury outcomes involving school-age children between 5 and 18 years of age in the capital cities of Santiago, Chile, and Seoul, South Korea. We conduct descriptive analysis of the child pedestrian-vehicle collision (P-VC) data (904 collisions for Santiago and 3,505 for Seoul) reported by the police between 2010 and 2011. We also statistically analyze factors associated with child P-VCs, by both incident severity and age group, using 3 regression models: negative binomial, probit, and spatial lag models. Descriptive statistics suggest that child pedestrians in Seoul have a higher risk of being involved in traffic crashes than their counterparts in Santiago. However, in Seoul a greater proportion of children are unharmed as a result of these incidents, whereas more child pedestrians are killed in Santiago. Younger children in Seoul suffer more injuries from P-VCs than in Santiago. The majority of P-VCs in both cities tend to occur in the afternoon and evening, at intersections in Santiago and at midblock locations in Seoul. Our model results suggest that the resident population of children is positively associated with P-VCs in both cities, and school concentrations apparently increase P-VC risk among older children in Santiago. Bus stops are associated with higher P-VCs in Seoul, and subway stations relate to higher P-VCs among older children in Santiago. Zone-level land use mix was negatively related to child P-VCs in Seoul but not in Santiago. Arterial roads are associated with fewer P-VCs, especially for younger children in both cities. A share of collector roads is associated with increased P-VCs in Seoul but fewer P-VCs in Santiago. Hilliness is related to fewer P-VCs in both cities. Differences in these model results for Santiago and Seoul warrant additional analysis, as do the differences in results across model type (negative binomial versus spatial lag models). To reduce child P-VCs, this study suggests the need to assess subway station and bus stop area conditions in Santiago and Seoul, respectively; areas with high density of schools in Santiago; areas with greater concentrations of children in both cities; and collector roads in Seoul.


Alpha-lipoic acid treatment of 31 patients with sore, burning mouth.
To review a series of patients with sore, burning mouth treated with alpha-lipoic acid between 2000 and May 2006 and subjectively evaluate improvement in symptoms. Retrospective review of medical records of 195 consecutive patients who sought treatment for sore, burning mouth. Treatment of 47 patients was a prescription/recommendation for alpha-lipoic acid. Of these patients, 35 were available for follow-up. Tertiary care academic medical center. Ambulatory patients given prescription /recommendation for alpha-lipoic acid 600 mg per day, in divided doses. Reported improvement in symptoms documented in medical records and at follow-up (visits or telephone interviews). Thirty-one of the 35 patients (66% of all 47) actually took alpha-lipoic acid as recommended. No patient reported a complete alleviation of symptoms. Six (19%) of these 31 patients felt mostly better, five (16%) felt somewhat better, and 14 (45%) reported no difference. Two patients (7%) reported a worsening of symptoms and four (13%) did not know whether there had been improvement. Eleven of 31 patients (35%) reported benefit from taking alpha-lipoic acid. Because we examined only a small number of patients and relied on a subjective outcome assessment, further larger studies using a prospective, randomized, controlled, and double-blind structure are warranted.


Characteristics of the structural and Johari-Goldstein relaxations in Pd-based metallic glass-forming liquids.
The dynamics of Pd-based metallic glass-forming liquids (Pd(40)Ni(10)Cu(30)P(20), Pd(42.5)Ni(7.5)Cu(30)P(20), Pd(40)Ni(40)P(20), and Pd(30)Ni(50)P(20)) was studied by mechanical spectroscopy and modulated differential scanning calorimetry (MDSC). We found that the change in composition has a significant effect on the α relaxation dynamics; the largest difference corresponds to an increase of the glass transition temperature Tg of ∼ 15 K, for materials in which 30% Ni was substituted by 30% Cu (i.e., from Pd(40)Ni(40)P(20) to Pd(40)Ni(10)Cu(30)P(20)). We also found that all Pd-based metallic glasses have very similar fragilities, 59 < m < 67, and Kohlrausch stretched exponents, 0.59 < βKWW < 0.60. It is interesting that the values of m and βKWW correlate well with the general relation proposed by Böhmer et al. for nonmetallic glass formers (Böhmer, R.; et al. J. Chem. Phys. 1993, 99, 4201-4209), which for the observed βKWW values predicts 58 < m < 61. From a linear deconvolution of the α and β relaxations, we find that the substitution of the Ni with Cu induced a large change in the time constant of the Johari-Goldstein relaxation, τβ. The activation energy, Uβ, of the β relaxation was largely independent of chemical composition. In all cases, 25 < Uβ/RT < 28, a range in agreement with results for other glass formers (Kudlik, A.; et al. Europhys. Lett. 1997, 40, 649-654 and Ngai, K. L.; et al. Phys. Rev. E 2004, 69, 031501). From the heat capacity and mechanical loss, estimates were obtained for the number of dynamically correlated units, Nc; we find significantly larger values for these metallic glass-forming liquids than Nc for other glass-forming materials.


Separation of cobalt and nickel by solvent extraction with two mutually immiscible ionic liquids.
The proof-of-principle for the separation of metals by solvent extraction using two mutually immiscible ionic liquids is given. Cobalt was extracted from the ionic liquid 1-ethyl-3-methylimidazolium chloride to the ionic liquid trihexyl(tetradecyl)phosphonium bis(2,4,4-trimethylpentyl)phosphinate. A distribution ratio of 44 was obtained. Cobalt could be selectively separated from nickel, with a separation factor of 207. The extraction mechanism was elucidated using UV-VIS absorption measurements. The mutual solubility between the two ionic liquids was determined by (1)H NMR. Processing steps such as washing, stripping and regeneration of the ionic liquid phases are discussed.


The role of C5 in septic lung injury.
One proposed mechanism for the pathogenesis of lung injury in septic animals is the stimulation by C5a of granulocytes to produce and release toxic oxygen radicals that damage cellular membranes in pulmonary capillaries. The authors have investigated the possible role of C5 in septic lung injury, utilizing C5-sufficient and C5-deficient twin mice strains. In this lethal sepsis model, mean survival time is increased in C5-deficient mice in comparison to the survival of their C5-sufficient twins. Morphometric results demonstrate a significant increase in intracapillary granulocrit and air-blood barrier thickness 24 hours after cecal ligation and puncture in C5-sufficient septic mice. Similarly, mean arterial pO2 is significantly decreased in the C5-sufficient animals. Intracapillary granulocrit, air-blood barrier thickness, and arterial pO2 are normal in the septic C5-deficient twins of these animals. These data support the hypothesis that C5 is involved in the pathogenesis of septic lung injury.


Cultural and phylogenetic analysis of mixed microbial populations found in natural and commercial bioleaching environments.
A range of autotrophic and heterotrophic enrichment cultures were established to determine the cultural bacterial diversity present in samples obtained from the acidic runoff of a chalcocite overburden heap and from laboratory-scale (1- to 4-liter) batch and continuous bioreactors which were being used for the commercial assessment of the bioleachability of zinc sulfide ore concentrates. Strains identified as Thiobacillus ferrooxidans, Thiobacillus thiooxidans, "Leptospirillum ferrooxidans," and Acidiphilium cryptum were isolated from both the natural site and the batch bioreactor, but only "L. ferrooxidans," a moderately thermophilic strain of T. thiooxidans, and a moderately thermophilic iron-oxidizing bacterium could be recovered from the continuous bioreactor running under steady-state conditions. Sequence analysis of the 16S rRNA genes of 33 representative strains revealed that all of the strains were closely related to strains which have been sequenced previously and also confirmed the phylogenetic diversity of bacteria present in bioleaching environments.


Hind limb somatosensory evoked potentials in the monkey: the effects of distal axonopathy.
Computer-averaged short-latency somatosensory evoked potentials (SLSEP) to unilateral stimulation of the peroneal nerve were recorded from surface electrodes overlying the peripheral nerve, cauda equina, spinal cord, brainstem, and contralateral sensorimotor region. Seven monkeys were studied under normal conditions and at various stages of distal axonopathy induced by systematic acrylamide intoxication. With the use of a noncephalic reference, a series of five small-amplitude positive components were identified that precede the initial cortical activity. On the basis of timing and topography of the components, the source of the first one, SLSPEP1, was localized to the lumbar dorsal root fibers and that of the second, SLSEP2, to the ascending spinal tracts, principally gracile fasciculus. Bipolar recordings of the SLSEP2 overlying the rostral extreme of the cervical spinal cord provided a sensitive measure of the onset of distal axonopathy. Changes in the timing of this component antedated both abnormalities of spinal or peripheral nerve conduction and behavioral signs of intoxication. The initial alteration was specific to stimulation of the hind limb and was associated with early morphological change limited to the terminal and preterminal portions of the long axons in the gracile fasciculus.


Could Residents Adequately Assess the Severity of Hidradenitis Suppurativa? Interrater and Intrarater Reliability Assessment of Major Scoring Systems.
A wide variety of assessment tools have been proposed for hidradenitis suppurativa (HS) until now, but none of them meets the criteria for an ideal score. Because there is no gold standard scoring system, the choice of the measure instrument depends on the purpose of use and even on the physician's experience in the subject of HS. The aim of this study was to assess the intrarater and interrater reliability of 6 scoring systems commonly used for grading severity of HS: the Hurley Staging System, the Refined Hurley Staging, the Hidradenitis Suppurativa Severity Score System (IHS4), the Hidradenitis Suppurativa Severity Index (HSSI), the Sartorius Hidradenitis Suppurativa Score and the Hidradenitis Suppurativa Physician's Global Assessment Scale (HS-PGA). On the scoring day, 9 HS patients underwent a physical examination and disease severity assessment by a group of 16 dermatology residents using all evaluated instruments. Then, intrarater reliability was calculated using intraclass correlation coefficient (ICC), and interrater variability was evaluated using the coefficient of variation (CV). In all 6 scorings the ICCs were >0.75, indicating high intrarater reliability of all presented scales. The study has also demonstrated moderate agreement between raters in most of the evaluated measure instruments. The most reproducible methods, according to CVs, seem to be the Hurley staging, IHS4, and HSSI. None of the 6 evaluated scoring systems showed a significant advantage over the other when comparing ICCs, and all the instruments seem to be very reliable methods. The interrater reliability was usually good, but the most repeatable results between researchers were obtained for the easiest scales, including Hurley scoring, IHS4 and HSSI.


Opportunities and challenges with decentralized trials in Neuroscience.
Decentralized clinical trials (DCTs), that is, studies integrating elements of telemedicine and mobile/local healthcare providers allowing for home-based assessments, are an important concept to make studies more resilient and more patient-centric by taking into consideration participant's views and shifting trial activities to better meet the needs of trial participants. There are however, not only advantages but also challenges associated with DCTs. An area to be addressed by appropriate statistical methodology is the integration of data resulting from a possible mix of home and clinic assessments at different visits for the same variable, especially in adjusting for sources of possible systematic differences. One source of systematic bias may be how a participant perceives their disease and treatment in their home versus in a clinical setting. In this paper, we will discuss these issues with a focus on Neuroscience when participants have the choice between home and clinic assessments to illustrate how to identify systematic biases and describe appropriate approaches to maintain clinical trial scientific rigor. We will describe the benefits and challenges of DCTs in Neuroscience and then describe the relevance of home versus clinic assessments using the estimand framework. We outline several options to enable home assessments in a study. Results of simulations will be presented to help deciding between design and analysis options in a simple scenario where there might be differences in response between clinic and home assessments.


In Situ Fixation Redefines Quiescence and Early Activation of Skeletal Muscle Stem Cells.
State of the art techniques have been developed to isolate and analyze cells from various tissues, aiming to capture their in vivo state. However, the majority of cell isolation protocols involve lengthy mechanical and enzymatic dissociation steps followed by flow cytometry, exposing cells to stress and disrupting their physiological niche. Focusing on adult skeletal muscle stem cells, we have developed a protocol that circumvents the impact of isolation procedures and captures cells in their native quiescent state. We show that current isolation protocols induce major transcriptional changes accompanied by specific histone modifications while having negligible effects on DNA methylation. In addition to proposing a protocol to avoid isolation-induced artifacts, our study reveals previously undetected quiescence and early activation genes of potential biological interest.


mRNA poly(A) tail, a 3' enhancer of translational initiation.
To evaluate the hypothesis that the 3' poly(A) tract of mRNA plays a role in translational initiation, we constructed derivatives of pSP65 which direct the in vitro synthesis of mRNAs with different poly(A) tail lengths and compared, in reticulocyte extracts, the relative efficiencies with which such mRNAs were translated, degraded, recruited into polysomes, and assembled into messenger ribonucleoproteins or intermediates in the translational initiation pathway. Relative to mRNAs which were polyadenylated, we found that nonpolyadenylated [poly(A)-]mRNAs had a reduced translational capacity which was not due to an increase in their decay rates, but was attributable to a reduction in their efficiency of recruitment into polysomes. The defect in poly(A)- mRNAs affected a late step in translational initiation, was distinct from the phenotype associated with cap-deficient mRNAs, and resulted in a reduced ability to form 80S initiation complexes. Moreover, poly(A) added in trans inhibited translation from capped polyadenylated mRNAs but stimulated translation from capped poly(A)- mRNAs. We suggest that the presence of a 3' poly(A) tail may facilitate the binding of an initiation factor or ribosomal subunit at the mRNA 5' end.


Therapeutic Response of Vitamin A, Vitamin B Complex, Essential Fatty Acids (EFA) and Vitamin E in the Treatment of Phrynoderma: A Randomized Controlled Study.
In the treatment of phrynoderma, various nutrients have been tried in different dosages and routes with variable therapeutic outcomes. The present study was undertaken to compare the efficacy of various nutrients in the treatment of phrynoderma. An open label randomized controlled study was conducted in the out-patient department of Dermatology in a tertiary care hospital. The patients were divided into group of five and each patient received one of the five regimens [10 injections of Vitamin A 1 lakh units, intramuscularly (IM) on alternate day, 10 injections of Vitamin B complex, 2cc IM on alternate day, 2 table spoon of safflower oil, two times daily with meals, Tab Vitamin E 400mg once daily, and only topical keratolytic (salicylic acid 3% ointment) two times daily] respectively. The first four regimens also received topical keratolytic. The primary outcome measured was therapeutic response at the end of regimen. The response was graded based on the percentage of flattening and decrease in number of lesions. Less than 25% improvement was graded as poor, 26-50% improvement as moderate, 51-75% improvement as good, and more than 75% improvement as excellent response. In the statistical analysis, comparison was done using Chi-square and Fisher's exact test. A total of 125 patients were included in the study with 25 patients each in five regimen groups. There were 79 (63.2%) males and 46 (36.8%) females with a ratio of 1.72:1. The age of the patients ranged from 3 to 26 years with mean of 10.1±4.3 years. Out of 125 patients, 105 completed the study. In regimen 1 and 2, significant number of patients showed good to excellent response whereas significant number of patients in remaining regimen showed moderate to poor response with a p value of <0.05. The therapeutic response to Vitamin A and Vitamin B complex therapy was significantly better than other regimens. Intramuscular injections of Vitamin A or Vitamin B are effective in the treatment of phrynoderma. Addition of topical keratolytics helps in faster clearance of keratotic lesions.


Puzzle-Formed Modified Turkish Delight for Nasal Dorsum Augmentation.
Structural deficiencies of the nasal dorsum are most commonly of congenital, traumatic, or iatrogenic etiology. Various grafts, including autografts, homografts, and synthetic materials, have been used to this end and are described in the literature.Autologous septal cartilage is the most commonly used graft material when limited augmentation rhinoplasty is planned. However, it is difficult to retain sufficient cartilage to allow of such augmentation in instances where most of the septal cartilage has been used. The authors place moderately crushed cartilage beneath a monolayer of surgicel when performing limited nasal dorsum augmentation. The aim of the present study is to describe authors' approach and its utility by reviewing other methods reported in the literature.


[The interest shown by medical students and recently qualified doctors in a career in psychiatry].
In view of the current shortage of psychiatrists in the Netherlands it is important to find out what attracts medical students and recently qualified doctors to a career in psychiatry. To discover what aspects of psychiatry are of interest to medical students and recently qualified doctors and to determine what interest profile is suited to the practice of psychiatry. Medical students and recently qualified doctors from the Free University medical school in Amsterdam and from Utrecht University medical school completed a questionnaire which investigated why certain specialisms, including psychiatry, were chosen as future careers, and which also examined the appeal of 47 aspects of a career in medicine. About 30% of the students expressed an interest in becoming psychiatrist. The interest was slightly greater among first-year students but decreased in the course of their medical training. About 6% of recently qualified doctors actually work in psychiatry and a larger percentage want to become psychiatrist in five years' time. The interest profile of persons interested in psychiatry differs from that of persons not interested in psychiatry and is different for men and women. The interest of students in a career in psychiatry decreases in the course of their medical training. This is in keeping with the general decrease in interest in any other career in medicine and probably reflects the current increasing focus on only one single medical specialism. The interest profile of persons interested in a career in psychiatry lies more in the communicative and psychosocial sphere and is focused in relationships that develop during long-term treatment rather than on medical-technical aspects. After qualifying as doctors, women with an interest in psychiatry often develop an interest in improvisation, diagnostics and pharmacotherapy.


Lymphoma and peripheral neuropathy: a clinical review.
Lymphoma occasionally affects the peripheral nervous system. When it does, the diagnosis can be elusive since many patients present without known lymphoma. Most peripheral nerve complications are due to non-Hodgkin's lymphoma (NHL), which infiltrates nerves causing axonal damage. This disorder can affect nerve roots and cranial nerves, often associated with lymphomatous meningitis. NHL may also infiltrate peripheral nerves and cause plexopathy, mononeuropathy, or generalized neuropathy. These neuropathies may resemble an asymmetric mononeuropathy multiplex or a generalized disorder such as chronic inflammatory demyelinating polyradiculoneuropathy. When NHL infiltrates diffusely, the term neurolymphomatosis is used. Hodgkin's lymphoma (HL), by contrast, rarely infiltrates nerves. More often, HL causes immunological disorders of the peripheral nervous system such as inflammatory plexopathy or Guillain-Barré syndrome. Other rare lymphomas such as intravascular lymphoma and Waldenstrom's macroglobulinemia can also affect peripheral nerves in specific ways. In addition, other malignant and nonmalignant lymphoproliferative disorders enter into the differential diagnosis of lymphomatous neuropathy. This review discusses the multiple peripheral nerve presentations of lymphoma from the clinician's point of view and provides a guide to the evaluation and diagnosis of these uncommon, challenging disorders.


The high atherosclerotic risk among epileptics: the atheroprotective role of multivitamins.
Neurologists have little concern about the high atherosclerotic risk among epileptics. Recent evidences mount that chronic epilepsy and prolonged use of antiepileptic drugs (AEDs) are associated with multiple risk factors that are critically implicated in pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis. This review is concerned with three metabolic alterations, which are attributed as major risk factors for atherosclerosis among epileptics: altered metabolism of a) homocysteine (Hcy), b) lipids and lipoproteins, and c) uric acid. Most conventional AEDs reduce folic acid levels, thereby raising Hcy levels. Hyperhomosysteinemia is recently believed to induce endothelial dysfunction and promote atherosclerosis through complex oxidative and excitatory neurotoxic molecular mechanisms. However, Hcy itself is a convulsing substance with increased seizure recurrence and intractability to antiepileptic medications. AEDs can disturb lipid metabolism with resultant hypercholestrolemia and dyslipidemia, common recognized risks for atherosclerosis. Altered uric acid metabolism is common among epileptics. Uric acid has been implicated in endothelial cell damage and decreased endothelial nitric oxide bioavailability. In the presence of atherosclerotic milieu, uric acid interacts with other substrate toxicities and increased reactive oxygen species, accelerating atherosclerosis. The above information forms the rationale for future routine screening and correction of such metabolic alterations in epileptics. A convincing argument now develops that routine polyvitamin supplementation (folic acid, vitamin B12, vitamin B6, vitamin C, vitamin E, and beta-carotene) becomes increasingly important for women and men receiving AEDs at all ages. The atheroprotective effect of multivitamins is through their antioxidant and anti-inflammatory effects together with their lipid and Hcy lowering effects.


Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants.
A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). Indomethacin is used as standard therapy to close a PDA, but is associated with reduced blood flow to the brain, kidneys and gastrointestinal tract. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin, with fewer side effects. To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a PDA in preterm and/or low birth weight infants. To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitors (including indomethacin, mefenamic acid) for closing a PDA in preterm and/or low birth weight infants. Randomized or quasi-randomized controlled trials (RCTs) comparing ibuprofen to placebo or indomethacin or mefenamic acid for therapy of PDA were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1996 - August 2007), CINAHL (1982 - August 2007), EMBASE (1980 - August 2007), reference lists of published RCTs and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1991 - April 2005) or on their website (to August 2007). No language restrictions were applied. 1) DESIGN: Randomized or quasi-randomized controlled trials2) POPULATION: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) with a clinically or echocardiographically diagnosed PDA3) INTERVENTION: Administration of ibuprofen (orally or intravenously) for the closure of PDA4) OUTCOMES: At least one of the following outcomes were reported: failure to close a PDA, mortality, surgical ductal ligation, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), NEC, decreased urine output, retinopathy of prematurity (ROP), chronic lung disease (CLD), sepsis, pulmonary hemorrhage, pulmonary hypertension, duration of supplementary oxygen, duration of mechanical ventilation, duration of hospital stay, and serum creatinine levels following treatment. At least two review authors worked independently at each step of the original review, then compared results and resolved differences. The current update was conducted by one review author (AO). Methodological quality of eligible studies was assessed according to blinding of randomization, of intervention and of outcome assessment, and completeness of follow up. Weighted treatment effects, calculated using RevMan 4.2.10, included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNT) or harm (NNH), and weighted mean difference (WMD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I-squared test (I(2)) were performed to assess the appropriateness of pooling the data. No studies using mefenamic acid were identified. Sixteen studies enrolling 876 infants were identified. Four additional trials were identified for this update and two studies published as abstracts were now available as full articles. One study compared ibuprofen to placebo, but the results were not reported unblinded to intervention group. Fifteen studies including 740 infants compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [typical RR 0.99 (95% CI 0.78, 1.27); typical RD 0.00 (95% CI -0.06, 0.06)]. There were no statistically significant differences in mortality, reopening of the ductus, need for surgical duct ligation, duration of ventilator support, duration of supplementary oxygen, pulmonary hemorrhage, pulmonary hypertension, CLD, IVH, PVL, NEC, intestinal perforation, gastrointestinal bleed, time to full enteral feeds, time to regain birth weight, ROP, sepsis, duration of hospitalization. Ibuprofen treatment was associated with statistically significantly lower serum creatinine levels after treatment (6 trials, 336 infants; WMD - 8.2 (95% CI -13.3, -3.2) mmol/L and lower incidence of 'decreased urine output' [3 trials, 336 infants; typical RR; 0.22 (95% CI 0.09, 0.51); typical RD -0.12 (95% CI -0.18, -0.06); NNT 8 (95% CI 6,17)]. There was moderate heterogeneity of treatment effect for the outcomes 'time to regain birth weight' and 'decreased urine output". Heterogeneity was not noted for other outcomes. For several of these outcomes, the sample size was small and the estimates imprecise. There are not enough data available regarding the effectiveness of oral ibuprofen compared with indomethacin to close a PDA [3 trials, 69 infants; typical RR 1.41 (95% CI 0.68, 2.93); typical RD 0.10 (95% CI -0.10, 0.30)]. Pulmonary hypertension was noted in one infant receiving ibuprofen to close a PDA enrolled in a trial in this review and an additional report of such a case was identified from the literature. No statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing a PDA was found. Ibuprofen compared with indomethacin reduces the risk of oliguria and is associated with lower serum creatinine levels following treatment. Pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen and one infant receiving ibuprofen for treatment in this review developed pulmonary hypertension. One additional case of pulmonary hypertension following treatment with ibuprofen to close a PDA was identified from the literature. The available data support the use of either drug for the treatment of a PDA. As both drugs are equally effective in closing a PDA, the clinician needs to weigh the potential side effects of one drug vs. the other when making a decision which drug to use. The most urgent research question to be answered is whether ibuprofen compared to indomethacin confers an improved rate of intact survival (survival without impairment) at 18 months corrected age and at the age of school entry.


Non-progressive cerebellar ataxia and previous undetermined acute cerebellar injury: a mysterious clinical condition.
Cerebellar ataxias represent a wide group of neurological diseases secondary to dysfunctions of cerebellum or its associated pathways, rarely coursing with acute-onset acquired etiologies and chronic non-progressive presentation. We evaluated patients with acquired non-progressive cerebellar ataxia that presented previous acute or subacute onset. Clinical and neuroimaging characterization of adult patients with acquired non-progressive ataxia were performed. Five patients were identified with the phenotype of acquired non-progressive ataxia. Most patients presented with a juvenile to adult-onset acute to subacute appendicular and truncal cerebellar ataxia with mild to moderate cerebellar or olivopontocerebellar atrophy. Establishing the etiology of the acute triggering events of such ataxias is complex. Non-progressive ataxia in adults must be distinguished from hereditary ataxias.


Elevated CO2 increases constitutive phenolics and trichomes, but decreases inducibility of phenolics in Brassica rapa (Brassicaceae).
Increasing global atmospheric CO2 has been shown to affect important plant traits, including constitutive levels of defensive compounds. However, little is known about the effects of elevated CO2 on the inducibility of chemical defenses or on plant mechanical defenses. We grew Brassica rapa (oilseed rape) under ambient and elevated CO2 to determine the effects of elevated CO2 on constitutive levels and inducibility of carbon-based phenolic compounds, and on constitutive trichome densities. Trichome density increased by 57% under elevated CO2. Constitutive levels of simple, complex, and total phenolics also increased under elevated CO2, but inducibility of each decreased. Induction of simple phenolics occurred only under ambient CO2. Although induction of complex and total phenolics occurred under both ambient and elevated CO2, the damage-induced increases were 64% and 75% smaller, respectively, under elevated CO2. Constitutive phenolic levels were positively correlated with leaf C:N ratio, and inducibility was positively correlated with leaf N and negatively correlated with leaf C:N ratio, as would be expected if inducibility were constrained by nitrogen availability under elevated CO2. We conclude that B. rapa is likely to exhibit higher constitutive levels of both chemical and mechanical defenses in the future, but is also likely to be less able to respond to herbivore damage by inducing phenolic defenses. To our knowledge, this is only the second study to report a negative effect of elevated CO2 on the inducibility of any plant defense.


Risk of Plasmodium vivax parasitaemia after Plasmodium falciparum infection: a systematic review and meta-analysis.
A 14-day course of primaquine is used for radical cure of Plasmodium vivax and Plasmodium ovale malaria only. We quantified the risk of P vivax parasitaemia after treatment of Plasmodium falciparum with commonly used antimalarial drugs to assess the potential benefits of radical cure for all patients with uncomplicated malaria in co-endemic regions. In this systematic review and meta-analysis, we searched MEDLINE, Embase, Web of Science, and the Cochrane Database of Systematic Reviews for prospective clinical studies in any language, published between Jan 1, 1960, and Jan 5, 2018, assessing drug efficacy in patients with uncomplicated P falciparum malaria in countries co-endemic for P vivax. Studies were included if the presence or absence of P vivax parasitaemia was recorded after treatment. The primary outcome was the risk of P vivax parasitaemia between day 7 and day 42 after initiation of antimalarial treatment for P falciparum, with the pooled risk calculated by random-effects meta-analysis. We compared the risk of P vivax parasitaemia after treatment with different artemisinin-based combination therapies (ACTs). This study is registered with PROSPERO, number CRD42017064838. 153 of 891 screened studies were included in the analysis, including 31 262 patients from 323 site-specific treatment groups: 130 (85%) studies were from the Asia-Pacific region, 16 (10%) from the Americas, and seven (5%) from Africa. The risk of P vivax parasitaemia by day 42 was 5·6% (95% CI 4·0-7·4; I2=92·0%; 117 estimates). The risk of P vivax parasitaemia was 6·5% (95% CI 4·6-8·6) in regions of short relapse periodicity compared with 1·9% (0·4-4·0) in regions of long periodicity, and was greater after treatment with a more rapidly eliminated ACT: 15·3% (5·1-29·3) for artemether-lumefantrine compared with 4·5% (1·2-9·3) for dihydroartemisinin-piperaquine and 5·2% (2·9-7·9) for artesunate-mefloquine. Recurrent parasitaemia was delayed in patients treated with ACTs containing mefloquine or piperaquine compared with artemether-lumefantrine, but by day 63 the risk of vivax parasitaemia was more than 15% for all ACTs assessed. Our findings show a high risk of vivax parasitaemia after treatment of falciparum malaria, particularly in areas with short relapse periodicity and after rapidly eliminated treatment. In co-endemic regions, universal radical cure for all patients with uncomplicated malaria has the potential to substantially reduce recurrent malaria. Australian National Health and Medical Research Council, Royal Australasian College of Physicians, Wellcome Trust, and Bill & Melinda Gates Foundation.


Mycobacterium abscessus as a cause of pacemaker infection.
Mycobacterial infections of a pacemaker insertion site are very rare clinical events. Such infections are caused primarily by staphylococci and streptococci and, less frequently, Gram-negative organisms. We describe a case of pacemaker infection caused by Mycobacterium abscessus which is, to our knowledge, only the second such case described in the literature. The patient responded well to removal of the pacemaker wire and treatment with six months of clarithromycin. Mycobacteria have been very infrequently reported as causes of pacemaker infections. To our knowledge, only one case of such infection caused by M. abscessus has been described in the literature. Herein we present the second case of a patient with pacemaker infection caused by Mycobacterium abscessus. This case underscores the importance of considering atypical mycobacteria in pacemaker infections, particularly if the Gram stain or the standard cultures are negative. Removal of the contaminated foreign body seems to be an integral part of successful management.


A pilot feasibility study exploring the practising of compassionate imagery exercises in a nonclinical population.
This study assessed the acceptability of practising compassionate imagery as an online task without clinician support. Participants completed questionnaires at baseline, after, and 6 months of follow-up. Participants engaged safely and successfully with the tasks. There were significant improvements in questionnaire scores which were largely maintained over 6 months. People can practise compassionate imagery tasks in an unsupervised way from online recordings and not suffer adverse effects (even with higher baseline scores in self-criticism). Compassionate imagery recordings may be used as an adjunct to improve traditional psychotherapy.


High prevalence of a variant of SENV in intravenous drug user HIV-infected patients.
The prevalence, route of transmission, and clinical significance of SEN virus (SENV) infection was evaluated in 715 samples obtained from 150 blood donors, 165 patients infected by HIV, 150 with HCV/HBV infection, 80 with autoimmune diseases, 40 with Primary Immunodeficiency, 40 with sexually transmitted diseases, 40 polytransfused, and from 50 unselected patients. The identification of SENV-DNA was performed by polymerase chain reaction and hybridization, followed by an immunoenzymatic method that identify different SENV strains. SENV-A variant is largely represented among HIV-infected patients, being found in 71% of HIV(+) intravenous drug users and in 26% of individuals that had acquired HIV through sex. A high prevalence of SENV-A was observed also in HIV- polytransfused (27%) or in patients with sexually transmitted diseases (30%). These percentages are significantly higher than those observed in an unselected population and in blood donors. Prevalence of SENV-A is, therefore, high among HIV(+) patients with parental risk of exposure, but this infection does not appear to influence the clinical or immune status of HIV(+) patients.


Preventive Dental Care Utilization in Asian Americans in Austin, Texas: Does Neighborhood Matter?
Although dental care is an essential component of comprehensive health care, a substantial proportion of the U.S. population lacks access to it. Disparities in dental care are most pronounced in racial/ethnic minority communities. Given the rapid population growth of Asian Americans, as well as the growing attention of neighborhood-level effects on health care use, the present study examines how individual-level variables (i.e., age, gender, marital status, ethnicity, education, place of birth, length of stay in the U.S., dental insurance, and self-rated oral health) and neighborhood-level variables (i.e., poverty level, density of Asian population, dentist availability, and Asian-related resources and services) contribute to predicting the use of preventive dental care in a sample of Asian Americans in Austin, TX. This study adds to the growing literature on the effect of neighborhood-level factors on health care as sources of disparities. Those living in the Census area with higher level of available dentists were more likely to use preventive dental care services. Findings suggest the importance of the location (proximity or accessibility) to dental clinics. In a planning perspective for health care policy, identifying the neighborhood with limited healthcare services could be a priority to diminish the disparity of the access.


Bottle-feeding and the Risk of Pyloric Stenosis.
Bottle-feeding has been suggested to increase the risk of pyloric stenosis (PS). However, large population-based studies are needed. We examined the effect of bottle-feeding during the first 4 months after birth, by using detailed data about the timing of first exposure to bottle-feeding and extensive confounder information. We performed a large population-based cohort study based on the Danish National Birth Cohort, which provided information on infants and feeding practice. Information about surgery for PS was obtained from the Danish National Patient Register. The association between bottle-feeding and the risk of PS was evaluated by hazard ratios (HRs) estimated in a Cox regression model, adjusting for possible confounders. Among 70148 singleton infants, 65 infants had surgery for PS, of which 29 were bottle-fed before PS diagnosis. The overall HR of PS for bottle-fed infants compared with not bottle-fed infants was 4.62 (95% confidence interval [CI]: 2.78-7.65). Among bottle-fed infants, risk increases were similar for infants both breast and bottle-fed (HR: 3.36 [95% CI: 1.60-7.03]), formerly breastfed (HR: 5.38 [95% CI: 2.88-10.06]), and never breastfed (HR: 6.32 [95% CI: 2.45-16.26]) (P = .76). The increased risk of PS among bottle-fed infants was observed even after 30 days since first exposure to bottle-feeding and did not vary with age at first exposure to bottle-feeding. Bottle-fed infants experienced a 4.6-fold higher risk of PS compared with infants who were not bottle-fed. The result adds to the evidence supporting the advantage of exclusive breastfeeding in the first months after birth.


Interneurons hyperpolarize pyramidal cells along their entire somatodendritic axis.
Although GABAergic interneurons are the main source of synaptic inhibition in the cortex, activation of GABA(A) receptors has been shown to depolarize specific neuronal compartments, resulting in excitation. By using a noninvasive approach to monitor the effect of individual interneurons on the pyramidal cell population, we found that rat hippocampal interneurons hyperpolarized pyramidal cells irrespective of the location of their synapses along the somato-dendritic axis.


Quantitative Genetics of DROSOPHILA MELANOGASTER. I. Sexual Dimorphism in Genetic Parameters for Wing Traits.
Sexual dimorphism in genetic parameters is examined for wing dimensions of Drosophila melanogaster. Data are fit to a quantitative genetic model where phenotypic variance is a linear function of additive genetic autosomal variance (common to both sexes), additive genetic X-linked variances distinct for each sex, variance due to common rearing environment of families, residual environmental variance, random error variance due to replication, and variance due to measurement error and developmental asymmetry (left vs. right sides). Polygenic dosage compensation and its effect on genetic variances and covariances between sexes is discussed. Variance estimates for wing length and other wing dimensions highly correlated with length support the hypothesis that the Drosophila system of dosage compensation will cause male X-linked genetic variance to be substantially larger than female X-linked variance. Results for various wing dimensions differ, suggesting that the level of dosage compensation may differ for different traits. Genetic correlations between sexes for the same trait are presented. Total additive genetic correlations are near unity for most wing traits; this indicates that selection in the same direction in both sexes would have a minor effect on changing the magnitude of difference between sexes. Additive X-linked correlations suggest some genotype x sex interactions for X-linked effects.


Pnck induces ligand-independent EGFR degradation by probable perturbation of the Hsp90 chaperone complex.
We have recently described a novel role for pregnancy-upregulated non-ubiquitous calmodulin kinase (Pnck) in the induction of ligand-independent epidermal growth factor receptor (EGFR) degradation (Deb TB, Coticchia CM, Barndt R, Zuo H, Dickson RB, and Johnson MD. Am J Physiol Cell Physiol 295: C365-C377, 2008). In the current communication, we explore the probable mechanism by which Pnck induces ligand-independent EGFR degradation. Pnck-induced EGFR degradation is calcium/calmodulin independent and is regulated by cell density, with the highest EGFR degradation observed at low cell density. Pnck is a novel heat shock protein 90 (Hsp90) client protein that can be co-immunoprecipitated with Hsp90. Treatment of Pnck-overexpressing cells with the pharmacologic Hsp90 inhibitor geldanamycin results in enhanced EGFR degradation, and destruction of Pnck. In cells in which Pnck is inducing EGFR degradation, we observed that Hsp90 exhibits reduced electrophoretic mobility, and through mass spectrometric analysis of immunopurified Hsp90 protein we demonstrated enhanced phosphorylation at threonine 89 and 616 (in both Hsp90-α and -β) and serine 391 (in Hsp90-α). Kinase-active Pnck protein is degraded by the proteasome, concurrent with EGFR degradation. A Pnck mutant (T171A) protein with suppressed kinase activity induced EGFR degradation to essentially the same level as wild-type (WT) Pnck, suggesting that Pnck kinase activity is not required for the induction of EGFR degradation. Although EGFR is degraded, overexpression of WT Pnck paradoxically promoted cellular proliferation, whereas cells expressing mutant Pnck (T171A) were growth inhibited. WT Pnck promoted S to G(2) transition, but cells expressing the mutant exhibited higher residency time in S phase. Basal MAP kinase activity was inhibited by WT Pnck but not by mutant T171A Pnck protein. Cyclin-dependent kinase (Cdk) inhibitor p21/Cip-1/Waf-1 was transcriptionally suppressed downstream to MAP kinase inhibition by WT Pnck, but not the mutant protein. Collectively, these data suggest that 1) Pnck induces ligand-independent EGFR degradation most likely through perturbation of Hsp90 chaperone activity due to Hsp90 phosphorylation, 2) EGFR degradation is coupled to proteasomal degradation of Pnck, and 3) modulation of basal MAP kinase activity, p21/Cip-1/Waf-1 expression, and cellular growth by Pnck is independent of Pnck-induced ligand-independent EGFR degradation.


Topological Nodal Cooper Pairing in Doped Weyl Metals.
We generalize the concept of Berry connection of the single-electron band structure to that of a two-particle Cooper pairing state between two Fermi surfaces with opposite Chern numbers. Because of underlying Fermi surface topology, the pairing Berry phase acquires nontrivial monopole structure. Consequently, pairing gap functions have topologically protected nodal structure as vortices in the momentum space with the total vorticity solely determined by the pair monopole charge q_{p}. The nodes of gap function behave as the Weyl-Majorana points of the Bogoliubov-de Gennes pairing Hamiltonian. Their relation with the connection patterns of the surface modes from the Weyl band structure and the Majorana surface modes inside the pairing gap is also discussed. Under the approximation of spherical Fermi surfaces, the pairing symmetry are represented by monopole harmonic functions. The lowest possible pairing channel carries angular momentum number j=|q_{p}|, and the corresponding gap functions are holomorphic or antiholomorphic functions on Fermi surfaces. After projected on the Fermi surfaces with nontrivial topology, all the partial-wave channels of pairing interactions acquire the monopole charge q_{p} independent of concrete pairing mechanism.


Sources of isocyanic acid (HNCO) indoors: a focus on cigarette smoke.
The sources and sinks of isocyanic acid (HNCO), a toxic gas, in indoor environments are largely uncharacterized. In particular, cigarette smoke has been identified as a significant source. In this study, controlled smoking of tobacco cigarettes was investigated in both an environmental chamber and a residence in Toronto, Canada using an acetate-CIMS. The HNCO emission ratio from side-stream cigarette smoke was determined to be 2.7 (±1.1) × 10-3 ppb HNCO/ppb CO. Side-stream smoke from a single cigarette introduced a large pulse of HNCO to the indoor environment, increasing the HNCO mixing ratio by up to a factor of ten from background conditions of 0.15 ppb. Although there was no evidence for photochemical production of HNCO from cigarette smoke in the residence, it was observed in the environmental chamber via oxidation by the hydroxyl radical (1.1 × 107 molecules per cm3), approximately doubling the HNCO mixing ratio after 30 minutes of oxidation. Oxidation of cigarette smoke by O3 (15 ppb = 4.0 × 1017 molecules per cm3) and photo-reaction with indoor fluorescent lights did not produce HNCO. By studying the temporal profiles of both HNCO and CO after smoking, it is inferred that gas-to-surface partitioning of HNCO acts as an indoor loss pathway. Even in the absence of smoking, the indoor HNCO mixing ratios in the Toronto residence were elevated compared to concurrent outdoor measurements by approximately a factor of two.


Acetyl Radical Generation in Cigarette Smoke: Quantification and Simulations.
Free radicals are present in cigarette smoke and can have a negative effect on human health. However, little is known about their formation mechanisms. Acetyl radicals were quantified in tobacco smoke and mechanisms for their generation were investigated by computer simulations. Acetyl radicals were trapped from the gas phase using 3-amino-2, 2, 5, 5-tetramethyl-proxyl (3AP) on solid support to form stable 3AP adducts for later analysis by high performance liquid chromatography (HPLC), mass spectrometry/tandem mass spectrometry (MS-MS/MS) and liquid chromatography-mass spectrometry (LC-MS). Simulations were performed using the Master Chemical Mechanism (MCM). A range of 10-150 nmol/cigarette of acetyl radical was measured from gas phase tobacco smoke of both commerial and research cigarettes under several different smoking conditions. More radicals were detected from the puff smoking method compared to continuous flow sampling. Approximately twice as many acetyl radicals were trapped when a glass filber particle filter (GF/F specifications) was placed before the trapping zone. Simulations showed that NO/NO2 reacts with isoprene, initiating chain reactions to produce hydroxyl radical, which abstracts hydrogen from acealdehyde to generate acetyl radical. These mechanisms can account for the full amount of acetyl radical detected experimentally from cigarette smoke. Similar mechanisms may generate radicals in second hand smoke.


Alcohol consumption and viral load are synergistically associated with CIN1.
We investigated the association between alcohol consumption and risk of cervical intraepithelial neoplasia (CIN) and cervical cancer, and determined whether these associations were modified by human papillomavirus (HPV) viral load in high-risk HPV-positive women participating in the Korean HPV cohort study (KHPV). Among the women recruited in the KHPV (n = 1,243) from March 2006 to December 2009, we analyzed normal cytology (n = 581) as control group, CIN1 (n = 299), CIN2/3 (n = 161), or cervical cancer (n = 202). Multinomial logistic analysis was performed to estimate multivariate-adjusted odds ratios (OR). Alcohol drinkers had an increased risk of CIN1 (OR = 2.18, 95% CI 1.22-3.89) compared with non-drinkers after adjusting for potential confounders. Subjects with more frequent alcohol consumption had a higher risk of CIN1 (p for linear trend <0.0001). Higher ethanol consumption was associated with an increased risk of CIN1 (p for linear trend = 0.0001). We also observed a synergistic effect between HPV viral load and alcohol consumption: drinkers with a high HPV viral load (≥100 RLU/PC) were associated with a significantly increased risk of CIN1 (OR = 19.1; 95% CI, 6.60-55.3, interaction p<0.001). There were no associations between alcohol drinking and CIN2/3 or cervical cancer. HPV viral load and alcohol was associated with the risk of CIN1 among high-risk HPV-positive women. This is the first demonstration that alcohol is an independent and combined risk factor of CIN1.


Viruses in the sea.
Viruses exist wherever life is found. They are a major cause of mortality, a driver of global geochemical cycles and a reservoir of the greatest genetic diversity on Earth. In the oceans, viruses probably infect all living things, from bacteria to whales. They affect the form of available nutrients and the termination of algal blooms. Viruses can move between marine and terrestrial reservoirs, raising the spectre of emerging pathogens. Our understanding of the effect of viruses on global systems and processes continues to unfold, overthrowing the idea that viruses and virus-mediated processes are sidebars to global processes.


Perceptions of quality of health care among veterans with psychiatric disorders.
An estimated 37% to 40% of veterans treated by the U.S. Department of Veterans Affairs (VA) have a psychiatric disorder, and many of them have comorbid general medical problems. This study examined the impact of demographic and clinical characteristics on perceptions of outpatient health care experiences among veterans with psychiatric disorders. Responses from the Survey of Health Care Experiences (SHEP) administered by the Veterans Health Administration (VHA) and administrative data from the VA were collected for 55,578 patients aged 18 and older with a psychiatric disorder surveyed in fiscal year 2005. Bivariate and multivariable analyses were used to examine the associations between demographic and clinical characteristics and patients' responses about providers' attentiveness, collaboration in health care decisions, confidence in providers, and overall quality of care. Most veterans with psychiatric disorders perceived their health care experiences positively. However, those who were younger, were nonwhite, had lower incomes, had a service-connected disability, and had been diagnosed as having PTSD or a substance use disorder were less likely to perceive their health care experiences positively. An opportunity exists to improve clinical practice and design health care services to better serve certain groups of patients at VHA facilities. Areas of improvement may include rapport building and developing ways to include patients in decisions about their health care.


Realist review--a new method of systematic review designed for complex policy interventions.
Evidence-based policy is a dominant theme in contemporary public services but the practical realities and challenges involved in using evidence in policy-making are formidable. Part of the problem is one of complexity. In health services and other public services, we are dealing with complex social interventions which act on complex social systems--things like league tables, performance measures, regulation and inspection, or funding reforms. These are not 'magic bullets' which will always hit their target, but programmes whose effects are crucially dependent on context and implementation. Traditional methods of review focus on measuring and reporting on programme effectiveness, often find that the evidence is mixed or conflicting, and provide little or no clue as to why the intervention worked or did not work when applied in different contexts or circumstances, deployed by different stakeholders, or used for different purposes. This paper offers a model of research synthesis which is designed to work with complex social interventions or programmes, and which is based on the emerging 'realist' approach to evaluation. It provides an explanatory analysis aimed at discerning what works for whom, in what circumstances, in what respects and how. The first step is to make explicit the programme theory (or theories)--the underlying assumptions about how an intervention is meant to work and what impacts it is expected to have. We then look for empirical evidence to populate this theoretical framework, supporting, contradicting or modifying the programme theories as it goes. The results of the review combine theoretical understanding and empirical evidence, and focus on explaining the relationship between the context in which the intervention is applied, the mechanisms by which it works and the outcomes which are produced. The aim is to enable decision-makers to reach a deeper understanding of the intervention and how it can be made to work most effectively. Realist review does not provide simple answers to complex questions. It will not tell policy-makers or managers whether something works or not, but will provide the policy and practice community with the kind of rich, detailed and highly practical understanding of complex social interventions which is likely to be of much more use to them when planning and implementing programmes at a national, regional or local level.


Major element variation and possible source materials of apollo 12 crystalline rocks.
Nine different crystalline rocks of the Apollo 12 samples have been analyzed with conventional chemical rock analysis methods. Five of the rocks have normative quartz, whereas the others have normative olivine and hypersthene. The rocks show a wide range in the ratio of iron to magnesium, and their compositions fall on relatively smooth curves in the oxide variation diagram. It is suggested that these rocks, with one exception, represent different parts of a differentiated magmatic body, in which magmatic differentiation by crystallization and settling of olivine was most effective. The source material of the original magma may be peridotite with or without minor amounts of plagioclase or spinel or garnet, with the presence or absence of these minerals dependent on the depth of magma generation.


The role of rosemary extract in degeneration of hippocampal neurons induced by kainic acid in the rat: A behavioral and histochemical approach.
Systemic Kainic Acid (KA) administration has been used to induce experimental temporal lobe epilepsy in rats. The aim of this study was to evaluate the neuroprotective effect of rosemary extract (RE, 40% Carnosic acid) against KA-induced neurotoxicity in hippocampus and impaired learning and memory. Animals received a single dose of KA (9.5 mg/kg) intraperitoneally (i.p.) (KA group) and were observed for 2 h and were scored from 0 (for normal, no convulsion) to 5 (for continuous generalized limbic seizures). RE (100 mg/kg, orally) was administered daily for 23 days, starting a week before KA injection (KA+RE group). Neuronal degeneration in hippocampus was demonstrated by using Fluoro-Jade B immunofluorescence. The number of pyramidal cells in hippocampus was evaluated by Nissl staining. Also, the Morris Water Maze and Shuttle box have been used to assess spatial memory and passive avoidance learning, respectively. Our results revealed that, after treatment with RE, neuronal loss in CA1 decreased significantly in the animals in KA+RE group. The Morris water navigation task results revealed that spatial memory impairment decreased in the animals in KA+RE group. Furthermore, results in Shuttle box test showed that passive avoidance learning impairment significantly, upgraded in the animals in KA+RE group. These results suggest that RE may improve the spatial and working memory deficits and also neuronal degeneration induced by toxicity of KA in the rat hippocampus, due to its antioxidant activities.


Hysteroscopy in the management of endometrial hyperplasia and cancer in reproductive aged women: new developments and current perspectives.
Over the last twenty years, the incidence of early endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) among women of reproductive age is increasing rapidly, likely due to a combination of factors including increased prevalence of obesity and delayed of childbirths. Regarding preoperative diagnosis of endometrial neoplasia, it is still debated which is the most accurate and reliable method to obtain endometrial histopathological samples with fractional dilatation and curettage (D&C) having been considered, for a long time, as the method of choice. Nowadays, the advent of in-office endometrial biopsy with or without hysteroscopy has radically changed the approach, giving the opportunity to perform the endometrial biopsy under direct visualization. However, the lack of agreement about its diagnostic accuracy is still relevant. Since a significant number of women with AEH and/or EC are of childbearing age, a fertility-sparing diagnostic and therapeutic approach should be considered in all cases. The feasibility, safety and efficacy of fertility-sparing strategies involving hysteroscopic focal resections in conjunction with hormonal therapies have been evaluated and beneficial effects have been confirmed in several studies and one meta-analysis. Both local and systemic administration of hormonal therapies are currently used. Oral progestin, including medroxyprogesterone acetate (MPA) and megestrol acetate, are the most commonly used therapies. Nowadays, new therapeutic approaches, such as levonorgestrel intrauterine systems (LNG-IUS), gonadotropin-releasing hormone (GnRH) agonists, combined megestrol acetate and metformin, and other combinations of therapies are also used as first line therapies or after the hysteroscopic resection of the lesion. However, it is still unclear which approach provides higher clinical response with lower relapse rate, in addition to preserving fertility in women desiring to conceive. The aim of this narrative review is to summarize the available evidence regarding the evaluation and management with fertility-sparing treatments options of women with AEC and EC.


Asymmetric and symmetric dimethylarginines and mortality in patients with hematological malignancies-A prospective study.
The study was designed to determine the associations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginines plasma concentrations with all-cause mortality in patients with hematological malignancies. 33 patients with acute myeloid leukemia (AML), 31 patients with non-Hodgkin's lymphoma (nHL), 32 patients with chronic lymphocytic leukemia (CLL) and 48 patients without malignancy were enrolled into the study. Each patient was followed until death or for at least 14.5 months (range: 14.5-53). Median ADMA and SDMA were significantly elevated in AML, nHL and CLL compared to controls (ADMA: 1.36, 1.24, 1.03, 0.55 μmol/l respectively, p<0.0001; SDMA: 0.86, 0.76, 0.71, 0.52 μmol/l respectively, p<0.0001). High ADMA and SDMA were associated with increased risk for all-cause mortality in CLL group (Hazard ratio (HR) for ADMA: 3.05, 95% CI:1.58-5.88, p = 0.001; HR for SDMA: 4.71, 95% CI:1.91-11.58, p = 0.001). Our study suggests that ADMA and SDMA could be novel prognostic factors for all-cause mortality in CLL patients.


Diet and risk of non-Hodgkin lymphoma in older women.
To test whether high dietary intakes of fat, protein, and milk are associated with the development of non-Hodgkin lymphoma in older women. Prospective cohort study with a 7-year follow-up period. General community. Sample of 35 156 Iowa women aged 55 to 69 years with no prior history of cancer who returned the 1986 baseline questionnaire. Non-Hodgkin lymphoma (104 incident cases). After controlling for age, marital status, residence, total energy intake, and transfusion history, the relative risks (RRs) for the highest tertile of intake compared with the lowest were 2.00 (95% confidence interval [CI], 1.21-3.30; P for trend = .01) for animal fat, 1.69 (95% CI, 1.07-2.67; P for trend = .02) for saturated fat, and 1.90 (95% CI, 1.18-3.04; P for trend = .01) for monounsaturated fat, and there was no association with vegetable fat or polyunsaturated fat. Greater intake of animal protein (RR = 1.52; 95% CI, 0.94-2.44; P for trend = .08), but not vegetable protein, was associated with elevated risk, and this was mainly explained by greater consumption of red meat (RR = 1.98; 95% CI, 1.13-3.47; P for trend = .02) and hamburger in particular (RR = 2.35; 95% CI, 1.23-4.48; P for trend = .02). Milk and dairy product consumption were not associated with elevated risk. There was also a decreased risk of non-Hodgkin lymphoma with greater consumption of fruits (RR = 0.64; 95% CI, 0.40-1.05; P for trend = .07). A high-meat diet and a high intake of fat from animal sources is associated with an increased risk of non-Hodgkin lymphoma in older women.


Causes of mortality in farmed mink in the Intermountain West, North America.
The primary causes of mortality were identified in postmortem examination of 339 (90.9%) of 373 farmed mink (Neovison vison; syn. Mustela vison) from January 2009 through June 2014 at the Utah Veterinary Diagnostic Laboratory (Logan, Utah). Mink were raised under farm conditions in the Intermountain West in North America, except for 1 submission of mink from Wisconsin. In the 339 mink where cause(s) of death were established, 311 (91.7%) died from a single disease or condition, whereas 28 (8.3%) had 2 diseases or conditions contributing to death. Where cause(s) of death were evident, 11 diseases accounted for 321 (94.7%) of the diagnoses: bacterial pneumonia (67, 18.8%), Aleutian mink disease (61, 17.7%), mink viral enteritis (56, 16.2%), hepatic lipidosis (28, 8.1%), nutritional myopathy (24, 7%), bacterial enterocolitis (17, 4.9%), bacterial septicemia (16, 4.6%), starvation (15, 4.3%), epizootic catarrhal gastroenteritis of mink (14, 4.1%), pancreatitis (13, 3.8%), and bacterial metritis (10, 2.9%). In 34 (9.1%) animals, a cause of death was not evident. In an additional 16 (4.3%) of the mink, botulism was suspected from clinical history but could not be confirmed by laboratory testing. Control measures for the most common causes of death in farmed mink include testing and removal of positive animals (Aleutian mink disease), vaccination (Pseudomonas aeruginosa pneumonia, mink viral enteritis), avoidance of obesity in mink (hepatic lipidosis), and environmental management, including maintaining clean water cups, floors, feed troughs, cages, feed silos, feed truck tires, workers' shoes, dining areas for farm personnel, leather mink handling gloves, street clothes, and coveralls.


Repolarization abnormalities in survivors of out-of-hospital ventricular fibrillation.
Survivors of out-of-hospital ventricular fibrillation (VF) are at high risk for recurrent VF, probably reflecting continued myocardial electrical instability. In this study 12-lead ECGs of 125 VF survivors with coronary heart disease were examined and compared to those of 98 ambulatory post-MI patients. The study was part of an effort to define clinical identifiers of patients likely to develop sudden cardiac death. Ventricular fibrillation survivors were commonly had premature ventricular complexes (PVCs):30% versus 13% (P less than 0.01). In addition, ECGs of VF survivors showed a significantly greater prevalence of ST-segment depression (46% versus 10%), T wave flattening (52% versus 26%), and QTc prolongation (35% versus 18%). It is proposed that these repolarization abnormalities represent asynchronous repolarization, which together with frequent PVCs, may set the stage for re-entrant ventricular dysrhythmias and ultimately VF. It is also possible that repolarization abnormalities together with premature ventricular contractions might serve as markers of patients with coronary heart disease who are at increased risk for sudden cardiac death.


Surveillance after treatment for cervical intraepithelial neoplasia: outcomes, costs, and cost-effectiveness.
To estimate outcomes and costs of surveillance strategies after treatment for high-grade cervical intraepithelial neoplasia (CIN). A hypothetical cohort of women was evaluated after treatment for CIN 2 or 3 using a Markov model incorporating data from a large study of women treated for CIN, systematic reviews of test accuracy, and individual preferences. Surveillance strategies included initial conventional or liquid-based cytology, human papillomavirus testing, or colposcopy 6 months after treatment, followed by annual or triennial cytology. Estimated outcomes included CIN, cervical cancer, cervical cancer deaths, life expectancy, costs, cost per life-year, and cost per quality-adjusted life-year. Conventional cytology at 6 and 12 months, followed by triennial cytology, was least costly. Compared with triennial cytology, annual cytology follow-up reduced expected cervical cancer deaths by 73% to 77% and had an average incremental cost per life-year gained of $69,000 to $81,000. For colposcopy followed by annual cytology, the incremental cost per life-year gained ranged from $70,000 to more than $1 million, depending on risk. Between-strategy differences in mean additional life expectancy per woman were less than 4 days; differences in mean incremental costs per woman were as high as $822. In the cost-utility analysis, colposcopy at 6 months followed by annual cytology had an incremental cost per quality-adjusted life-year of less than $5,500. Human papillomavirus testing or liquid-based cytology added little to no improvement to life-expectancy with higher costs. Annual conventional cytology surveillance reduced cervical cancers and cancer deaths compared with triennial cytology. For high risk of recurrence, a strategy of colposcopy at 6 months increased life expectancy and quality-adjusted life expectancy. Human papillomavirus testing and liquid-based cytology increased costs, but not effectiveness, compared with traditional approaches.


Pharmacotherapy Update and Review for Family Medicine Residents Using Jeopardy-Style Game.
Pharmacotherapy is an important, required aspect of family medicine residency training. MedEdPORTAL has very limited pharmacotherapy content that is targeted to a graduate medical education audience. I implemented a Jeopardy-style game during a 1-hour didactic session to actively engage the family medicine residents. The game focused on reinforcing guidelines and teaching new medications. I created a session-specific evaluation tool to assess the residents' enjoyment of and learning from the activity. Twenty-six family medicine residents participated in the session, working in groups of three or four. I evaluated the session using the session-specific evaluation tool and a standard didactics evaluation. Twenty-three of 26 residents completed the session-specific evaluation; all 26 completed the standard evaluation. All the residents agreed or strongly agreed that the session was enjoyable, an opportunity for learning, and something they would look forward to in the future. All the residents also agreed that the information presented applied to clinical practice. Comments primarily focused on the difficulty of the questions and the enjoyment of the session. Based upon the results of the evaluations and comments, the residents felt the session was a valuable opportunity for learning. The session could be easily implemented by other family medicine or internal medicine programs. The tool can and should be updated as required to remain accurate and current.


Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau.
Fyn kinase plays an important role during myelination and has been shown to promote morphological differentiation of cultured oligodendrocytes. We analyzed the downstream targets of Fyn kinase in oligodendrocytes. Because process outgrowth and wrapping of axons involve cytoskeletal rearrangement, we focused on cytoskeletal proteins linked to Fyn. Here we demonstrate that Fyn binds to the cytoskeletal proteins Tau and alpha-Tubulin in oligodendrocytes. Tau interacts with the Fyn SH3 domain whereas alpha-Tubulin binds to the Fyn SH2 and SH3 domains. To study the function of the Fyn-Tau interaction in oligodendrocytes, we designed a Tau deletion mutant that would compete with endogenous Tau-Fyn binding in transfected cells. The mutant Tau protein binds to the Fyn SH3 domain but lacks the microtubuli interaction domain and thus cannot bind to microtubuli. In the presence of the mutant Tau protein, a reduction of the process number and process length in oligodendroglial cells was observed. This effect is likely to be caused by interference with the Fyn-Tau-microtubuli cascade rather than inactivation of the kinase, because Fyn bound to the mutant Tau retains activity. A similar inhibition of process outgrowth was observed when oliogodendroglial cells were cultured in the presence of Fumonisin B1, an inhibitor of sphingolipid synthesis that prevents the formation of rafts. Because ligation of the cell adhesion molecule F3 on oligodendrocytes leads to activation of Fyn kinase localized in rafts, these findings suggest that recruitment of Tau and Tubulin to activated Fyn kinase in rafts is an important step in the initiation of myelination.


Pathophysiologic mechanisms of persistent cardiac troponin I elevation in stabilized patients after an episode of acute coronary syndrome.
Recently, a high prevalence of small persistent cardiac troponin I (cTnI) elevations has been reported in patients who had been stabilized after a recent episode of acute coronary syndrome (ACS). We now have studied the associations of persistently elevated cTnI levels to cardiac performance, inflammation, coagulation, coronary status, and treatment strategy in these patients. Cardiac troponin I was determined at 6 weeks, 3 months, and 6 months after randomization in 898 stabilized ACS patients from the FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC) II trial and using the high-sensitive Access AccuTnI assay (Beckman Coulter, Fullerton, CA). All patients were followed up for at least 5 years. Persistent cTnI elevation >0.01 microg/L at the 3 measurement instances was detected in 233 patients (26%). N-terminal pro-brain natriuretic peptide (NT-proBNP) at 6 months (OR 2.5, 95% CI 2.0-3.1), male sex (OR 2.2, 95% CI 1.4-3.7), and randomization to an early invasive strategy (OR 1.8, 95% CI 1.2-2.7) independently predicted persistently elevated cTnI levels. Persistently cTnI-positive patients in the invasive cohort had significantly lower NT-proBNP levels compared to noninvasively treated patients, indicating that the mechanisms causing cTnI elevation in this group may be prognostically less harmful. No independent associations were found for markers of inflammation or coagulation. Persistent cTnI elevation occurs frequently late after an ACS. The NT-proBNP level at 6 months was the strongest predictor for elevated cTnI levels that thus appear to be predominantly related to impaired left ventricular function.


El Niño-based malaria epidemic warning for Oromia, Ethiopia, from August 2016 to July 2017.
Tropical highland malaria intensifies and shifts to higher altitudes during exceptionally warm years. Above-normal temperatures associated with El Niño during boreal winter months (December-March) may intensify malaria in East African highlands. We assessed the malaria risk for Oromia, the largest region of Ethiopia with around 30 million inhabitants. Simple linear regression and spatial analyses were used to associate sea surface temperatures (SST) in the Pacific and surface temperatures in Ethiopia with annual malaria risk in Oromia, based on confirmed cases of malaria between 1982 and 2005. A strong association (R2 = 0.6, P < 0.001) was identified between malaria and sea surface temperatures in the Pacific, anticipating a 70% increase in malaria risk for the period from August 2016 to July 2017. This forecast was quantitatively supported by elevated land surface temperatures (+1.6 °C) in December 2015. When more station data become available and mean March 2016 temperatures from meteorological stations can be taken into account, a more robust prediction can be issued. An epidemic warning is issued for Oromia, Ethiopia, between August 2016 and July 2017 and may include the pre-July short malaria season. Similar relationships reported for Madagascar point to an epidemic risk for all East African highlands with around 150 million people. Preparedness for this high risk period would include pre-emptive intradomestic spraying with insecticides, adequate stocking of antimalarials, and spatial extension of diagnostic capacity and more frequent reporting to enable a rapid public health response when and where required.


Identification of novel gene expression in healing fracture callus tissue by DNA microarray.
Fracture healing requires controlled expression of thousands of genes. Only a small fraction of these genes have been isolated and fewer yet have been shown to play a direct role in fracture healing. The purpose of this study was threefold: (1) to develop a reproducible open femur model of fracture healing that produces consistent fracture calluses for subsequent RNA extraction, (2) to use this model to determine temporal expression patterns of known and unknown genes using DNA microarray expression profiling, and (3) to identify and validate novel gene expression in fracture healing. In the initial arm of the study, a total of 56 wild-type C57BL/6 mice were used. An open, stabilized diaphyseal femur fracture was created. Animals were killed at 1, 5, 7, 10, 14, 21, and 35 days after surgery and the femurs were harvested for analysis. At each time point, fractures were radiographed and sectioned for histologic analyses. Tissue from fracture callus at all stages following fracture yielded reproducibly large amounts of mRNA. Expression profiling revealed that genes cluster by function in a manner similar to the histologic stages of fracture healing. Based on the expression profiling of fracture tissue, temporal expression patterns of several genes known to be involved in fracture healing were verified. Novel expression of multiple genes in fracture callous tissue was also revealed including leptin and leptin receptor. In order to test whether leptin signaling is required for fracture repair, mice deficient in leptin or its receptor were fractured using the same model. Fracture calluses of mice deficient in both leptin or leptin receptor are larger than wild-type mice fractures, likely due to a delay in mineralization, revealing a previously unrecognized role of leptin signaling in fracture healing. This novel model of murine fracture repair is useful in examining both global changes in gene expression as well as individual signaling pathways, which can be used to identify specific molecular mechanisms of fracture healing.


How Neighborhood Poverty Structures Types and Levels of Social Integration.
Social integration is fundamental to health and well-being. However, few studies have explored how neighborhood contexts pattern types and levels of social integration that individuals experience. We examined how neighborhood poverty structures two dimensions of social integration: integration with neighbors and social integration more generally. Using data from the United States Third National Health and Nutrition Examination Survey, we linked study participants to percent poverty in their neighborhood of residence (N = 16,040). Social integration was assessed using a modified Social Network Index and neighborhood integration based on yearly visits with neighbors. We fit multivariate logistic regression models that accounted for the complex survey design. Living in high poverty neighborhoods was associated with lower social integration but higher visits with neighbors. Neighborhood poverty distinctly patterns social integration, demonstrating that contexts shape the extent and quality of social relationships.


A phenomenological model of the synapse between the inner hair cell and auditory nerve: long-term adaptation with power-law dynamics.
There is growing evidence that the dynamics of biological systems that appear to be exponential over short time courses are in some cases better described over the long-term by power-law dynamics. A model of rate adaptation at the synapse between inner hair cells and auditory-nerve (AN) fibers that includes both exponential and power-law dynamics is presented here. Exponentially adapting components with rapid and short-term time constants, which are mainly responsible for shaping onset responses, are followed by two parallel paths with power-law adaptation that provide slowly and rapidly adapting responses. The slowly adapting power-law component significantly improves predictions of the recovery of the AN response after stimulus offset. The faster power-law adaptation is necessary to account for the "additivity" of rate in response to stimuli with amplitude increments. The proposed model is capable of accurately predicting several sets of AN data, including amplitude-modulation transfer functions, long-term adaptation, forward masking, and adaptation to increments and decrements in the amplitude of an ongoing stimulus.


Cloned human neuropeptide Y receptor couples to two different second messenger systems.
Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammalian nervous system and exhibits a diverse range of important physiological activities, including effects on psychomotor activity, food intake, regulation of central endocrine secretion, and potent vasoactive effects on the cardiovascular system. Two major subtypes of NPY receptor (Y1 and Y2) have been defined by pharmacological criteria. We report here the molecular cloning of a cDNA sequence encoding a human NPY receptor and the corrected sequence for a rat homologue. Analysis of this sequence confirms that the receptor is a member of the G protein-coupled receptor superfamily. When expressed in Chinese hamster ovary (CHO) or human embryonic kidney (293) cells, the receptor exhibits the characteristic ligand specificity of a Y1 type of NPY receptor. In the 293 cell line, the receptor is coupled to a pertussis toxin-sensitive G protein that mediates the inhibition of cyclic AMP accumulation. In the CHO cell line, the receptor is coupled not to the inhibition of adenylate cyclase but rather to the elevation of intracellular calcium. These results demonstrate that second messenger coupling of the NPY-Y1 receptor is cell type specific, depending on the specific repertoire of G proteins and effector systems present in any cell type.


New pathogenic insights into rheumatoid arthritis.
Rheumatoid arthritis (RA) is a heterogeneous chronic immune-mediated inflammatory disease, associated with significant morbidity and reduced life expectancy. Here, we review recent discoveries; particularly those which have attempted to integrate genome-wide association studies (GWAS) with biological pathways and cell types known to play a role in disease pathology in order to expand our current understanding of the pathogenesis of RA. As the role of stromal cells in the pathogenesis of RA has been reviewed in detail in Current Opinions in Rheumatology, this area will not be covered in this review. Although our understandings of the pathogenic processes that drive disease in RA remain incomplete, remarkable advances over the past year can be highlighted. GWAS have raised awareness of important new risk loci with genes that either are the targets of approved therapies for RA, or involve pathways for drugs that could be repurposed from other disease indications such as cancer. Furthermore, promising strides have been made in predicting the likelihood of developing RA in those at risk using human leukocyte antigen (HLA), smoking, and autoantibody status prediction models. These findings give a fresh insight into RA pathogenesis and help identify new, or repurpose known therapeutic targets from other disease areas. The findings discussed in this review underscore the progress made to date and the need for future studies, investigating disease mechanisms in RA, with particular interest in at-risk RA gene loci, their function in immune and stromal cells within the synovium, and how they interact with environmental factors to initiate and perpetuate disease.


Periodontal treatment effects on endothelial function and cardiovascular disease biomarkers in subjects with chronic periodontitis: protocol for a randomized clinical trial.
Periodontal disease (PD) is an infectious clinical entity characterized by the destruction of supporting tissues of the teeth as the result of a chronic inflammatory response in a susceptible host. It has been proposed that PD as subclinical infection may contribute to the etiology and to the pathogenesis of several systemic diseases including Atherosclerosis. A number of epidemiological studies link periodontal disease/edentulism as independent risk factor for acute myocardial infarction, peripheral vascular disease, and cerebrovascular disease. Moreover, new randomized controlled clinical trials have shown an improvement on cardiovascular surrogate markers (endothelial function, sICAM, hsPCR level, fibrinogen) after periodontal treatment. Nonetheless, such trials are still limited in terms of external validity, periodontal treatment strategies, CONSORT-based design and results consistency/extrapolation. The current study is designed to evaluate if periodontal treatment with scaling and root planning plus local delivered chlorhexidine improves endothelial function and other biomarkers of cardiovascular disease in subjects with moderate to severe periodontitis. This randomized, single-blind clinical trial will be performed at two health centers and will include two periodontal treatment strategies. After medical/periodontal screening, a baseline endothelium-dependent brachial artery flow-mediated dilatation (FMD) and other systemic surrogate markers will be obtained from all recruited subjects. Patients then will be randomized to receive either supragingival/subgingival plaque cleaning and calculus removal plus chlorhexidine (treatment group) or supragingival plaque removal only (control group). A second and third FMD will be obtained after 24 hours and 12 weeks in both treatment arms. Each group will consist of 49 patients (n = 98) and all patients will be followed-up for secondary outcomes and will be monitored through a coordinating center. The primary outcomes are FMD differences baseline, 24 hours and 3 months after treatment. The secondary outcomes are differences in C-reactive protein (hs-CRP), glucose serum levels, blood lipid profile, and HOMA index. This RCT is expected to provide more evidence on the effects of different periodontal treatment modalities on FMD values, as well as to correlate such findings with different surrogate markers of systemic inflammation with cardiovascular effects. ClinicalTrials.gov Identifier: NCT00681564.