The selectivity of charged phenyl radicals in hydrogen atom abstraction reactions with isopropanol.
The vertical electron affinity is demonstrated to be a key factor in controlling the selectivity of charged phenyl radicals in hydrogen atom abstraction from isopropanol in the gas phase. The measurement of the total reaction efficiencies (hydrogen and/or deuterium atom abstraction) for unlabeled and partially deuterium-labeled isopropanol, and the branching ratios of hydrogen and deuterium atom abstraction, by using a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer, allowed the determination of the selectivity for each site in the unlabeled isopropanol. Examination of hydrogen atom abstraction from isopropanol by eight structurally different radicals revealed that the preferred site is the CH group. The selectivity of the charged phenyl radicals correlates with the radical's vertical electron affinity and the reaction efficiency. The smaller the vertical electron affinity of a radical, the lower its reactivity, and the greater the preference for the thermodynamically favored CH group over the CH3 group or the OH group. As the vertical electron affinity increases from 4.87 to 6.28 eV, the primary kinetic isotope effects decrease from 2.9 to 1.3 for the CD group, and the mixture of primary and alpha-secondary kinetic isotopes decreases from 6.0 to 2.4 for the CD3 group.


Development of an injectable thiolated icariin functionalized collagen/hyaluronic hydrogel to promote cartilage formation in vitro and in vivo.
Development of an in situ injectable hydrogel with controlled-release of bioactive molecules is an effective strategy to maintain chondrocyte phenotype and promote cartilage formation for clinical applications. In this study, we developed an injectable thiolated icariin functionalized hyaluronic acid/collagen hydrogel (HIC) under physiological conditions. In order to covalently introduce icariin (Ica) into an injectable hydrogel and increase its loading, thiolated icariin (Ica-SH) was successfully synthesized. Ica-SH could not only decrease the cytotoxicity of Ica, but also increase the Ica loading in hydrogels. Compared to hyaluronic acid/collagen hydrogels, HICs facilitated chondrocyte proliferation, maintained chondrocyte phenotype and promoted the secretion of the cartilage extracellular matrix. Overall, this study suggests that HIC has great potential to be developed as an effective and less invasive candidate for clinical application in articular cartilage repair.


Surgical advances for extracranial carotid stenosis.
Carotid endarterectomy is a commonly performed operation to prevent stroke in patients who have asymptomatic or symptomatic internal carotid artery atherosclerotic stenosis. Carotid angioplasty and stenting has also been advocated for treatment of these patients. In this article, we address a number of questions for which a review of available data will advance our understanding of the role of carotid endarterectomy in stroke prevention. These include the following: Are carotid endarterectomy and carotid angioplasty and stenting equivalent procedures for the treatment of carotid artery disease? Which patients should be deemed at high risk for carotid endarterectomy? Should carotid endarterectomy be an urgent procedure in symptomatic patients with severe internal carotid artery stenosis? Finally, what is the role of carotid endarterectomy in asymptomatic patients? We also review the senior author's personal experience with >2000 consecutive carotid endarterectomies, with special attention to his present approach to this operation. We believe that carotid endarterectomy, in experienced hands, is a minimally invasive operation that remains the procedure of choice for most patients with carotid artery disease who will benefit from invasive treatment.


First human experience with autologous Schwann cells to supplement sciatic nerve repair: report of 2 cases with long-term follow-up.
OBJECTIVE Long-segment injuries to large peripheral nerves present a challenge to surgeons because insufficient donor tissue limits repair. Multiple supplemental approaches have been investigated, including the use of Schwann cells (SCs). The authors present the first 2 cases using autologous SCs to supplement a peripheral nerve graft repair in humans with long-term follow-up data. METHODS Two patients were enrolled in an FDA-approved trial to assess the safety of using expanded populations of autologous SCs to supplement the repair of long-segment injuries to the sciatic nerve. The mechanism of injury included a boat propeller and a gunshot wound. The SCs were obtained from both the sural nerve and damaged sciatic nerve stump. The SCs were expanded and purified in culture by using heregulin β1 and forskolin. Repair was performed with sural nerve grafts, SCs in suspension, and a Duragen graft to house the construct. Follow-up was 36 and 12 months for the patients in Cases 1 and 2, respectively. RESULTS The patient in Case 1 had a boat propeller injury with complete transection of both sciatic divisions at midthigh. The graft length was approximately 7.5 cm. In the postoperative period the patient regained motor function (Medical Research Council [MRC] Grade 5/5) in the tibial distribution, with partial function in peroneal distribution (MRC Grade 2/5 on dorsiflexion). Partial return of sensory function was also achieved, and neuropathic pain was completely resolved. The patient in Case 2 sustained a gunshot wound to the leg, with partial disruption of the tibial division of the sciatic nerve at the midthigh. The graft length was 5 cm. Postoperatively the patient regained complete motor function of the tibial nerve, with partial return of sensation. Long-term follow-up with both MRI and ultrasound demonstrated nerve graft continuity and the absence of tumor formation at the repair site. CONCLUSIONS Presented here are the first 2 cases in which autologous SCs were used to supplement human peripheral nerve repair in long-segment injury. Both patients had significant improvement in both motor and sensory function with correlative imaging. This study demonstrates preliminary safety and efficacy of SC transplantation for peripheral nerve repair.


[Giant retroperitoneal tumors: a 13.5 kg liposarcoma case report].
Retroperitoneal sarcomas (RS) are a rare group of malignant soft-tissue tumors. They generally grow until they reach large size before becoming symptomatic, often involving surrounding structures. The paper reports the case of a particularly large retroperitoneal liposarcoma (diameter: 48 x 44 x 32 cm, weight: 13.500 kg) surgically treated in a 92-year old woman: the patient tolerated the procedure well and was discharged after a short hospitalization. The paper, moreover, focuses on the diagnostic and therapeutic aspects of this tumour. The need for radical surgery to remove the entire mass is certain, even if it is particularly large; furthermore, the patient must be carefully monitored since retroperitoneal recurrence is frequent and must be treated, wherever possible, surgically. After a review of the literature there is an evidence that higher tumor grade, non-liposarcoma histology, advanced stage, incomplete surgical resection, and microscopic infiltration of surgery resection margins were found to be significantly negative prognostic factors. The study underlines the role of liposarcoma surgery management in order to offer the best chance of long-term survival and, especially on elderly patients, a better quality of life.


Caring for pregnant opioid abusers in Vermont: A potential model for non-urban areas.
Opioid addiction is no longer a primarily urban problem. As dependence on heroin and prescription pain relievers has become a significant issue in rural areas, the need for effective treatment of opioid-dependent pregnant women and their neonates has grown accordingly. In addition to the adverse perinatal outcomes associated with opioid addiction in pregnant women, the high costs of caring for these mothers and their babies motivate efforts to develop appropriate treatment models. We found that integration and coordination of services that promote maternal recovery and ability to parent are key requirements for treatment of opioid dependence during pregnancy. Unfortunately, lack of experience and resources makes such coordination a real challenge in rural areas. In this review, we discuss how we managed the challenges of developing a comprehensive program for treatment of opioid dependence during pregnancy. In addition, we outline our approach for facilitating the development of community-based programs to help these patients and families in rural regions of Vermont. Close relationships between our tertiary care center, local hospitals, community health care infrastructure, and legislators bolstered our efforts. In particular, appreciation for the severity and importance of the opioid-dependence problem in Vermont among health care providers and state legislators was paramount for our success in developing a state-wide treatment program. This approach can inform similar efforts in other rural regions of the United States, and has great potential to improve both access and quality of care for women struggling with opioid dependence.


Video analysis of sensory-motor features in infants with fragile X syndrome at 9-12 months of age.
This study utilized retrospective video analysis to distinguish sensory-motor patterns in infants with fragile X syndrome (FXS) (n = 11) from other infants [i.e., autism (n = 11), other developmental delay (n = 10), typical (n = 11)] at 9-12 months of age. Measures of development, autistic features, and FMRP were assessed at the time of entry into the study. Home videos collected from families were edited and coded with previously validated procedures. Findings revealed a pattern of sensory-motor features (e.g., repetitive leg movements, posturing, less sophistication/repetitive use of objects) associated with FXS, and suggest these infants were most similar to the group of infants with other developmental delays, irrespective of co-existing autistic symptoms later in life. Infant sensory-motor features in the FXS group were more predictive of an early developmental milestone (i.e., age walking) than later, more broad, developmental outcomes, or FMRP. Implications for early identification and differential diagnosis are discussed.


Lung cancer mortality among workers in the European production of man-made mineral fibers--a Poisson regression analysis.
One hundred and eighty-one lung cancer deaths among workers during 301,085 person-years in European man-made mineral fiber production between 1930-1955 and 1982 were analyzed according to Poisson regression models including age, calendar period, country, and exposure variables. Time since first employment was the variable most strongly associated with lung cancer risk in both the rock-slag wool and glass wool subcohorts. Workers in the early technological phase were at higher risk than those in other categories, particularly in rock-slag wool production. No clear trend with duration of employment was suggested. No major changes occurred in the interpretation of the results when workers with less than one year of employment or less than 20 years since first exposure were excluded. The original results, based on analyses for standardized mortality ratios, were confirmed, and workers with a short duration of employment or a short time since first employment did not need to be excluded from the analysis.


Respiratory failure following delayed intrathecal morphine pump refill: a valuable, but costly lesson.
Spinal analgesia, mediated by opioid receptors, requires only a fraction of the opioid dose that is needed systemically. By infusing a small amount of opioid into the cerebrospinal fluid in close proximity to the receptor sites in the spinal cord, profound analgesia may be achieved while sparing some of the side effects due to systemic opioids. Intraspinal drug delivery (IDD) has been increasingly used in patients with intractable chronic pain, when these patients have developed untoward side effects with systemic opioid usage. The introduction of intrathecal opioids has been considered one of the most important breakthroughs in pain management in the past three decades. A variety of side effects associated with the long-term usage of IDD have been recognized. Among them, respiratory depression is the most feared. To describe a severe adverse event, i.e., respiratory failure, following delayed intrathecal morphine pump refill. A 65-year-old woman with intractable chronic low back pain, due to degenerative disc disease, and was referred to our clinic for an intraspinal drug delivery evaluation, after failing to respond to multidisciplinary pain treatment. Following a psychological evaluation confirming her candidacy, she underwent an outpatient patient-controlled continuous epidural morphine infusion trial. The infusion trial lasted 12 days and was beneficial in controlling her pain. The patient reported more than 90% pain reduction with improved distance for ambulation. She subsequently consented and was scheduled for permanent intrathecal morphine pump implantation. The intrathecal catheter was inserted at right paramedian L3-L4, with catheter tip advanced to L1, confirmed under fluoroscopy. Intrathecal catheter placement was confirmed by positive CSF flow and by myelogram. A non-programmable Codman 3000 constant-flow rate infusion pump was placed in the right mid quandrant between right rib cage and right iliac crest. The intrathecal infusion consisted of preservative free morphine, delivering 1.0 mg /day. Over the following 6 months, the dosage was gradually titrated up to 4 mg/day with satisfactory pain control without significant side effects. However, the patient was not able to return to the clinic for pump refill until 12 days later than the previously scheduled pump-refill date. Her pump was accessed and was noted to be empty. Her intrathecal pump was refilled with preservative free morphine, delivering 4 mg/day (the same daily dose as her previous refill). However, on the night of pump refill, 10 hours after the pump refill, the patient was found to be unresponsive by her family members. 911 was called. Upon arriving, paramedics found her in respiratory failure, with shallow breathing at a rate of 5/min, pulse oxymetry showing oxygen saturation about 55-58%. She was emergently intubated on site and rushed to local hospital ER. The on call physician for our clinic was immediately contacted, and advised the administration of intravenous Naloxone. Her respiratory effort improved dramatically after receiving a total of 0.6 mg IV Naloxone IV over 25 minutes. Her intrathecal pump was immediately accessed by clinic on call physician and the remainder of the medication in the catheter space was aspirated. The pump infusate was immediately diluted with preservative free normal saline, to deliver preservative free morphine at 1mg/day. She was transferred to the intensive care unit and extubated the next morning. She recovered fully without any sequelae. Loss of opioid tolerance due to delayed pump refill may subject patients to the development of severe respiratory depression. Meticulous approach should be employed when refilling pumps in these patients when their pumps are completely empty. To our knowledge, this is the first reported case of this type.


The Mlc1 Promoter Directs Müller Cell-specific Gene Expression in the Retina.
Because the importance of glia in regulating brain functions has been demonstrated, genetic technologies that manipulate glial cell-specific gene expression in the brain have become essential and have made great progress. However, it is unknown whether the same strategy that is used in the brain can be applied to the retina because retinal glia differs from glia in the brain. Here, we aimed to find a method for selective gene expression in Müller cells (characteristic glial cells in the retina) and identified Mlc1 as a specific promoter of Müller cells. Mlc1-tTA::Yellow-Cameleon-NanotetO/tetO (YC-Nano) mice were used as a reporter line. YC-Nano, a fluorescent protein, was ectopically expressed in the cell type controlled by the Mlc1 promotor. Immunofluorescence staining was used to identify the cell type expressing YC-Nano protein. YC-Nano-positive (+) signals were observed as vertical stalks in the sliced retina and spanned from the nerve fiber layer through the outer nuclear layer. The density of YC-Nano+ cells was higher around the optic nerve head and lower in the peripheral retina. The YC-Nano+ signals colocalized with vimentin, a marker of Müller cells, but not with the cell markers for blood vessels, microglia, neurons, or astrocytes. The Mlc1 promoter allows us to manipulate gene expression in Müller cells without affecting astrocytes in the retina. Gene manipulation under control of Mlc1 promoter offers novel technique to investigate the role of Müller cells.


Acute high-intensity interval exercise reduces human monocyte Toll-like receptor 2 expression in type 2 diabetes.
Type 2 diabetes (T2D) is characterized by chronic low-grade inflammation that contributes to disease pathophysiology. Exercise has anti-inflammatory effects, but the impact of high-intensity interval training (HIIT) is not known. The purpose of this study was to determine the impact of a single session of HIIT on cellular, molecular, and circulating markers of inflammation in individuals with T2D. Participants with T2D (n = 10) and healthy age-matched controls (HC; n = 9) completed an acute bout of HIIT (7 × 1 min at ~85% maximal aerobic power output, separated by 1 min of recovery) on a cycle ergometer with blood samples obtained before (Pre), immediately after (Post), and at 1 h of recovery (1-h Post). Inflammatory markers on leukocytes were measured by flow cytometry, and TNF-α was assessed in both LPS-stimulated whole blood cultures and plasma. A single session of HIIT had an overall anti-inflammatory effect, as evidenced by 1) significantly lower levels of Toll-like receptor (TLR) 2 surface protein expression on both classical and CD16+ monocytes assessed at Post and 1-h Post compared with Pre (P < 0.05 for all); 2) significantly lower LPS-stimulated TNF-α release in whole blood cultures at 1-h Post (P < 0.05 vs. Pre); and 3) significantly lower levels of plasma TNF-α at 1-h Post (P < 0.05 vs. Pre). There were no differences between T2D and HC, except for a larger decrease in plasma TNF-α in HC vs. T2D (group × time interaction, P < 0.05). One session of low-volume HIIT has immunomodulatory effects and provides potential anti-inflammatory benefits to people with, and without, T2D.


Opioid inaccessibility and its human consequences: reports from the field.
Strong opioids such as morphine are rarely accessible in low- and middle-income countries, even for patients with the most severe pain. The three cases reported here from three diverse countries provide examples of the terrible and unnecessary suffering that occurs everyday when this essential, inexpensive, and safe medication is not adequately accessible by patients in pain. The reasons for this lack of accessibility are explored, and ways to resolve the problem are proposed.


Sox9-haploinsufficiency causes glucose intolerance in mice.
The HMG box transcription factor Sox9 plays a critical role in progenitor cell expansion during pancreas organogenesis and is required for proper endocrine cell development in the embryo. Based on in vitro studies it has been suggested that Sox9 controls expression of a network of important developmental regulators, including Tcf2/MODY5, Hnf6, and Foxa2, in pancreatic progenitor cells. Here, we sought to: 1) determine whether Sox9 regulates this transcriptional network in vivo and 2) investigate whether reduced Sox9 gene dosage leads to impaired glucose homeostasis in adult mice. Employing two genetic models of temporally-controlled Sox9 inactivation in pancreatic progenitor cells, we demonstrate that contrary to in vitro findings, Sox9 is not required for Tcf2, Hnf6, or Foxa2 expression in vivo. Moreover, our analysis revealed a novel role for Sox9 in maintaining the expression of Pdx1/MODY4, which is an important transcriptional regulator of beta-cell development. We further show that reduced beta-cell mass in Sox9-haploinsufficient mice leads to glucose intolerance during adulthood. Sox9-haploinsufficient mice displayed 50% reduced beta-cell mass at birth, which recovered partially via a compensatory increase in beta-cell proliferation early postnatally. Endocrine islets from mice with reduced Sox9 gene dosage exhibited normal glucose stimulated insulin secretion. Our findings show Sox9 plays an important role in endocrine development by maintaining Ngn3 and Pdx1 expression. Glucose intolerance in Sox9-haploinsufficient mice suggests that mutations in Sox9 could play a role in diabetes in humans.


PEITC triggers multiple forms of cell death by GSH-iron-ROS regulation in K7M2 murine osteosarcoma cells.
Phenethyl isothiocyanate (PEITC) is an isothiocyanate that largely exists in cruciferous vegetables and exhibits chemopreventive and chemotherapeutic potential against various cancers. However, it is little known about the molecular mechanisms of its antitumor action against osteosarcoma, which is the second highest cause of cancer-related death in children and adolescents. In this study, we investigated the effects of PEITC on K7M2 murine osteosarcoma both in vitro and in vivo. We found that treatment with PEITC dose-dependently inhibited the viability of K7M2 murine osteosarcoma cells with an IC50 value of 33.49 μM at 24 h. PEITC (1, 15, 30 μM) dose-dependently inhibited the cell proliferation, caused G2/M cell cycle arrest, depleted glutathione (GSH), generated reactive oxygen species (ROS), altered iron metabolism, and triggered multiple forms of cell death, namely ferroptosis, apoptosis, and autophagy in K7M2 cells. We further revealed that PEITC treatment activated MAPK signaling pathway, and ROS generation was a major cause of PEITC-induced cell death. In a syngeneic orthotopic osteosarcoma mouse model, administration of PEITC (30, 60 mg/kg every day, ig, for 24 days) significantly inhibited the tumor growth, but higher dose of PEITC (90 mg/kg every day) compromised its anti-osteosarcoma effect. Histological examination showed that multiple cell death processes were initiated, iron metabolism was altered and MAPK signaling pathway was activated in the tumor tissues. In conclusion, we demonstrate that PEITC induces ferroptosis, autophagy, and apoptosis in K7M2 osteosarcoma cells by activating the ROS-related MAPK signaling pathway. PEITC has promising anti-osteosarcoma activity. This study sheds light on the redox signaling-based chemotherapeutics for cancers.


Challenges to depression care documentation in an EHR.
Patients with depression most frequently present in primary care. Electronic health records (EHR) have the potential to improve depression care through improved clinical documentation and information exchange. This report provides an example of how an EHR can fail to capture important information regarding depression care. A 6-month baseline period in 2009 was defined to identify ambulatory patients age 18 or older in the EHR with an ICD-9 coded new depression diagnosis. Data was abstracted electronically, and charts were reviewed by hand for patient demographics and to assess the clinical documentation of depression screening, diagnosis, and treatment practices among four community-based family medicine clinics. Electronic abstraction of baseline data identified 200 adult patients with a documented new diagnosis of depression. Review of charts by hand was required to obtain clinical documentation of screening (9% of patients), use of diagnostic tools (73%), discussion of treatment options (83%), medication treatment (71%), and follow-up characteristics (75%). Despite having a robust EHR, we encountered significant challenges finding documentation of depression care, which also made it difficult to track and evaluate the implementation of evidence-based treatment. Clinical documentation in the EHR needs to be simplified and standardized if data extraction and exporting processes of clinician performance data are to become efficient and routine practice.


On the universality of the flow properties of soft-particle glasses.
We identify the minimal interparticle interactions necessary for a particle dynamics simulation to predict the structure and flow behaviour of soft particle glasses (SPGs). Generally, two kinds of forces between the particles must be accounted for in simulations of SPGs: viscous or frictional drag forces and elastic contact forces. Far field drag forces are required to dissipate energy in the simulations and capture the effect of the rheology of the suspending fluid. Elastic forces are found to be dominant compared to near-field drag or other forms of friction forces and are the most important component to compute the rheology. The shear stress, the first and second normal stress differences for different interparticle force laws collapse onto universal master curves of the Herschel-Bulkley form by non-dimensionalizing the stress with the yield stress and the shear rate with the viscosity of the suspending fluid divided by the low-frequency shear modulus. The Herschel-Bulkley exponents are close to 0.5 with a slight dependence on the repulsive pairwise elastic forces.


Three-dimensional nonlinear microspectroscopy and imaging of soft condensed matter.
We report on the realization of a sensitive microspectroscopy and imaging approach based on a three-color femtosecond coherent anti-Stokes Raman scattering (CARS) technique with high spectral, time, and spatial resolution. Independently tunable, high-repetition rate optical parametric oscillators were used to attain a dynamic range of 5 orders of magnitude for time-domain CARS signal. The attained sensitivity permitted tracing the decay of weak and structurally complex Raman active modes in soft condensed matter. Application of this approach to imaging of the biological specimen shows a great potential in quantitative characterization of live biological media with an ability to access inter- and intra-molecular interactions.


The influence of population characteristics on variation in general practice based morbidity estimations.
General practice based registration networks (GPRNs) provide information on morbidity rates in the population. Morbidity rate estimates from different GPRNs, however, reveal considerable, unexplained differences. We studied the range and variation in morbidity estimates, as well as the extent to which the differences in morbidity rates between general practices and networks change if socio-demographic characteristics of the listed patient populations are taken into account. The variation in incidence and prevalence rates of thirteen diseases among six Dutch GPRNs and the influence of age, gender, socio economic status (SES), urbanization level, and ethnicity are analyzed using multilevel logistic regression analysis. Results are expressed in median odds ratios (MOR). We observed large differences in morbidity rate estimates both on the level of general practices as on the level of networks. The differences in SES, urbanization level and ethnicity distribution among the networks' practice populations are substantial. The variation in morbidity rate estimates among networks did not decrease after adjusting for these socio-demographic characteristics. Socio-demographic characteristics of populations do not explain the differences in morbidity estimations among GPRNs.


Reexamination of the Si(100) surface reconstruction.
Arguments in favor of 2 x 2-type reconstructions and against a purely 2 x 1 reconstruction on the Si(100) surface are presented. These are based on (1) total-energy calculations, (2) the extra ((1/2), (1/2)) diffuse intensities observed in He and electron diffraction experiments, (3) a comparison of the experimental and calculated surface state band dispersions, and (4) the observation in angle resolved photoemission measurements of two surface states with equal binding energies but differing by a ((1/2), (1/2))-type wave vector.


Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7.
Chemotactic cytokines (chemokines) attract immune cells, although their original evolutionary role may relate more closely with embryonic development. We noted differential expression of the chemokine receptor CXCR7 (RDC-1) on marginal zone B cells, a cell type associated with autoimmune diseases. We generated Cxcr7(-/-) mice but found that CXCR7 deficiency had little effect on B cell composition. However, most Cxcr7(-/-) mice died at birth with ventricular septal defects and semilunar heart valve malformation. Conditional deletion of Cxcr7 in endothelium, using Tie2-Cre transgenic mice, recapitulated this phenotype. Gene profiling of Cxcr7(-/-) heart valve leaflets revealed a defect in the expression of factors essential for valve formation, vessel protection, or endothelial cell growth and survival. We confirmed that the principal chemokine ligand for CXCR7 was CXCL12/SDF-1, which also binds CXCR4. CXCL12 did not induce signaling through CXCR7; however, CXCR7 formed functional heterodimers with CXCR4 and enhanced CXCL12-induced signaling. Our results reveal a specialized role for CXCR7 in endothelial biology and valve development and highlight the distinct developmental role of evolutionary conserved chemokine receptors such as CXCR7 and CXCR4.


A single dose of hydrocortisone does not alter interhemispheric transfer of information or transcallosal integration.
Stress has been suggested as a factor that may explain the link between altered functional lateralization and psychopathology. Modulation of the function of the corpus callosum via stress hormones may be crucial in this regard. Interestingly, there is evidence that interhemispheric integration and hemispheric asymmetries are modifiable by endocrinological influences. In previous studies, our group could show an enhancing effect of acute stress on interhemispheric integration. To investigate if this effect can be attributed to an increase in the stress hormone cortisol, 50 male participants received 20 mg hydrocortisone or a placebo in a double-blind crossover design. In each test session, we collected EEG data while participants completed a lexical decision task and a Poffenberger paradigm. In the lexical decision task, we found shorter latencies of the N1 ERP component for contralateral compared to ipsilateral presentation of lexical stimuli. Similarly, we replicated the classical Poffenberger effect with shorter ERP latencies for stimuli presented in the contralateral visual field compared to the ipsilateral visual field. However, no effect of cortisol on latency differences between hemispheres could be detected. These results suggest that a temporary increase in cortisol alone might not be enough to affect the interhemispheric transfer of information via the corpus callosum. Together with previous results from our group, this suggests that chronically elevated stress hormone levels play a more central role in the relationship between altered hemispheric asymmetries and a variety of mental disorders.


Innovating team-based outpatient mental health care in the Veterans Health Administration: Staff-perceived benefits and challenges to pilot implementation of the Behavioral Health Interdisciplinary Program (BHIP).
In the past decade, the demand for Veterans Health Administration (VHA) mental health care has increased rapidly. In response to the increased demand, the VHA developed the Behavioral Health Interdisciplinary Program (BHIP) team model as an innovative approach to transform VHA general outpatient mental health delivery. The present formative evaluation gathered information about pilot implementation of BHIP to understand the struggles and successes that staff experienced during facility transitions to the BHIP model. Using a purposive, nonrandom sampling approach, we conducted 1-on-1, semistructured interviews with 37 licensed and nonlicensed clinical providers and 13 clerical support staff assigned to BHIP teams in 21 facilities across the VHA. Interviews revealed that having actively involved facility mental health leaders, obtaining adequate staffing for teams to meet the requirements of the BHIP model, creating clear descriptions and expectations for team member roles within the BHIP framework, and allocating designated time for BHIP team meetings challenged many VHA sites but are crucial for successful BHIP implementation. Despite the challenges, staff reported that the transition to BHIP improved team work and improved patient care. Staff specifically highlighted the potential for the BHIP model to improve staff working relationships and enhance communication, collaboration, morale, and veteran treatment consistency. Future evaluations of the BHIP implementation process and BHIP team functioning focusing on patient outcomes, organizational outcomes, and staff functioning are recommended for fully understanding effects of transitioning to the BHIP model within VHA general mental health clinics and to identify best practices and areas for improvement. (PsycINFO Database Record


Nucleic acid-based fluorescent probes and their analytical potential.
It is well known that nucleic acids play an essential role in living organisms because they store and transmit genetic information and use that information to direct the synthesis of proteins. However, less is known about the ability of nucleic acids to bind specific ligands and the application of oligonucleotides as molecular probes or biosensors. Oligonucleotide probes are single-stranded nucleic acid fragments that can be tailored to have high specificity and affinity for different targets including nucleic acids, proteins, small molecules, and ions. One can divide oligonucleotide-based probes into two main categories: hybridization probes that are based on the formation of complementary base-pairs, and aptamer probes that exploit selective recognition of nonnucleic acid analytes and may be compared with immunosensors. Design and construction of hybridization and aptamer probes are similar. Typically, oligonucleotide (DNA, RNA) with predefined base sequence and length is modified by covalent attachment of reporter groups (one or more fluorophores in fluorescence-based probes). The fluorescent labels act as transducers that transform biorecognition (hybridization, ligand binding) into a fluorescence signal. Fluorescent labels have several advantages, for example high sensitivity and multiple transduction approaches (fluorescence quenching or enhancement, fluorescence anisotropy, fluorescence lifetime, fluorescence resonance energy transfer (FRET), and excimer-monomer light switching). These multiple signaling options combined with the design flexibility of the recognition element (DNA, RNA, PNA, LNA) and various labeling strategies contribute to development of numerous selective and sensitive bioassays. This review covers fundamentals of the design and engineering of oligonucleotide probes, describes typical construction approaches, and discusses examples of probes used both in hybridization studies and in aptamer-based assays.


RAS in pancreatic cancer.
The pancreas is a gland composed mainly by endocrine and exocrine cells, giving rise to three main tumour types. Pancreatic neuroendocrine tumour or PNET arise from the endocrine portion of the pancreas. On the contrary, pancreatic exocrine neoplasms include pancreatic ductal adenocarcinoma (PDAC) and acinar cell carcinoma. PDAC is the most common type of pancreatic cancer and one of the leading causes of cancer-related death. It has been shown that less than 3% of PDAC patients have an overall survival of up to 5 years in the U.K. This mainly arises since the majority of patients diagnosed with PDAC present with advanced unresectable disease, which is highly resistant to all forms of chemotherapy and radiotherapy. Activating mutations of an isoform of the RAS protein, KRAS, are found in almost all PDAC cases and occur during early stages of malignant transformation. KRAS mutations play a critical role as they are involved in both initiating and maintaining PDAC development. The interaction of RAS with GDP/GTP along with its recruitment to the membrane affects transduction of its activating signals to downstream effectors. In this review, we aim to summarise different mutations of RAS and their prevalence in pancreatic cancer along with other RAS-induced tumours. In addition, we briefly discuss the genetically engineered mouse models that have been developed to study KRAS-mutated adenocarcinomas in the pancreas. These provide an opportunity to also address the importance of targeting RAS for better treatment response in PDAC patients along with the challenges incurred herein.


Strategies for gender-equitable HIV services in rural India.
The emergence of HIV in rural India has the potential to heighten gender inequity in a context where women already suffer significant health disparities. Recent Indian health policies provide new opportunities to identify and implement gender-equitable rural HIV services. In this review, we adapt Mosley and Chen's conceptual framework of health to outline determinants for HIV health services utilization and outcomes. Examining the framework through a gender lens, we conduct a comprehensive literature review for gender-related gaps in HIV clinical services in rural India, focusing on patient access and outcomes, provider practices, and institutional partnerships. Contextualizing findings from rural India in the broader international literature, we describe potential strategies for gender-equitable HIV services in rural India, as responses to the following three questions: (1) What gender-specific patient needs should be addressed for gender-equitable HIV testing and care? (2) What do health care providers need to deliver HIV services with gender equity? (3) How should institutions enforce and sustain gender-equitable HIV services? Data at this early stage indicate substantial gender-related differences in HIV services in rural India, reflecting prevailing gender norms. Strategies including gender-specific HIV testing and care services would directly address current gender-specific patient needs. Rural care providers urgently need training in gender sensitivity and HIV-related communication and clinical skills. To enforce and sustain gender equity, multi-sectoral institutions must establish gender-equitable medical workplaces, interdisciplinary HIV services partnerships, and oversight methods, including analysis of gender-disaggregated data. A gender-equitable approach to rural India's rapidly evolving HIV services programmes could serve as a foundation for gender equity in the overall health care system.


Does the temporal cortex make us human? A review of structural and functional diversity of the primate temporal lobe.
Temporal cortex is a primate specialization that shows considerable variation in size, morphology, and connectivity across species. Human temporal cortex is involved in many behaviors that are considered especially well developed in humans, including semantic processing, language, and theory of mind. Here, we ask whether the involvement of temporal cortex in these behaviors can be explained in the context of the 'general' primate organization of the temporal lobe or whether the human temporal lobe contains unique specializations indicative of a 'step change' in the lineage leading to modern humans. We propose that many human behaviors can be explained as elaborations of temporal cortex functions observed in other primates. However, changes in temporal lobe white matter suggest increased integration of information within temporal cortex and between posterior temporal cortex and other association areas, which likely enable behaviors not possible in other species.


Ascorbic acid during the suckling period is required for proper DNA demethylation in the liver.
Ascorbic acid (AA, vitamin C) serves as a cofactor for ten-eleven translocation (TET) enzymes and induces DNA demethylation in vitro. However, its role in DNA demethylation in vivo remains unclear. We previously reported that DNA demethylation in the mouse liver was enhanced during the suckling period. Therefore, we hypothesized that DNA demethylation is enhanced in an AA-dependent manner during the suckling period. To examine our hypothesis, we employed wild-type (WT) mice, which synthesize AA, and senescence marker protein-30/gluconolactonase (SMP30/GNL) knockout (KO) mice, which cannot synthesize AA, and analyzed the DNA methylation status in the livers of offspring in both the suckling period and adulthood. SMP30/GNL KO offspring showed DNA hypermethylation in the liver possibly due to low plasma and hepatic AA levels during the suckling period despite the administration of rescue-dose AA to dams. Furthermore, DNA hypermethylation of the fibroblast growth factor 21 gene (Fgf21), a PPARα target gene, persisted into adulthood. In contrast, a high-dose AA administration to SMP30/GNL KO dams during the lactation period restored DNA demethylation in the livers of offspring. Even though a slight increase was observed in plasma AA levels with the administration of rescue-dose AA to WT dams during the gestation and lactation periods, DNA demethylation in the livers of offspring was minimally enhanced. The present results demonstrate that AA intake during the suckling period is required for proper DNA demethylation in the liver.


Later-life mental health in Europe: a country-level comparison.
To investigate the influence of country of residence on depression and well-being among older Europeans, after establishing the between-country measurement invariance of both constructs. We used data from a cross-sectional nationally representative population-based sample of older Europeans, the Survey of Health, Ageing, and Retirement in Europe (SHARE). The analysis sample comprised 13,498 older Europeans from nine countries. The EURO-D was used to measure depression, and a well-being outcome was derived from self-report items available in SHARE. The between-country measurement invariance of both mental health outcomes was established using modern psychometric modeling techniques. After adjustment for demographic characteristics and the presence of chronic illness, Spain was the country scoring highest on depression and Denmark highest on well-being. Optimal mental health was associated with higher educational attainment and being married. There is considerable between-country heterogeneity in later-life mental health in Europe. The Scandinavian countries, the Netherlands, and Austria, do best (low depression/high well-being), followed by Germany and France, whereas residents of Spain, Italy, and Greece report the worst mental health.


Quantitative magnetic resonance imaging phantoms: A review and the need for a system phantom.
The MRI community is using quantitative mapping techniques to complement qualitative imaging. For quantitative imaging to reach its full potential, it is necessary to analyze measurements across systems and longitudinally. Clinical use of quantitative imaging can be facilitated through adoption and use of a standard system phantom, a calibration/standard reference object, to assess the performance of an MRI machine. The International Society of Magnetic Resonance in Medicine AdHoc Committee on Standards for Quantitative Magnetic Resonance was established in February 2007 to facilitate the expansion of MRI as a mainstream modality for multi-institutional measurements, including, among other things, multicenter trials. The goal of the Standards for Quantitative Magnetic Resonance committee was to provide a framework to ensure that quantitative measures derived from MR data are comparable over time, between subjects, between sites, and between vendors. This paper, written by members of the Standards for Quantitative Magnetic Resonance committee, reviews standardization attempts and then details the need, requirements, and implementation plan for a standard system phantom for quantitative MRI. In addition, application-specific phantoms and implementation of quantitative MRI are reviewed. Magn Reson Med 79:48-61, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States.
To provide a single source for the best available estimates of the national prevalence of arthritis in general and of selected musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the spondylarthropathies, systemic lupus erythematosus, scleroderma, polymyalgia rheumatica/giant cell arteritis, gout, fibromyalgia, and low back pain). The National Arthritis Data Workgroup reviewed data from available surveys, such as the National Health and Nutrition Examination Survey series. For overall national estimates, we used surveys based on representative samples. Because data based on national population samples are unavailable for most specific musculoskeletal conditions, we derived data from various smaller survey samples from defined populations. Prevalence estimates from these surveys were linked to 1990 US Bureau of the Census population data to calculate national estimates. We also estimated the expected frequency of arthritis in the year 2020. Current national estimates are provided, with important caveats regarding their interpretation, for self-reported arthritis and selected conditions. An estimated 15% (40 million) of Americans had some form of arthritis in 1995. By the year 2020, an estimated 18.2% (59.4 million) will be affected. Given the limitations of the data on which they are based, this report provides the best available prevalence estimates for arthritis and other rheumatic conditions overall, and for selected musculoskeletal disorders, in the US population.


Coffee, tea, and fatal oral/pharyngeal cancer in a large prospective US cohort.
Epidemiologic studies suggest that coffee intake is associated with reduced risk of oral/pharyngeal cancer. The authors examined associations of caffeinated coffee, decaffeinated coffee, and tea intake with fatal oral/pharyngeal cancer in the Cancer Prevention Study II, a prospective US cohort study begun in 1982 by the American Cancer Society. Among 968,432 men and women who were cancer free at enrollment, 868 deaths due to oral/pharyngeal cancer occurred during 26 years of follow-up. Cox proportional hazards regression was used to estimate multivariable-adjusted relative risk. Intake of >4 cups/day of caffeinated coffee was associated with a 49% lower risk of oral/pharyngeal cancer death relative to no/occasional coffee intake (relative risk = 0.51, 95% confidence interval: 0.40, 0.64) (1 cup/day = 237 ml). A dose-related decline in relative risk was observed with each single cup/day consumed (P(trend) < 0.001). The association was not modified by sex, smoking status, or alcohol use. An inverse association for >2 cups/day of decaffeinated coffee intake was suggested (relative risk = 0.61, 95% confidence interval: 0.37, 1.01). No association was found for tea drinking. In this large prospective study, caffeinated coffee intake was inversely associated with oral/pharyngeal cancer mortality. Research is needed to elucidate biologic mechanisms whereby coffee might help to protect against these often fatal cancers.


Luteinizing hormone receptor ectodomain splice variant misroutes the full-length receptor into a subcompartment of the endoplasmic reticulum.
The luteinizing hormone receptor (LHR) is a G protein-coupled receptor that is expressed in multiple RNA messenger forms. The common rat ectodomain splice variant is expressed concomitantly with the full-length LHR in tissues and is a truncated transcript corresponding to the partial ectodomain with a unique C-terminal end. Here we demonstrate that the variant alters the behavior of the full-length receptor by misrouting it away from the normal secretory pathway in human embryonic kidney 293 cells. The variant was expressed as two soluble forms of M(r) 52,000 and M(r) 54,000, but although the protein contains a cleavable signal sequence, no secretion to the medium was observed. Only a very small fraction of the protein was able to gain hormone-binding ability, suggesting that it is retained in the endoplasmic reticulum (ER) by its quality control due to misfolding. This was supported by the finding that the variant was found to interact with calnexin and calreticulin and accumulated together with these ER chaperones in a specialized juxtanuclear subcompartment of the ER. Only proteasomal blockade with lactacystin led to accumulation of the variant in the cytosol. Importantly, coexpression of the variant with the full-length LHR resulted in reduction in the number of receptors that were capable of hormone binding and were expressed at the cell surface and in targeting of immature receptors to the juxtanuclear ER subcompartment. Thus, the variant mediated misrouting of the newly synthesized full-length LHRs may provide a way to regulate the number of cell surface receptors.


Accelerated coronary angiogenesis by vegfr1-knockout endocardial cells.
During mouse heart development, ventricular endocardial cells give rise to the coronary arteries by angiogenesis. Myocardially-derived vascular endothelial growth factor-a (Vegfa) regulates embryonic coronary angiogenesis through vascular endothelial growth factor-receptor 2 (Vegfr2) expressed in the endocardium. In this study, we investigated the role of endocardially-produced soluble Vegfr1 (sVegfr1) in the coronary angiogenesis. We deleted sVegfr1 in the endocardium of the developing mouse heart and found that this deletion resulted in a precocious formation of coronary plexuses. Using an ex vivo coronary angiogenesis assay, we showed that the Vegfr1-null ventricular endocardial cells underwent excessive angiogenesis and generated extensive endothelial tubular networks. We also revealed by qPCR analysis that expression of genes involved in the Vegf-Notch pathway was augmented in the Vegfr1-null hearts. We further showed that inhibition of Notch signaling blocked the formation of coronary plexuses by the ventricular endocardial cells. These results establish that Vegfr1 produced in the endocardium negatively regulates embryonic coronary angiogenesis, possibly by limiting the Vegf-Notch signaling.


Expanded Endoscopic Endonasal Transtuberculum Approach for Tuberculum Sellae Meningioma: Operative Video With 360-Degree Fly-Through and Surgical Rehearsal in Virtual Reality: 2-Dimensional Operative Video.
This video demonstrates the technique of the "Expanded Endoscopic Endonasal Transtuberculum Approach" and the utility of preoperative planning and surgical rehearsal in virtual reality (VR). VR can be utilized to improve endoscopic skull base surgery in various ways. The patient is a 57-yr-old woman with sudden right abducens palsy. Transcranial surgery has been the gold-standard treatment of the tuberculum sellae meningioma that was found, but for suitable tumors, the endoscopic endonasal approach is equally effective for tumor resection with better visual outcomes.1-4 The three-dimensional, 360°, multicolored VR rendering (Surgical Theater SRP7.4.0, Cleveland, Ohio) of her tuberculum sellae meningioma clearly demonstrated that there was no encasement of the anterior cerebral arteries, the tumor did not extend lateral to the carotid arteries, and the surgical corridor was wide enough for endoscopic endonasal resection. The surgical exposure was then rehearsed with the sphenoidectomy and drilling of the sella floor and tuberculum performed in VR space. The step-by-step process of the endoscopic endonasal transtuberculum resection is demonstrated in the operative video. Surgical planning in VR can be helpful to the early-career endoscopic surgeon. The three-dimensional renderings are quick to set up (15 min), and the examination of the anatomy is useful for choosing the surgical approach. Despite the lack of haptic feedback and tissue response such as vascularity and firmness in the current software, rehearsing the drilling for exposure can improve the efficiency in surgery. Patient consent was obtained prior to the creation of the video and is available on request.


Atypical hemispheric specialization for faces in infants at risk for autism spectrum disorder.
Among the many experimental findings that tend to distinguish those with and without autism spectrum disorder (ASD) are face processing deficits, reduced hemispheric specialization, and atypical neurostructural and functional connectivity. To investigate the earliest manifestations of these features, we examined lateralization of event-related gamma-band coherence to faces during the first year of life in infants at high risk for autism (HRA; defined as having an older sibling with ASD) who were compared with low-risk comparison (LRC) infants, defined as having no family history of ASD. Participants included 49 HRA and 46 LRC infants who contributed a total of 127 data sets at 6 and 12 months. Electroencephalography was recorded while infants viewed images of familiar/unfamiliar faces. Event-related gamma-band (30-50 Hz) phase coherence between anterior-posterior electrode pairs for left and right hemispheres was computed. Developmental trajectories for lateralization of intra-hemispheric coherence were significantly different in HRA and LRC infants: by 12 months, HRA infants showed significantly greater leftward lateralization compared with LRC infants who showed rightward lateralization. Preliminary results indicate that infants who later met criteria for ASD were those that showed the greatest leftward lateralization. HRA infants demonstrate an aberrant pattern of leftward lateralization of intra-hemispheric coherence by the end of the first year of life, suggesting that the network specialized for face processing may develop atypically. Further, infants with the greatest leftward asymmetry at 12 months where those that later met criteria for ASD, providing support to the growing body of evidence that atypical hemispheric specialization may be an early neurobiological marker for ASD.


Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria: a pilot study.
Patients with tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency may benefit from BH4 therapy instead or in addition to the low-phenylalanine diet. Different loading test protocols are currently used to detect these patients. As a consequence, data on the rate of BH4-responsiveness within patients with mild phenylketonuria (PKU) and/or more severe phenotypes show high variation and a more sensitive and standardised BH4 loading test protocol needs to be defined. We modified the current standard BH4 loading test (20 mg/kg) to a second administration of 20 mg/kg after 24 h and extended blood sampling to 48 h in 24 patients with PAH deficiency. Using this extended loading test (2 x 20 mg BH4/kg), the rate of BH4-responsiveness was calculated at 8, 24, and 48 h after BH4 administration. We defined three groups of patients: "rapid responders" in 10/24 patients (4 mild HPA, 2 mild PKU, 2 moderate PKU, and 2 classic PKU), "moderate responders" in 4/24 patients (4 classic PKU), and "slow responder" in 4/24 patients (4 mild PKU). Six out of 24 patients (1 mild HPA, 1 moderate PKU, and 4 classic PKU) were found to be "non-responder." Individual phenylalanine profiles show variations in responsiveness at different time points and sampling over 48 h was more informative than over 24h in patients with mild and moderate PKU compared to mild HPA. Analysis of BH4 loading tests in 209 patients with the standard BH4 loading test protocol confirms only minor importance of the 24 h response: the rate of responsiveness to BH4 after 24 h was shown to be equal to or even lower than after 8h among most phenotypes. However, extension of the BH4 loading test to 48 h and repeated BH4 administration seems to be useful to detect BH4-responsiveness in more severe phenotypes and allows detecting "slow responders" who may benefit from BH4 therapy.


Human-proto-oncogene nucleotide sequences corresponding to the transforming region of simian sarcoma virus.
The nucleotide sequences of the six regions within the normal human cellular locus (c-sis) that correspond to the entire transforming region of the simian sarcoma virus (SSV) genome (v-sis) were determined. The regions are bounded by acceptor and donor splice sites and, except for region 6, resemble exons. Region 6 lacks a 3' donor splice site and terminates -5 base pairs from the 3' v-sis-helper-viral junction. This is consistent with a model proposing that SSV was generated by recombination between proviral DNA of a simian sarcoma associated virus and proto-sis and that introns were spliced out subsequently from a fused viral-sis messenger RNA. This also suggests that the 3' recombination occurred within an exon of the woolly monkey (Lagothrix) genome. The open reading frames predicting the v-sis and c-sis gene products coincide with the stop codon of c-sis located 123 nucleotides into the fifth region of homology. The overall nucleotide homology was 91 percent with substitutions mainly in the third codon positions within the open reading frame and with greatest divergence within the untranslated 3' portion of the sequences. The predicted protein products for v-sis and c-sis are 93 percent homologous. The predicted c-sis gene product is identical in 31 of 31 amino acids to one of the published sequences of platelet-derived growth factor. Thus, c-sis encodes one chain of human platelet-derived growth factor.


Sex differences in catheter ablation of atrial fibrillation: results from AXAFA-AFNET 5.
Study sex-differences in efficacy and safety of atrial fibrillation (AF) ablation. We assessed first AF ablation outcomes on continuous anticoagulation in 633 patients [209 (33%) women and 424 (67%) men] in a pre-specified subgroup analysis of the AXAFA-AFNET 5 trial. We compared the primary outcome (death, stroke or transient ischaemic attack, or major bleeding) and secondary outcomes [change in quality of life (QoL) and cognitive function] 3 months after ablation. Women were older (66 vs. 63 years, P < 0.001), more often symptomatic, had lower QoL and a longer history of AF. No sex differences in ablation procedure were found. Women stayed in hospital longer than men (2.1 ± 2.3 vs. 1.6 ± 1.3 days, P = 0.004). The primary outcome occurred in 19 (9.1%) women and 26 (6.1%) men, P = 0.19. Women experienced more bleeding events requiring medical attention (5.7% vs. 2.1%, P = 0.03), while rates of tamponade (1.0% vs. 1.2%) or intracranial haemorrhage (0.5% vs. 0%) did not differ. Improvement in QoL after ablation was similar between the sexes [12-item Short Form Health Survey (SF-12) physical 5.1% and 5.9%, P = 0.26; and SF-12 mental 3.7% and 1.6%, P = 0.17]. At baseline, mild cognitive impairment according to the Montreal Cognitive Assessment (MoCA) was present in 65 (32%) women and 123 (30%) men and declined to 23% for both sexes at end of follow-up. Women and men experience similar improvement in QoL and MoCA score after AF ablation on continuous anticoagulation. Longer hospital stay, a trend towards more nuisance bleeds, and a lower overall QoL in women were the main differences observed.


The role of the dorsal hippocampus in two versions of the touchscreen automated paired associates learning (PAL) task for mice.
The CANTAB object-location paired-associate learning (PAL) test can detect cognitive deficits in schizophrenia and Alzheimer's disease. A rodent version of touch screen PAL (dPAL) has been developed, but the underlying neural mechanisms are not fully understood. Although there is evidence that inactivation of the hippocampus following training leads to impairments in rats, this has not been tested in mice. Furthermore, it is not known whether acquisition, as opposed to performance, of the rodent version depends on the hippocampus. This is critical as many mouse models may have hippocampal dysfunction prior to the onset of task training. The objectives of this study are to examine the effects of dorsal hippocampal (dHp) dysfunction on both performance and acquisition of mouse dPAL and to determine if hippocampal task sensitivity could be increased using a newly developed context-disambiguated PAL (cdPAL) paradigm. In experiment 1, C57Bl/6 mice received post-acquisition dHp infusions of the GABA agonist muscimol. In experiment 2, C57Bl/6 mice received excitotoxic dHp lesions prior to dPAL/cdPAL acquisition. Post-acquisition muscimol dose-dependently impaired dPAL and cdPAL performance. Pre-acquisition dHp lesions had only mild effects on both PAL tasks. Behavioural challenges including addition of objects and degradation of the visual stimuli with noise did not reveal any further impairments. dPAL and cdPAL performance is hippocampus-dependent in the mouse, but both tasks can be learned in the absence of a functional dHp.


Changes imposed by pyrolysis, thermal gasification and incineration on composition and phosphorus fertilizer quality of municipal sewage sludge.
Fertilizer quality of ash and char from incineration, gasification and pyrolysis of a single municipal sewage sludge sample were investigated by comparing composition and phosphorus (P) plant availability. A process for post oxidation of gasification ash and pyrolysis char was developed and the oxidized materials were investigated as well. Sequential extraction with full elemental balances of the extracted pools as well as scanning electron microscopy with energy dispersive X-ray spectroscopy were used to investigate the mechanisms driving the observed differences in composition and P plant availability in a short-term soil incubation study. The compositional changes related mainly to differences in the proximate composition as well as to the release of especially nitrogen, sulfur, cadmium and to some extent, phosphorus (P). The cadmium load per unit of P was reduced with 75-85% in gasification processes and 10-15% in pyrolysis whereas no reduction was observed in incineration processes. The influence on other heavy metals was less pronounced. The plant availability of P in the substrates varied from almost zero to almost 100% of the plant availability of P in the untreated sludge. Post-oxidized slow pyrolysis char was found to be the substrate with the highest P fertilizer value while ash from commercial fluid bed sludge incineration had the lowest P fertilizer quality. The high P fertilizer value in the best substrate is suggested to be a function of several different mechanisms including structural surface changes and improvements in the association of P to especially magnesium, calcium and aluminum.


Smoothing of nanoscale roughness based on the Kelvin effect.
A novel method of smoothing surfaces with nanoscale roughness is described, based on the Kelvin effect. The problem of vapor redistribution in cylindrical channels and over rough planar walls with nanoscale texture is posed and solved analytically. Vapor deposition (condensation) on the walls initially produces a deposit emulating the surface landscape. After a saturated state at the deposit surface is reached, the Kelvin effect should result in higher vapor pressure/ concentration near the convex sections of the wall and in lower vapor pressure/ concentration near the concave sections. As a result, local vapor fluxes should arise directed from the locally convex to the locally concave regions. Accordingly, the deposited layer at the wall should vaporize (or sublimate) at the convex sections due to depletion and vapor should condense at the concave sections, thus causing smoothing of physical surface unevenness. This mechanism of smoothing of nanoscale roughness has not been considered in detail or used before, even though the basic physics of the Kelvin effect is well known. In the present work, the smoothing kinetics is predicted and the characteristic timescales are calculated in the general case of axisymmetric and non-axisymmetric perturbations of the cylindrical channel walls, as well as for planar surfaces. In addition, experimental data are presented to show that the theoretically motivated approach is also practically realizable.


Weight loss referrals for adults in primary care (WRAP): protocol for a multi-centre randomised controlled trial comparing the clinical and cost-effectiveness of primary care referral to a commercial weight loss provider for 12 weeks, referral for 52 weeks, and a brief self-help intervention [ISRCTN82857232].
Recent trials demonstrate the acceptability and short term efficacy of primary care referral to a commercial weight loss provider for weight management. Commissioners now need information on the optimal duration of intervention and the longer term outcomes and cost effectiveness of such treatment to give best value for money. This multicentre, randomised controlled trial with a parallel design will recruit 1200 overweight adults (BMI ≥28 kg/m2) through their primary care provider. They will be randomised in a 2:5:5 allocation to: Brief Intervention, Commercial Programme for 12 weeks, or Commercial Programme for 52 weeks. Participants will be followed up for two years, with assessments at 0, 3, 12 and 24 months. The sequential primary research questions are whether the CP interventions achieve significantly greater weight loss from baseline to 12 months than BI, and whether CP52 achieves significantly greater weight loss from baseline to 12 months than CP12. The primary outcomes will be an intention to treat analysis of between treatment differences in body weight at 12 months. Clinical effectiveness will be also be assessed by measures of weight, fat mass, and blood pressure at each time point and biochemical risk factors at 12 months. Self-report questionnaires will collect data on psychosocial factors associated with adherence, weight-loss and weight-loss maintenance. A within-trial and long-term cost-effectiveness analysis will be conducted from an NHS perspective. Qualitative methods will be used to examine the participant experience. The current trial compares the clinical and cost effectiveness of referral to a commercial provider with a brief intervention. This trial will specifically examine whether providing longer weight-loss treatment without altering content or intensity (12 months commercial referral vs. 12 weeks) leads to greater weight loss at one year and is sustained at 2 years. It will also evaluate the relative cost-effectiveness of the three interventions. This study has direct implications for primary care practice in the UK and will provide important information to inform the decisions of practitioners and commissioners about service provision. Current Controlled Trials ISRCTN82857232. Date registered: 15/10/2012.


Pain increases during sympathetic arousal in patients with complex regional pain syndrome.
To investigate the effect of sympathetic arousal on pain and vasomotor responses in healthy control subjects and patients with complex regional pain syndrome (CRPS), and to determine whether pain increases in patients with particular symptoms. In experiments 1 and 2, capsaicin was applied to the forearm of 24 healthy subjects to induce thermal hyperalgesia. Vascular responses were monitored and subjects rated thermal hyperalgesia before and after being startled (experiment 1), and before, during, and after mental arithmetic, breath holding, forehead cooling, the Valsalva maneuver, and a cold pressor test in experiment 2. In a third experiment, sensitivity to heat, cold, and mechanical stimulation was investigated in 61 patients with CRPS. Pain ratings and vascular and electrodermal responses were recorded after patients were startled and during forehead cooling. In experiment 1, thermal hyperalgesia decreased in healthy control subjects after they were startled, and digital blood vessels constricted symmetrically. In experiment 2, thermal hyperalgesia decreased during and after other forms of sympathetic arousal. However, in experiment 3, ratings of clinical pain increased during forehead cooling or after being startled in over 70% of patients with CRPS. Pain increased most consistently during forehead cooling in patients with cold allodynia or punctate allodynia. Digital blood vessels constricted more intensely on the symptomatic than the nonsymptomatic side in patients with CRPS during sympathetic arousal. Normal inhibitory influences on pain during sympathetic arousal are compromised in the majority of patients with CRPS. The augmented vasoconstrictor response in the symptomatic limb during sympathetic arousal is consistent with adrenergic supersensitivity. An adrenergic sensitivity in nociceptive afferents might contribute to pain and hyperalgesia during sympathetic arousal in certain patients with CRPS.


Chancroid and Haemophilus ducreyi: an update.
Haemophilus ducreyi is a fastidious gram-negative bacillus that causes the sexually transmitted infection chancroid. Chancroid is a major genital ulcerative disease in Africa, Southeast Asia, the Caribbean, and Latin America and is of increasing concern in the United States. Genital ulcerative disease and chancroid in particular have been associated with facilitating the transmission of human immunodeficiency virus. The diagnosis of chancroid based on the clinical appearance of the genital lesion or on the isolation of H. ducreyi on selective medium is relatively insensitive. However, recent advances in nonculture diagnostic tests have enhanced our ability to diagnose chancroid. There has been renewed interest in understanding the pathogenesis of H. ducreyi. In vitro and in vivo models have been developed to help identify important virulence determinants. Through the use of biochemical and molecular techniques, macromolecular components that may be important in virulence have been identified.


Long-term fertility control in female cats with GonaCon™, a GnRH immunocontraceptive.
The uncontrolled reproduction of free-roaming feral cats contributes to overpopulation and associated concerns regarding their welfare and impact on public health and the environment. Nonsurgical fertility control that could be administered to feral cats in the field would be a powerful tool for cat population control. The objective was to test the efficacy and duration of activity of a single-dose GnRH immunocontraceptive vaccine (GonaCon™) on the fertility of adult female laboratory cats. Vaccinated cats (n = 15) received a single injection of vaccine containing a GnRH-KLH conjugate (200 μg) emulsified in a mycobacterial and oil adjuvant on study Day 0. Sham-treated cats (n = 5) received a single injection containing all vaccine components except the GnRH-KLH conjugate. A breeding trial started on study Day 120. Vaccinated cats had a longer time to conception (median 39.7 mo) compared to sham-treated cats (4.4 mo; P < 0.001). A total of 93% of vaccinated cats remained infertile for the first year following vaccination, whereas 73, 53, and 40% were infertile for 2, 3, and 4 y, respectively. At study termination (5 y after a single GnRH vaccine was administered), four cats (27%) remained infertile. The GnRH antibody titers declined more rapidly in short-term responding cats with < 2 y of infertility (n = 4), compared to long-term responding cats that experienced fertility control for >2 y (n = 11) (P < 0.05). Non-painful but persistent late-onset granulomatous injection site masses appeared 2 y after initial vaccination in five cats. We concluded that GnRH immunocontraception is an ideal candidate for further development for feral cat control.


Youth homelessness and housing stability: What outcomes should we be looking for?
In North America, the key performance indicator of success in community strategies to address homelessness is whether a homeless person is housed or not. In this article, we argue that for young people experiencing homelessness, we need to advance a broader consideration of outcomes to include a range of well-being indicators designed to understand the needs of developing adolescents and young adults and contribute to housing stability. We articulate that the positive outcomes of young people across life domains that include housing stability as well as their safety and security, health and well-being, social connections to peers, family and meaningful adults, connections to groups/neighbourhoods/communities, interests and recreation and leisure, and school and career/work aspirations and goals must be at the centre of these efforts. The Making the Shift project is designed to test this outcomes framework in order to enhance service and measurement capacity and ultimately improve outcomes for youth.


DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood.
Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342,596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formal mediation analysis. DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing β cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-term metabolic health. The specific mechanism awaits elucidation.


Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry.
The totally subcutaneous implantable-defibrillator (S-ICD) is a new alternative to the conventional transvenous ICD system to minimize intravascular lead complications. There are limited data describing the long-term performance of the S-ICD. This paper presents the first large international patient population collected as part of the EFFORTLESS S-ICD Registry. The EFFORTLESS S-ICD Registry is a non-randomized, standard of care, multicentre Registry designed to collect long-term, system-related, clinical, and patient reported outcome data from S-ICD implanted patients since June 2009. Follow-up data are systematically collected over 60-month post-implant including Quality of Life. The study population of 472 patients of which 241 (51%) were enrolled prospectively has a mean follow-up duration of 558 days (range 13-1342 days, median 498 days), 72% male, mean age of 49 ± 18 years (range 9-88 years), 42% mean left ventricular ejection fraction. Complication-free rates were 97 and 94%, at 30 and 360 days, respectively. Three hundred and seventeen spontaneous episodes were recorded in 85 patients during the follow-up period. Of these episodes, 169 (53%) received therapy, 93 being for Ventricular Tachycardia/Fibrillation (VT/VF). One patient died of recurrent VF and severe bradycardia. Regarding discrete VT/VF episodes, first shock conversion efficacy was 88% with 100% overall successful clinical conversion after a maximum of five shocks. The 360-day inappropriate shock rate was 7% with the vast majority occurring for oversensing (62/73 episodes), primarily of cardiac signals (94% of oversensed episodes). The first large cohort of real-world data from an International patient S-ICD population demonstrates appropriate system performance with clinical event rates and inappropriate shock rates comparable with those reported for conventional ICDs. Clinical trial registration URL: http://www.clinicaltrials.gov. Unique identifier NCT01085435.


Is hyperthermia combined with radiotherapy adequate in elderly patients with muscle-invasive bladder cancers? Thermo-radiobiological implications from an audit of initial results.
The aim of this study was to evaluate the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in elderly patients with muscle-invasive bladder cancers (MIBC). Twenty consecutive MIBC patients were treated with HTRT (n = 8) or HTCTRT (n = 12) following transurethral resection of their bladder tumours. Weekly HT was administered prior to RT to a mean temperature of 40.6-42.7 °C for 60 min. A mean RT dose of 54.6 Gy (SD ± 4.2) was delivered. Single-agent cisplatin (n = 2) or carboplatin (n = 10) was used in HTCTRT patients. The median age was 81 years. HTRT patients received a mean RT dose of 51.0 Gy compared to 57.1 Gy with HTCTRT (p < 0.001) in a shorter overall treatment time (OTT) (30.8 ± 6.9 versus 43.9 ± 4.0 days, p < 0.001). All HTRT patients had long-term local disease control, while 41.6% of HTCTRT recurred during follow-up. None of the HTRT patients experienced grade III/IV acute and late toxicities, while these were evident in two and one HTCTRT patients respectively. Taken together, the 3-year bladder preservation, local disease-free survival, cause-specific survival and overall survival were 86.6%, 60.7%, 55% and 39.5% respectively. Even though the mean biological effective dose (BED) for both groups was similar (57.8 Gy15), the thermo-radiobiological BED estimated from HT-induced reduction of α/β was significantly higher for HTRT patients (91 ± 4.4 versus 85.8 ± 4.3 Gy3, p = 0.018). Thermal radiosensitisation with consequent reduction in α/β results in a higher thermo-radiobiological BED with a relatively higher RT dose/fraction and shorter OTT. This translates into a favourable outcome in elderly MIBC patients. Any benefit of CT in these patients needs further investigation.


Remembered but unused: the accessory items in working memory that do not guide attention.
If we search for an item, a representation of this item in our working memory guides attention to matching items in the visual scene. We can hold multiple items in working memory. Do all these items guide attention in parallel? We asked participants to detect a target object in a stream of objects while they maintained a second item in memory for a subsequent task. On some trials, we presented this memory item as a distractor in the stream. Subjects did not confuse these memory items with the search target, as the false alarm rate on trials where the memory item was presented in the stream was comparable to that on trials with only regular distractors. However, a comparable performance does not exclude that the memory items are processed differently from normal distractors. We therefore recorded event-related potentials (ERPs) evoked by search targets, memory items, and regular distractors. As expected, ERPs evoked by search targets differed from those evoked by distractors. Search targets elicited an occipital selection negativity and a frontal selection positivity indexing selective attention, whereas the P3b component, which reflects the matching of sensory events to memory representations, was enhanced for targets compared to distractors. Remarkably, the ERPs evoked by memory items were indistinguishable from the ERPs evoked by normal distractors. This implies that the search target has a special status in working memory that is not shared by the other items. These other, "accessory" items do not guide attention and are excluded from the matching process.


Loving and angry? Happy and sad? Understanding and reporting of mixed emotions in mother-child relationships by 6- to 12-year-olds.
The Evaluative Space Model of emotions allows for the coactivation of positive-appetitive and negative-avoidant systems, but few studies have examined mixed emotions in child development. Existing research suggests children's understanding of opposite valence emotion combinations emerges by approximately 11 years of age. However, it is not yet clear whether various opposite valence combinations are understood at different ages, nor whether children can understand them in others before they have experienced such mixed emotions themselves. Semi-structured interviews with 97 children investigated whether they regarded six combinations of opposite valence mixed emotions as possible, could provide reasons for them, and report their own experience of each in the context of mother-child relationships. Both understanding that such combinations are possible and ability to provide reasons for them increased after age 6 and up to age 11, but were still incomplete in 12-year-olds. Understanding of different opposite valence combinations developed at different rates. At each age, fewer children who showed understanding of these combinations in others reported having had a similar experience themselves. The findings suggest a need to systematically examine a range of mixed emotions in order to develop a comprehensive theory of the development of mixed emotion understanding. They also suggest extending research into adolescence.


Personality disorders and self-perceived quality of life in an elderly psychiatric outpatient population.
The aim of this work was to assess the impact of personality disorder and traits on the subjective assessment of quality of life by a sample of elderly psychiatric outpatients (60 years or more). Sixty of the total number of subjects interviewed were included in the test sample since they met the Vragenlijst Klinishe Persoonlijkheid (VKP) criteria for personality disorder. A control sample was also formed, composed of 50 subjects without personality disorders or traits. Quality of life was assessed using the LEIPAD questionnaire. Personality disorder diagnoses were prevalently distributed in cluster C (25%) and in cluster A (20%). A total of 48.3% of patients (n = 29) had more than 1 personality disorder. Sixty percent of the sample (n = 36) presented with comorbid Axis I psychiatric disorders, in most cases depressive pathologies. Comparing the case and control groups, worse LEIPAD scores were achieved by subjects with personality disorders. Between clusters of personality disorders, the worst scores were observed in subjects with more than 1 personality disorder diagnosis. Elderly people who presented with a personality disorder were more vulnerable to late-life distress, especially those with more than one diagnosis. In keeping with linear regression analysis, widowhood, divorcehood and living with others appear to be variables able to negatively influence quality of life in this population. While the VKP needs to be adapted to the application in the elderly, it does seem to be a particularly useful screening instrument.


Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa.
Although type 2 immune responses to environmental Ags are thought to play pivotal roles in asthma and allergic airway diseases, the immunological mechanisms that initiate the responses are largely unknown. Many allergens have biologic activities, including enzymatic activities and abilities to engage innate pattern-recognition receptors such as TLR4. In this article, we report that IL-33 and thymic stromal lymphopoietin were produced quickly in the lungs of naive mice exposed to cysteine proteases, such as bromelain and papain, as a model for allergens. IL-33 and thymic stromal lymphopoietin sensitized naive animals to an innocuous airway Ag OVA, which resulted in production of type 2 cytokines and IgE Ab, and eosinophilic airway inflammation when mice were challenged with the same Ag. Importantly, upon exposure to proteases, uric acid (UA) was rapidly released into the airway lumen, and removal of this endogenous UA by uricase prevented type 2 immune responses. UA promoted secretion of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of naive animals induced extracellular release of IL-33, followed by both innate and adaptive type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated asthma phenotypes that were caused by repeated exposure to natural airborne allergens. These findings provide mechanistic insights into the development of type 2 immunity to airborne allergens and recognize airway UA as a key player that regulates the process in respiratory mucosa.


Direct admission versus inter-hospital transfer to a level I trauma unit improves survival: an audit of the new Inkosi Albert Luthuli Central Hospital trauma unit.
To audit the performance of a new level I trauma unit and trauma intensive care unit. Data on patients admitted to the level I trauma unit and trauma intensive care unit at Inkosi Albert Luthuli Central Hospital, Durban, from March 2007 to December 2008 were retrieved from the hospital informatics system and an independent database in the trauma unit. Four hundred and seven patients were admitted; 71% of admissions were inter-hospital transfers (IHT) and 29% direct from scene (DIR). The median age was 27 years (range 1 - 83), and 71% were male. Blunt injury accounted for 66.3% of admissions and penetrating trauma for 33.7%. Of the former, motor vehicle-related injury accounted for 87.4%, with 81% of paediatric admissions due to pedestrian-related injuries. The median injury severity score (ISS) for the entire cohort was 22 (survivors 18, deaths 29; p<0.001). Patients in the DIR group had a significantly higher mean ISS compared with the IHT group (DIR 25, IHT 20; p<0.02). The overall mortality rate was 26.3%. There were 37 deaths (31.1%) in the DIR group and 70 (24.3%) in the IHT group (p=0.19). In patients surviving more than 12 hours the overall mortality rate was 21.1% (DIR 13.7%, IHT 23.5%; p=0.042). Trauma is a major cause of premature death in the young. Despite a significantly higher median ISS in direct admissions, there was no difference in mortality. Of those surviving more than 12 hours, patients admitted directly had a significant decrease in mortality. Dedicated trauma units improve outcome in the critically injured.


Targeting tacrolimus to deeper layers of skin with improved safety for treatment of atopic dermatitis-Part II: in vivo assessment of dermatopharmacokinetics, biodistribution and efficacy.
The objective of present investigation was to study in vivo behavior of tacrolimus-loaded lipid-nanoparticles (T-LN) to understand its targeting potential for treatment of atopic-dermatitis-(AD). T-LN have shown significantly improved drug penetration to deeper epidermal and dermal skin-layers than commercial ointment-Protopic(®) and effectively reached target dendritic-immune-cells, responsible for immunopathogenesis of AD. Due to enhanced penetrability of T-LN, it became necessary to evaluate the toxicity of the nanocarrier and the drug at non-target tissues. This paper evaluates dermatopharmacokinetics (DPK), biodistribution, efficacy and safety of T-LN in comparison to Protopic(®) as reference. In vivo DPK in guinea pigs showed 3.02-fold higher bioavailability while γ-scintigraphy in albino-rats demonstrated 1.5-fold rapid penetration of radioactivity in skin for T-LN. Biodistribution in albino-rats revealed restricted localization at the target-skin-area with no general spreading to other body organs suggesting targeting potential of T-LN. In vivo efficacy studies in BALB/c mice showed highly efficient suppression of inflammatory AD-like skin-lesions with T-LN than reference and placebo. Dermal toxicity-studies revealed keratosis and collagenous mass-infiltration with repeated application of reference however interestingly, T-LN treated group showed no evident toxicity demonstrating significantly improved safety. Thus T-LN offered improved penetration to the target site without any toxic-effects and would represent an efficient and commercially viable alternative for AD treatment.


Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss.
Several lines of evidence suggest that male embryos may have greater vulnerability than female embryos to disordered inflammation; therefore, antiinflammatory drugs, such as low-dose aspirin (LDA), may alter the sex ratio. Here, we assessed the effect of LDA on male live birth and male offspring, incorporating pregnancy losses (n = 56) via genetic assessment, as part of a parallel-design, block-randomized, placebo-controlled trial of preconception LDA. Participants (615 treated with LDA, 613 treated with placebo) ranged in age from 18 to 40 years of age, with 1 to 2 prior pregnancy losses. We estimated the intention-to-treat (ITT) risk ratio (RR) and 95% CI and assessed interaction with baseline high-sensitivity C-reactive protein (hsCRP) serum concentration - a marker of systemic inflammation. Among the 1,078 women who completed follow-up (535 treated with LDA, 543 treated with placebo), the male live birth ITT RR equaled 1.31 (95% CI: 1.07-1.59). With increasing tertile of hsCRP, the proportion of males at birth decreased in the placebo group, and the effect of LDA on male live birth increased (first tertile: 48% male in LDA vs. 52% in placebo, ITT RR = 0.97, 95% CI: 0.70-1.35; second tertile: 57% male in LDA vs. 43% in placebo, ITT RR = 1.36, 95% CI: 0.98-1.90; third tertile: 53% male in LDA vs. 35% in placebo, ITT RR = 1.70, 95% CI: 1.13-2.57; P interaction = 0.03). Analysis of pregnancy with male offspring yielded similar results. Initiation of LDA prior to conception restored numbers of male live births and pregnancy with male offspring among women with 1 to 2 prior pregnancy losses. Moreover, our data suggest that LDA modulates inflammation that would otherwise reduce the conception or survival of male embryos. ClinicalTrials.gov NCT00467363. Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.


Dietary calcium and magnesium intake in relation to cancer incidence and mortality in a German prospective cohort (EPIC-Heidelberg).
To prospectively evaluate the associations of dietary calcium and magnesium intake with cancer incidence and mortality, data of 24,323 participants of the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg), who were aged 35-64 years and cancer-free at recruitment (1994-1998), were analyzed using multivariate Cox regression models. After an average follow-up time of 11 years, 2,050 incident cancers were diagnosed and 513 cancer deaths occurred. Dietary calcium intake was inversely but not statistically significantly associated with colorectal cancer risk (hazard ratio [HR] for per 100 mg increase in intake: 0.95; 95% confidence interval [CI]: 0.88, 1.02) and lung cancer risk (HR for per 100 mg increase in intake: 0.94; 95% CI: 0.87, 1.02). No statistically significant associations were observed between dietary calcium intake and site-specific or overall cancer incidence or mortality. Dietary magnesium intake was not statistically significantly associated with any of the investigated outcomes. This prospective cohort study provides no strong evidence to support that high dietary calcium and magnesium intake in the intake range observed in a German population may reduce cancer incidence or mortality.


Is Age or Surgical Approach Associated With Osteonecrosis in Patients With Developmental Dysplasia of the Hip? A Meta-analysis.
Osteonecrosis of the femoral head is a major complication that negatively impacts the clinical and radiographic long-term outcome after treatment of developmental hip dysplasia (DDH). There are conflicting results in the literature whether age at the time of closed or open reduction and a specific surgical approach are associated with osteonecrosis. Better understanding of the impact of age at reduction and surgical approach is important to reduce the risk of osteonecrosis in patients with DDH. We aimed to evaluate the association between occurrence of osteonecrosis and (1) age at closed reduction; (2) age at open reduction; and (3) medial versus anterior operative approaches. A systematic review identified studies reporting osteonecrosis occurrence after treatment of DDH and at least 2 years of followup. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Methodologic quality was assessed using the methodologic index for nonrandomized studies. Generalized logistic models were used to estimate pooled odds ratios (ORs) in the meta-analysis. Sixty-six studies were included in the systematic review and 24 in the meta-analysis. Data on 481 hips treated by closed reduction and 584 hips treated by open reduction were available to evaluate the association between osteonecrosis and age. The association between osteonecrosis and operative approach was assessed using data on 364 hips treated by medial open reduction and 220 hips treated by anterior open reduction. Age at reduction (> 12 months versus ≤ 12 months) was not associated with osteonecrosis after closed reduction (OR, 1.1; 95% confidence interval [CI], 0.4-3.2; p = 0.9) or open reduction (OR, 1.1; 95% CI, 0.7-1.9; p = 0.66). The overall, adjusted incidence of osteonecrosis (≥ Grade II) was 8.0% (95% CI, 2.8%-20.6%) among patients treated with closed reduction at or before 12 months of age and 8.4% (95% CI, 3.0%-21.5%) among those treated after 12 months. Similarly, the odds of osteonecrosis after open reduction did not differ between patients treated after the age of 12 months compared with those treated at or before 12 months (OR, 1.1; 95% CI, 0.7-1.9; p = 0.7). The incidence of osteonecrosis (≥ Grade II) was 18.3% (95% CI, 11.7%-27.4%) among patients who had index open reduction at or before 12 months of age and 20.0% (95% CI, 13.1%-29.4%) among those who had index open reduction after 12 months of age. Among hips treated with open reductions, there was no difference in osteonecrosis after medial versus anterior approaches (18.7% medial versus 19.6% anterior; OR, 1.1; 95% CI, 0.5-2.2; p = 0.9). Conclusions We did not find an association between closed or open reduction performed at or before 12 months of age and an increased risk of osteonecrosis of the femoral head. Delayed treatment past 1 year of age as a strategy to reduce the development of osteonecrosis was not supported by this meta-analysis. Open reduction through a medial or anterior approach may be recommended based on surgeon's preference, because we found no association between development of osteonecrosis and the type of surgical approach. However, many of the studies in the current literature are nonrandomized Level III or IV observational studies of inconsistent quality. Higher quality evidence is needed to better understand the effects of age at reduction and operative approach on the development of osteonecrosis after DDH treatment. Level III, therapeutic study.


Antibacterial activity of Psidium guajava leaf and bark against multidrug-resistant Vibrio cholerae: implication for cholera control.
In clinical cholera, a 3-day course of antibiotic complements extensive rehydration therapy by reducing stool volume, shortening the illness, and averting death. However, antibiotic therapy, which has lifesaving implications for cholera, is often hindered due to multidrug resistance in Vibrio cholerae, the cause of cholera. Crude aqueous mixture and water soluble methanol extract from leaf and bark of Psidium guajava, a tropical fruit guava of the family Myrtaceae, showed strong antibacterial activity against multidrug-resistant V. cholerae O1. The in vitro minimum inhibitory concentration of the crude aqueous mixture and water soluble methanol extract, which was bactericidal against 10(7) CFU/mL of V. cholerae was determined to be 1,250 microg/mL and 850 microg/mL, respectively. The antibacterial activity of P. guajava was stable at 100 degrees C for 15-20 min, suggesting nonprotein nature of the active component. The growth of V. cholerae in rice oral rehydration saline (ORS) was completely inhibited when 10 mg/mL (wt/vol) of crude aqueous mixture was premixed with the ORS in a ratio of 1:7 (vol. extract/vol. ORS). P. guajava, which is widely distributed in Bangladesh, thus offers great potential for use in indigenous, herbal medicine for controlling epidemics of cholera.