Relative contributions of history-taking, physical examination, and laboratory investigation to diagnosis and management of medical outpatients.
To evaluate the relative importance of the medical history, the physical examination, and laboratory investigations in the diagnosis and management of medical outpatients some physicians recorded their diagnosis and a prediction of the method of managementafter reading the patient's referral letter, again after taking the history, and againafter performing the physical examination. These diagnoses and predictions were compared with the diagnosis and method of management which had been adopted two months after the patient's initial attendance. A diagnosis that agreed with the one finally accepted was made after reading the referral letter and taking the history in 66 out of 80 new patients; the physical examination was useful in only seven patients, and the laboratory investigations in a further seven. In only one of six patients in whom the physician was unable to make any diagnosis after taking the history and examining the patient did laboratory investigations lead to a positive diagnosis.


Hiccups and breathing in human fetuses.
Serial recording in 45 low risk fetuses throughout the second and third trimesters showed that hiccups were the predominant diaphragmatic movement before 26 weeks' gestational age and that there was a significant negative correlation with gestational age. There was a pronounced reduction between 24 and 26 weeks, which was the result of a decrease in the number of episodes of hiccups rather than a change in the duration of episodes. In contrast, fetal breathing was positively correlated with gestational age, the greatest increase in breathing occurring between 26 and 32 weeks' gestation. This was the result of both an increase in the number and duration of episodes. From the time that rest-activity cycles of behaviour could be determined in recordings, both breathing and hiccups were dependent on behavioural state or cycle, occurring predominantly during active episodes. This association between quiet and active behaviour and breathing did not alter with increasing gestational age, and the variables in fetal behavioural state became increasingly closely linked. The importance of prolonged and repeated recording, and also the need to take account of other variables in fetal behaviour, before any sinister conclusions can be drawn about the absence of fetal breathing is emphasised.


Serologic markers in inflammatory bowel disease: state of the art.
A variety of serologic tests are emerging that are relevant to the diagnosis and treatment of Crohn's disease and ulcerative colitis. These laboratory tests include: anti-neutrophil cytoplasmic antibody with perinuclear staining (pANCA); anti-Saccharomyces cerevisiae antibody (ASCA); outer membrane porin C (Omp C); and I2 antibody (novel homologue of the bacterial transcription-factor families). The potential roles for serologic testing for inflammatory bowel disease (IBD) include adjunctive diagnostic testing in patients with known IBD, screening testing for IBD in patients with compatible gastrointestinal symptoms, and serving as a marker of unique disease course or prediction of response to specific treatments. This article reviews the use of pANCA, ASCA, I2, and Omp C in patients with IBD.


Patient-controlled analgesia in the terminally ill cancer patient.
Patient-controlled analgesia (PCA) is a relatively new therapeutic modality which has allowed postsurgical patients to safely and effectively self-administer doses of intravenous narcotics via a syringe pump and sequencing device. A pilot study was designed to evaluate PCA's safety and effectiveness in the terminally ill cancer patient. Eight patients whose chronic pain was not adequately controlled by oral narcotics were permitted to use PCA for a minimum of 48 hours. Respiratory rates, sedation rankings, and pain rankings indicated these patients achieved satisfactory analgesia with a minimum of sedation and experienced no respiratory depression. Three patients were switched to oral regimens using PCA dosing as a guide. Pain and sedation rankings were similar to those registered while exclusively on PCA. This self-dosing technique was judged to be safe, effective, and able to accommodate wide fluctuations in analgesic need when treating pain in the terminally ill cancer patient. The results obtained in these patients support further trials using PCA to individualize oral analgesic regimens.


Optical encryption based on computational ghost imaging.
Ghost imaging is an optical technique in which the information of an object is encoded in the correlation of the intensity fluctuations of light. The computational version of this fascinating phenomenon emulates, offline, the optical propagation through the reference arm, enabling 3D visualization of a complex object whose transmitted light is measured by a bucket detector. In this Letter, we show how computational ghost imaging can be used to encrypt and transmit object information to a remote party. Important features, such as key compressibility and vulnerability to eavesdropping, are experimentally analyzed.


Sebomic identification of sex- and ethnicity-specific variations in residual skin surface components (RSSC) for bio-monitoring or forensic applications.
"Residual skin surface components" (RSSC) is the collective term used for the superficial layer of sebum, residue of sweat, small quantities of intercellular lipids and components of natural moisturising factor present on the skin surface. Potential applications of RSSC include use as a sampling matrix for identifying biomarkers of disease, environmental exposure monitoring, and forensics (retrospective identification of exposure to toxic chemicals). However, it is essential to first define the composition of "normal" RSSC. Therefore, the aim of the current study was to characterise RSSC to determine commonalities and differences in RSSC composition in relation to sex and ethnicity. Samples of RSSC were acquired from volunteers using a previously validated method and analysed by high-pressure liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry (HPLC-APCI-MS). The resulting data underwent sebomic analysis. The composition and abundance of RSSC components varied according to sex and ethnicity. The normalised abundance of free fatty acids, wax esters, diglycerides and triglycerides was significantly higher in males than females. Ethnicity-specific differences were observed in free fatty acids and a diglyceride. The HPLC-APCI-MS method developed in this study was successfully used to analyse the normal composition of RSSC. Compositional differences in the RSSC can be attributed to sex and ethnicity and may reflect underlying factors such as diet, hormonal levels and enzyme expression.


Alpha oscillations correlate with the successful inhibition of unattended stimuli.
Because the human visual system is continually being bombarded with inputs, it is necessary to have effective mechanisms for filtering out irrelevant information. This is partly achieved by the allocation of attention, allowing the visual system to process relevant input while blocking out irrelevant input. What is the physiological substrate of attentional allocation? It has been proposed that alpha activity reflects functional inhibition. Here we asked if inhibition by alpha oscillations has behavioral consequences for suppressing the perception of unattended input. To this end, we investigated the influence of alpha activity on motion processing in two attentional conditions using magneto-encephalography. The visual stimuli used consisted of two random-dot kinematograms presented simultaneously to the left and right visual hemifields. Subjects were cued to covertly attend the left or right kinematogram. After 1.5 sec, a second cue tested whether subjects could report the direction of coherent motion in the attended (80%) or unattended hemifield (20%). Occipital alpha power was higher contralateral to the unattended side than to the attended side, thus suggesting inhibition of the unattended hemifield. Our key finding is that this alpha lateralization in the 20% invalidly cued trials did correlate with the perception of motion direction: Subjects with pronounced alpha lateralization were worse at detecting motion direction in the unattended hemifield. In contrast, lateralization did not correlate with visual discrimination in the attended visual hemifield. Our findings emphasize the suppressive nature of alpha oscillations and suggest that processing of inputs outside the field of attention is weakened by means of increased alpha activity.


Differentially expressed soluble proteins in aortic cells from atherosclerosis-susceptible and resistant pigeons.
Soluble proteins in aortic smooth muscle cells cultured from atherosclerosis-susceptible White Carneau and atherosclerosis-resistant Show Racer pigeons were extracted and separated on 2-dimensional electrophoresis gels. Spots were analyzed with Phoretix software and compared between the 2 breeds. Proteins differentially expressed were arrayed on a map, plotting molecular weight against isoelectric point. Eight discrete zones were identified, 5 that included only proteins unique to susceptible cells and 3 that included proteins unique to resistant cells. Of the 88 differentially expressed proteins from susceptible cells, 41 were located in unique zones, whereas 29 of 82 differentially expressed proteins from resistant cells were in unique zones. Selected proteins from susceptibility, and resistance zones were annotated by peptide mass fragments, molecular weights, isoelectric points, and correspondence with genes differentially expressed between cells from the 2 breeds. Some of the annotated proteins (such as smooth muscle myosin phosphatase, myosin heavy chain, fatty acid-binding protein, ribophorin, heat shock protein, and tumor necrosis factor alpha-inducing factor) corresponded to the current hypotheses to explain atherogenesis. In addition, the unique electrophoretic migration zones of proteins associated with susceptibility or resistance should prove useful as a diagnostic tool in clinical settings where species or phenotypes, or both, susceptible or resistant to atherosclerosis can be identified.


Brain magnetic resonance imaging in newly diagnosed systemic lupus erythematosus.
We wished to determine the prevalence of cerebral atrophy and focal lesions in a cohort of patients with newly diagnosed systemic lupus erythematosus (SLE) and the association of these brain abnormalities with clinical characteristics. A total of 97 patients with SLE, within 9 months of diagnosis, with 4 or more American College of Rheumatology classification criteria, were enrolled. Brain magnetic resonance imaging was performed. The patients were 97% female, mean age 38.1 (SD 12.2) years, education 15.1 (2.8) years; 59 Caucasian, 11 African American, 19 Hispanic, 5 Asian, and 3 other ethnicity. Cerebral atrophy was prevalent in 18% (95% CI 11%-27%): mild in 12%, moderate in 5%. Focal lesions were prevalent in 8% (95% CI 4%-16%): mild in 2%, moderate in 5%, severe in 1%. Patients with cerebral atrophy were more likely to have anxiety disorder (p = 0.04). Patients with focal lesions were more likely to be African American (p = 0.045) and had higher Safety of Estrogens in Lupus Erythematosus National Assessment SLEDAI scores (p = 0.02) and anti-dsDNA (p = 0.05). In this population with newly diagnosed SLE, brain abnormalities were prevalent in 25% of patients. These findings suggest that the brain may be affected extremely early in the course of SLE, even before the clinical diagnosis of SLE is made. Followup of these patients is planned, to determine the reversibility or progression of these abnormalities and their association with and potential predictive value for subsequent neuropsychiatric SLE manifestations.


Seasonal response to drought and rewatering in Portulacaria afra (L.) Jacq.
Gas exchange characteristics of droughted and rewatered Portulacaria afra were studied during the seasonal shift from CAM to C3 photosynthesis. 14CO2 uptake, stomatal conductance, and total titratable acidity were determined for both irrigated and 2, 4, and 7.5 month waterstressed plants from summer 1984 to summer 1985. Irrigated P. afra plants were utilizing the CAM pathway throughout the summer and shifted to C3 during the winter and spring. Beginning in September, P. afra plants shifted from CAM to CAM-idling after 2 months of water-stress. When water-stress was initiated later in the fall, exogenous CO2 uptake was still measurable after 4 months of drought. After 7.5 months of stress, exogenous CO2 uptake was absent. The shift from CAM to CAM-idling or C3 in the fall and winter was related to when water stress was initiated and not to the duration of the stress. Gas exchange resumed within 24 h of rewatering regardless of the duration of the drought. In the winter and spring, rewatering resulted in a full resumption of daytime CO2 uptake. Whereas during the summer, rewatering quickly resulted in early morning CO2 uptake, but nocturnal CO2 uptake through the CAM pathway was observed after 7 days. Gas exchange measurements, rewatering characteristics, and transpirational water loss support the hypothesis that the C3 pathway was favored during the winter and spring. The CAM pathway was functional during the summer when potential for water loss was greater. Our investigations indicate that P. afra has a flexible photosynthetic system that can withstand long-term drought and has a rapid response to rewatering.


Rare cause of back pain: Staphylococcus aureus vertebral osteomyelitis complicated by recurrent epidural abscess and severe sepsis.
An epidural abscess represents a rare acute medical emergency, with a reported incidence of 2.5/10 000 hospital admissions annually. The clinical features include fever, spinal pain, radiating nerve root pain and leg weakness. When sepsis is present, prompt recognition is required to initiate appropriate antimicrobial therapy and surgical decompression. We present the case of a man aged 68 years presenting to the emergency department with a 3-day history of fever, low back, right hip and leg pain. He was hypoxic, tachycardic and hypotensive. He required intubation and ventilation. An MRI spine confirmed a posterior epidural abscess from T12 to L4. Blood cultures revealed Staphylococcus aureus He started treatment with linezolid and underwent incision and drainage. He remained septic and 8 days later, a repeat MRI spine showed a peripherally enhancing posterior epidural collection from L2/L3 to L4/L5, consistent with a recurrent epidural abscess. Further drainage was performed. He developed bilateral knee pain requiring washout. His right knee synovial biopsy cultured S. aureus He continued treatment with linezolid for 6 weeks until his C reactive protein was 0.8 ng/L. He started neurorehabilitation. 10 weeks later, he became feverish with lumbar spine tenderness. An MRI spine showed discitis of the L5/S1 endplate. A CT-guided biopsy confirmed discitis and osteomyelitis. Histology was positive for S. aureus and he started treatment with oral linezolid. After 19 days, he was discharged with 1 week of oral linezolid 600 mg 2 times per day, followed by 1 further week of oral clindamycin 600 mg 4 times daily. This case report reinforces the importance of maintaining a high clinical suspicion, with a prompt diagnosis and combined medical and surgical treatment to prevent adverse outcomes in this patient cohort. With spinal surgical services centralised, physicians may not encounter this clinical diagnosis more often in day-to-day hospital medical practice. The unique aspect of this case is the persistence and then the recurrence (despite 6 weeks of antimicrobial therapy and a second debridement) of S. aureus infection. Furthermore, the paucity of clinical recommendations and the controversy regarding the adequate duration of antimicrobial therapy are notable features of this case.


Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study.
Poor tolerance and adverse drug reactions are main reasons for discontinuation of antiretroviral therapy (ART). Identifying predictors of ART discontinuation is a priority in HIV care. A genetic association study in an observational cohort to evaluate the association of pharmacogenetic markers with time to treatment discontinuation during the first year of ART. Analysis included 577 treatment-naive individuals initiating tenofovir (n = 500) or abacavir (n = 77), with efavirenz (n = 272), lopinavir/ritonavir (n = 184), or atazanavir/ritonavir (n = 121). Genotyping included 23 genetic markers in 15 genes associated with toxicity or pharmacokinetics of the study medication. Rates of ART discontinuation between groups with and without genetic risk markers were assessed by survival analysis using Cox regression models. During the first year of ART, 190 individuals (33%) stopped 1 or more drugs. For efavirenz and atazanavir, individuals with genetic risk markers experienced higher discontinuation rates than individuals without (71.15% vs 28.10%, and 62.5% vs 14.6%, respectively). The efavirenz discontinuation hazard ratio (HR) was 3.14 (95% confidence interval (CI): 1.35-7.33, P = .008). The atazanavir discontinuation HR was 9.13 (95% CI: 3.38-24.69, P < .0001). Several pharmacogenetic markers identify individuals at risk for early treatment discontinuation. These markers should be considered for validation in the clinical setting.


Complex dynamics of our economic life on different scales: insights from search engine query data.
Search engine query data deliver insight into the behaviour of individuals who are the smallest possible scale of our economic life. Individuals are submitting several hundred million search engine queries around the world each day. We study weekly search volume data for various search terms from 2004 to 2010 that are offered by the search engine Google for scientific use, providing information about our economic life on an aggregated collective level. We ask the question whether there is a link between search volume data and financial market fluctuations on a weekly time scale. Both collective 'swarm intelligence' of Internet users and the group of financial market participants can be regarded as a complex system of many interacting subunits that react quickly to external changes. We find clear evidence that weekly transaction volumes of S&P 500 companies are correlated with weekly search volume of corresponding company names. Furthermore, we apply a recently introduced method for quantifying complex correlations in time series with which we find a clear tendency that search volume time series and transaction volume time series show recurring patterns.


Crystal structure of the transcriptional regulator Rv1219c of Mycobacterium tuberculosis.
The Rv1217c-Rv1218c multidrug efflux system, which belongs to the ATP-binding cassette superfamily, recognizes and actively extrudes a variety of structurally unrelated toxic chemicals and mediates the intrinsic resistance to these antimicrobials in Mycobacterium tuberculosis. The expression of Rv1217c-Rv1218c is controlled by the TetR-like transcriptional regulator Rv1219c, which is encoded by a gene immediately upstream of rv1218c. To elucidate the structural basis of Rv1219c regulation, we have determined the crystal structure of Rv1219c, which reveals a dimeric two-domain molecule with an entirely helical architecture similar to members of the TetR family of transcriptional regulators. The N-terminal domains of the Rv1219c dimer are separated by a large center-to-center distance of 64 Å. The C-terminal domain of each protomer possesses a large cavity. Docking of small compounds to Rv1219c suggests that this large cavity forms a multidrug binding pocket, which can accommodate a variety of structurally unrelated antimicrobial agents. The internal wall of the multidrug binding site is surrounded by seven aromatic residues, indicating that drug binding may be governed by aromatic stacking interactions. In addition, fluorescence polarization reveals that Rv1219c binds drugs in the micromolar range.


Skin Burns: Review of Molecular Mechanisms and Therapeutic Approaches.
Burn wounds are one of the main causes of skin damage. Based on World Health Organization statistics, almost 300 000 people worldwide die of burns each year. In severe burns, the cells and blood vessels are often injured and the blood supply to the wound is disturbed. Many factors such as oxygenation, infection, aging, hormones, and nutrition potentially can influence burn progression and disrupt repair with unbalanced release of various growth factors and cytokines. Different treatment approaches such as dressings and skin substitutes have been applied to aid wound healing. A thorough understanding of the effective factors on burns can improve wound healing outcomes. This review evaluates articles published on the Scopus, EMBASE, and PubMed databases that attempt to explain the pathophysiology, molecular components, and therapeutic approaches involved in the burn wound healing process.


Methodological challenges in psychiatric treatment adherence research.
Reflecting an increasing awareness of the importance of treatment adherence on outcomes in psychiatric populations, the National Institute of Mental Health (NIMH) convened a panel of treatment adherence researchers on September 27-28, 2007 to discuss and articulate potential solutions for dealing with methodological adherence research challenges. Panel discussions and presentations were augmented with targeted review of the literature on specific topics, with a focus on adherence to medication treatments in adults with serious mental illness. The group discussed three primary methodological areas: participants, measures, and interventions. When selecting patients for adherence-enhancing interventions (AEIs), a three-tier model was proposed that draws from the universal (targeting all patients receiving medication treatment for a specific condition, regardless of current adherence), selective (targeting patients at risk for nonadherence), and indicated (targeting patients who are currently nonadherent) prevention model and emphasizes careful patient characterization in relevant domains and appropriate matching of interventions to the selected population. Proposals were also made to reduce problematic selection biases in patient recruitment and retention. The panel addressed the pros and cons of various methods that can be used to measure adherence, and concluded that it is appropriate to use multiple measures whenever possible. Finally, the panel identified a broad range of intervention approaches, and conditions under which these interventions are likely to be most effective at reducing barriers to adherence and reinforcing adherence behavior.


Detection of smoking-related covalent DNA adducts in human placenta.
The presence of covalent DNA chemical addition products (adducts) in human term placentas was investigated by recently developed immunologic and 32P-postlabeling assays. DNA from placental specimens of smokers showed a small but not statistically significant increase in adduct levels when tested by antibodies to DNA modified with a benzo[a]pyrene dihydrodiol epoxide (BPDE-I), the ultimate carcinogenic derivative of benzo[a]pyrene. The postlabeling assay detected several modified nucleotides, one of which (adduct 1) strongly related to maternal smoking during pregnancy. This adduct was present in placental tissue from 16 of 17 smokers, but only 3 of 14 nonsmokers. Among smokers, levels of adduct 1 in general were only weakly related to questionnaire and biochemical measures of the intensity of smoking exposures, which suggests modulation by individual susceptibility factors. The adduct seemed to be derived from an aromatic carcinogen, but it may not result from several of the most intensely studied polycyclic aromatic hydrocarbons or aromatic amines in tobacco smoke. The data show the association of cigarette smoking with covalent damage to human DNA in vivo.


Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain.
Alzheimer's disease (AD) is the most common form of dementia, and it affects more women than men. Mitochondrial dysfunction (MD) plays a key role in AD, and it is detectable at an early stage of the degenerative process in peripheral tissues, such as peripheral mononuclear blood cells (PBMCs). However, whether these changes are also reflected in cerebral energy metabolism and whether sex-specific differences in mitochondrial function occur are not clear. Therefore, we estimated the correlation between mitochondrial function in PBMCs and brain energy metabolites and examined sex-specific differences in healthy participants to elucidate these issues. The current pilot study included 9 male and 15 female healthy adults (mean age 30.8 ± 7.1 years). Respiration and activity of mitochondrial respiratory complexes were measured using a Clarke-electrode (Oxygraph-2k system), and adenosine triphosphate (ATP) levels were determined using a bioluminescence-based assay in isolated PBMCs. Citrate synthase activity as a mitochondrial marker was measured using a photometric assay. Concentrations of brain energy metabolites were quantified in the same individuals using 1H-magnetic resonance spectroscopy (MRS). We detected sex-associated differences in mitochondrial function. Mitochondrial complexes I, I+II, and IV and uncoupled respiration and electron transport system (ETS) capacity in PBMCs isolated from blood samples of females were significantly (p < 0.05; p < 0.01) higher compared to males. ATP levels in the PBMCs of female participants were approximately 10% higher compared to males. Citrate synthase (CS) activity, a marker of mitochondrial content, was significantly (p < 0.05) higher in females compared to males. Sex-associated differences were also found for brain metabolites. The N-acetylaspartate (NAA) concentration was significantly higher in female participants compared to males in targeted regions. This difference was observed in white matter (WM) and an area with a high percentage (> 50%) of gray matter (GM) (p < 0.05; p < 0.01). The effect sizes indicated a strong influence of sex on these parameters. Sex-associated differences were found in PBMCs and brain, but the determined parameters were not significantly correlated. Our study revealed sex-associated differences in mitochondrial function in healthy participants. The underlying mechanisms must be elucidated in more detail, but our study suggests that mitochondrial function in PBMCs is a feasible surrogate marker to detect differences in mitochondrial function and energy metabolism in humans and it underscores the necessity of sex-specific approaches in therapies that target mitochondrial dysfunction.


Data-driven identification of potential Zika virus vectors.
Zika is an emerging virus whose rapid spread is of great public health concern. Knowledge about transmission remains incomplete, especially concerning potential transmission in geographic areas in which it has not yet been introduced. To identify unknown vectors of Zika, we developed a data-driven model linking vector species and the Zika virus via vector-virus trait combinations that confer a propensity toward associations in an ecological network connecting flaviviruses and their mosquito vectors. Our model predicts that thirty-five species may be able to transmit the virus, seven of which are found in the continental United States, including Culex quinquefasciatus and Cx. pipiens. We suggest that empirical studies prioritize these species to confirm predictions of vector competence, enabling the correct identification of populations at risk for transmission within the United States.


Economic assessment of integrated cancer and cardiovascular registries: The Barbados experience.
This report describes the resources required to support the integrated approach of the Barbados National Registry for Chronic Non-communicable Diseases (BNR) to non-communicable disease (NCD) case registration, and to identify differences in cost for collecting and maintaining information on cancer and cardiovascular disease (CVD) case registration. We used the modified Centers for Disease Control and Prevention's International Registry Costing Tool to collect data from the CVD and cancer registries. We used cancer and CVD cost data for the annual period April 2014 through March 2015 to estimate the total cost and cost per case. We used prospectively collected average annual CVD cases, and for cancer cases we assumed 2 or 3 years are needed for retrospective data collection. The Ministry of Health provided 56% of the resources for the registries. Labor accounted for over 70% of both registries' budgets, while management and administration, along with data collection and analysis, incurred the highest costs per case. Total variable cost activities related to data collection and analysis were higher for the CVD component (US$131,297) than the cancer component (US$58,917). The CVD cost per case (US$489) was in between the cancer 2-year (US$382) and the cancer 3-year (US$573) cost-per-case estimates. These findings indicate that there are substantial fixed costs related to management and administration of NCD registries. All registries need management and administration support. When registries are combined, management and administration costs can be shared. We project that registries that can share fixed-cost infrastructure are likely to incur a lower total cost per case.


Selective loss of pattern discrimination in early glaucoma.
A new perimetric pattern discrimination test was compared with conventional automated perimetry (Humphrey program 30-2 or Octopus program 32) in glaucoma patients, glaucoma suspects, and control subjects. The new test is based on the rationale that a greater percentage of retinal ganglion cells should be needed to detect a stimulus by its shape, or pattern, than by its brightness. The pattern discrimination stimulus was apatch of nonrandom dots embedded in a surrounding random dot field of the same average density. Pattern discrimination thresholds were measured by changing the degree of regularity, or coherence, of the stimulus dots. The fully coherent target was a static, 1-s duration, 20 x 20-dot checkerboard. Using a criterion-free relative operating characteristic analysis, we estimated the ability of both the pattern discrimination and conventional tests to distinguish the normal data distribution from the suspect and glaucoma distributions. The pattern discrimination test appeared to produce separations greater than conventional perimetry for glaucoma suspects and separations equivalent to conventional perimetry for glaucoma patients.


Twenty-five years of bis-pentafluorophenyl borane: a versatile reagent for catalyst and materials synthesis.
In 1995, the synthesis, properties and remarkable hydroboration activity of bis-pentafluorophenyl borane was first reported. Its reactivity stems from the ready accessibility of the monomeric borane and its high Lewis acidity. In the intervening twenty five years, this reagent has been widely exploited as a means of incorporating Lewis acidic -B(C6F5)2 groups into complex structures for a range of applications. In this "25th Anniversary" Feature article, we highlight the synthetic methods to the borane, its fundamental properties and chemistry as well as the diverse array of uses of this borane. These include self-activating olefin polymerization catalysts, frustrated Lewis pair generation, small molecule activation, bond cleavage reactions, Lewis acid catalysis and modification of organic materials.


An examination of the causes, consequences, and policy responses to the migration of highly trained health personnel from the Philippines: the high cost of living/leaving-a mixed method study.
Dramatic increases in the migration of human resources for health (HRH) from developing countries like the Philippines can have consequences on the sustainability of health systems. In this paper, we trace the outflows of HRH from the Philippines, map out its key causes and consequences, and identify relevant policy responses. This mixed method study employed a decentered, comparative approach that involved three phases: (a) a scoping review on health workers' migration of relevant policy documents and academic literature on health workers' migration from the Philippines; and primary data collection with (b) 37 key stakeholders and (c) household surveys with seven doctors, 329 nurses, 66 midwives, and 18 physical therapists. Filipino health worker migration is best understood within the context of macro-, meso-, and micro-level factors that are situated within the political, economic, and historical/colonial legacy of the country. Underfunding of the health system and un- or underemployment were push factors for migration, as were concerns for security in the Philippines, the ability to practice to full scope or to have opportunities for career advancement. The migration of health workers has both negative and positive consequences for the Philippine health system and its health workers. Stakeholders focused on issues such as on brain drain, gain, and circulation, and on opportunities for knowledge and technology transfer. Concomitantly, migration has resulted in the loss of investment in human capital. The gap in the supply of health workers has affected the quality of care delivered, especially in rural areas. The opening of overseas opportunities has commercialized health education, compromised its quality, and stripped the country of skilled learning facilitators. The social cost of migration has affected émigrés and their families. At the household level, migration has engendered increased consumerism and materialism and fostered dependency on overseas remittances. Addressing these gaps requires time and resources. At the same time, migration is, however, seen by some as an opportunity for professional growth and enhancement, and as a window for drafting more effective national and inter-country policy responses to HRH mobility. Unless socioeconomic conditions are improved and health professionals are provided with better incentives, staying in the Philippines will not be a viable option. The massive expansion in education and training designed specifically for outmigration creates a domestic supply of health workers who cannot be absorbed by a system that is underfunded. This results in a paradox of underservice, especially in rural and remote areas, at the same time as underemployment and outmigration. Policy responses to this paradox have not yet been appropriately aligned to capture the multilayered and complex nature of these intersecting phenomena.


A new method to estimate the amplitude spectrum analysis of ventricular fibrillation during cardiopulmonary resuscitation.
Accurate ventricular fibrillation (VF) waveform analysis usually requires rescuers to discontinue cardiopulmonary resuscitation (CPR). However, prolonged "hands-off" time has a deleterious impact on the outcome. We developed a new filter technique that could clean the CPR artifacts and help preserve the shockability index of VF METHODS: We analyzed corrupted ECGs, which were constructed by randomly adding different scaled CPR artifacts to the VF waveforms. A newly developed algorithm was used to identify the CPR fluctuations. The algorithm contained two steps. First, decomposing the raw data by empirical mode decomposition (EMD) into several intrinsic mode fluctuations (IMFs) and combining the dominant IMFs to reconstruct a new signal. Second, calculating each CPR cycle frequency from the new signal and fitting the new signal to the original corrupted ECG by least square mean (LSM) method to derive the CPR artifacts. The estimated VF waveform was derived by subtraction of the CPR artifacts from the corrupted ECG. We then performed amplitude spectrum analysis (AMSA) for original VF, corrupted ECG and estimated VF. A total of 150 OHCA subjects with initial VF rhythm were included for analysis. Ten CPR artifacts signals were used to construct corrupted ECG. Even though the correlations of AMSA between the corrupted ECG vs. the original VF and the estimated VF vs. the original VF are all high (all p<0.001), the values of AMSA were obviously biased in corrupted ECG with wide limits of agreement in Bland-Altman mean-difference plot. ROC analysis of the AMSA in the prediction of defibrillation success showed that the new algorithm could preserve the cut-off AMSA value for CPR artifacts with power ratio to VF from 0 to 6 dB. The new algorithm could efficiently filter the CPR-related artifacts of the VF ECG and preserve the shockability index of the original VF waveform.


Preclinical characterization of a (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide: a selective androgen receptor modulator for hormonal male contraception.
The pharmacologic effects of (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) were characterized in male rats as an animal model of hormonal male contraception. S-23 showed high binding affinity (inhibitory constant = 1.7 +/- 0.2 nm) and was identified as a full agonist in vitro. In castrated male rats, the ED50 of S-23 in the prostate and levator ani muscle was 0.43 and 0.079 mg/d, respectively. In intact male rats treated for 14 d, S-23 alone suppressed LH levels by greater than 50% at doses greater than 0.1 mg/d, with corresponding decreases in the size of the prostate but increases in the size of levator ani muscle. In intact male rats treated for up to 10 wk with S-23 and estradiol benzoate (EB; necessary to maintain sexual behavior in rats), S-23 showed biphasic effects on androgenic tissues and spermatogenesis by suppressing serum concentrations of LH and FSH. EB alone showed no effect on spermatogenesis. In the EB + S-23 (0.1 mg/d) group, four of six animals showed no sperm in the testis and zero pregnancies (none of six) in mating trials. After termination of treatment, infertility was fully reversible, with a 100% pregnancy rate observed after 100 d of recovery. S-23 increased bone mineral density and lean mass but reduced fat mass in a dose-dependent manner. This is the first study to show that a selective androgen receptor modulator combined with EB is an effective and reversible regimen for hormonal male contraception in rats. The beneficial effects of S-23 on the muscle, tissue selectivity, and favorable pharmacokinetic properties make it a strong candidate for use in oral male contraception.


CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia.
T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents. T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance. Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine-receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications.


Anti-allergic effects of herbal product from Allium cepa (bulb).
Allium cepa (Family Liliaceae) is a reputed Indian medicinal herb that is prescribed as an effective remedy for several ailments in the Ayurvedic system of medicine. The aim of this study was to evaluate its efficacy against various events responsible for Type I allergic reactions. A herbal fraction (ALC-02) from A. cepa (bulb) inhibited histamine release and attenuated intracellular calcium levels in Compound 48/80-induced rat peritoneal mast cells. It also prevented Compound 48/80-mediated systemic anaphylaxis while lowering histamine levels in plasma. ALC-02 suppressed carrageenan-induced rat paw edema. It inhibited eosinophil peroxidase activity and protein content in bronchoalveolar lavage fluid (BALF) of ovalbumin-challenged mice. In this experiment ALC-02 also caused a substantial reduction in lipid peroxidation in BALF/lung tissue and augmented superoxide dismutase activity in lung tissue. ALC-02 suppressed erythrocytic lysis caused by Triton X-100. A significant quenching of 1,1-diphenyl-2-picrylhydrazyl radical by ALC-02 was observed. The results have shown a promising anti-allergic profile of ALC-02 that could be attributed to its potential antihistaminic, anti-inflammatory, and antioxidant activities.


Adiaspiromycosis: an unusual fungal infection of the lung. Report of 11 cases.
Adiaspiromycosis (ad"i-ah-spi"ro-mi-kósis) is a worldwide, noninfectious, nonarthropod transmitted fungal infection of lower vertebrates, most commonly rodents. Humans become an accidental host by inhaling dust-borne spores (conidia) of the saprophytic soil fungus, Emmonsia crescens (recently renamed Chrysosporium parvum variety crescens). We report 11 cases of this unusual deep mycosis from South America, Europe, and the United States. The severity of the disease depends on the number of spores inhaled. In limited inoculum, the disease remains localized (two cases), whereas in heavy inocula the fungus involves both lungs (nine cases) and presents as a diffuse reticulonodular infiltrate. In this disseminated form, patients usually complain of cough, dyspnea on exertion, and low-grade fever mimicking other systemic fungal infections and tuberculosis. It is difficult to unmask the fungus because it is not easily cultured nor is there a reliable serologic test. Therefore, a biopsy is required and the pathologist must recognize the large (ranging in size from 50 to 500 microns), round, Gomori methenamine-silver nitrate and periodic acid-Schiff reagent-positive spherules with a trilaminar wall. The spherules can be surrounded by either suppuration, epithelioid granulomas with or without necrosis, or concentric, hyalinized fibrosis. In the latter chronic stage, the organism may collapse, forming a variety of sizes and shapes thereby resembling other fungi, helminths, mineral particles, or inhaled pollen grains. Clinically, the infection most commonly regresses spontaneously, but may persist, or rarely progress, requiring surgical intervention with limited resection to attain cure.


Mutations in both sides of the photosystem I reaction center identify the phylloquinone observed by electron paramagnetic resonance spectroscopy.
The core of photosystem I (PS1) is composed of the two related integral membrane polypeptides, PsaA and PsaB, which bind two symmetrical branches of cofactors, each consisting of two chlorophylls and a phylloquinone, that potentially link the primary electron donor and the tertiary acceptor. In an effort to identify amino acid residues near the phylloquinone binding sites, all tryptophans and histidines that are conserved between PsaA and PsaB in the region of the 10th and 11th transmembrane alpha-helices were mutated in Chlamydomonas reinhardtii. The mutant PS1 reaction centers appear to assemble normally and possess photochemical activity. An electron paramagnetic resonance (EPR) signal attributed to the phylloquinone anion radical (A(1)(-)) can be observed either transiently or after illumination of reaction centers with pre-reduced iron-sulfur clusters. Mutation of PsaA-Trp(693) to Phe resulted in an inability to photo-accumulate A(1)(-), whereas mutation of the analogous tryptophan in PsaB (PsaB-Trp(673)) did not produce this effect. The PsaA-W693F mutation also produced spectral changes in the time-resolved EPR spectrum of the P(700)(+) A(1)(-) radical pair, whereas the analogous mutation in PsaB had no observable effect. These observations indicate that the A(1)(-) phylloquinone radical observed by EPR occupies the phylloquinone-binding site containing PsaA-Trp(693). However, mutation of either tryptophan accelerated charge recombination from the terminal Fe-S clusters.


Ultrafast Nanoimaging of the Photoinduced Phase Transition Dynamics in VO2.
Many phase transitions in correlated matter exhibit spatial inhomogeneities with expected yet unexplored effects on the associated ultrafast dynamics. Here we demonstrate the combination of ultrafast nondegenerate pump-probe spectroscopy with far from equilibrium excitation, and scattering scanning near-field optical microscopy (s-SNOM) for ultrafast nanoimaging. In a femtosecond near-field near-IR (NIR) pump and mid-IR (MIR) probe study, we investigate the photoinduced insulator-to-metal (IMT) transition in nominally homogeneous VO2 microcrystals. With pump fluences as high as 5 mJ/cm(2), we can reach three distinct excitation regimes. We observe a spatial heterogeneity on ∼50-100 nm length scales in the fluence-dependent IMT dynamics ranging from <100 fs to ∼1 ps. These results suggest a high sensitivity of the IMT with respect to small local variations in strain, doping, or defects that are difficult to discern microscopically. We provide a perspective with the distinct requirements and considerations of ultrafast spatiotemporal nanoimaging of phase transitions in quantum materials.


Vaginal douching in Cambodian women: its prevalence and association with vaginal candidiasis.
We determined the prevalence of vaginal douching (cleansing of the vagina with liquid) in a sample of Cambodian women, and examined the associations of douching with genitourinary symptoms and infections, after controlling for potential confounding factors, including genitourinary symptoms and sociodemographic factors. A total of 451 adolescent and adult females aged 15 to 49 years who attended 17 maternal and child health (MCH) clinics in 7 provinces of Cambodia in 2001 were consecutively enrolled as a part of the Sexually Transmitted Infection Sentinel Survey. Sociodemographic factors, genitourinary symptoms, and frequency of douching were assessed by face-to-face interviews using a structured questionnaire. Vaginal infections were examined by using standard diagnostic procedures specific to each pathogen. The proportion of participants who douched at least once a week was 76.7% (n = 346). Douching was significantly more prevalent in urban than in rural women (85.7%, n = 198 vs 67.3%, n = 148; P < 0.001). Frequency of douching was significantly associated with genitourinary symptoms, which were most prevalent in participants who douched from several times a week to once a day; genitourinary symptoms were less prevalent in those who douched more than once a day. Douching was significantly associated with vaginal candidiasis, but not with trichomoniasis or bacterial vaginosis, and this association persisted even after controlling for sociodemographic factors and genitourinary symptoms. Vaginal douching was very common among Cambodian women visiting MCH clinics. Further investigations are warranted to elucidate the reasons for douching. In addition, women should be informed that douching may endanger their reproductive health.


Strain and sex differences in serum cholesterol levels of mice.
Five inbred strains of mice differed significantly in serum cholesterol level. Cholesterol levels ranged from 128 mg/100 ml in C57B1/6 mice to 208 mg/100 ml in C3H mice. Cholesterol level was significantly higher in males than in females. The cholesterol level of 2-month-old mice did not differ from that of 1-year-old mice.


Integrating Social Needs Into Health Care: A Twenty-Year Case Study Of Adaptation And Diffusion.
The US health care system has recently begun to account for patients' unmet social needs in care delivery and payment reform. This article presents a twenty-year qualitative case study of five stages of diffusion-testing and learning, standardization, replication, shifting from doing to enabling, and catalyzing broad adoption-of a practical approach for integrating social needs into clinical care. This case study of Health Leads and its funders confirms the importance of focusing on a clear aim, investing in model testing and standardization to enable subsequent responsiveness to the market, and the willingness of innovators and their investors to cede control of a model to allow local adaption and accelerate broad adoption.


Toxoplasma gondii: 1908-2008, homage to Nicolle, Manceaux and Splendore.
The discovery of Toxoplasma gondii independently by Nicolle and Manceaux (1908) and Splendore (1908) was to open a 'Pandora's Box' that has led research on this parasite into a number of scientific disciplines. In the 100 years since its discovery, the mystery surrounding T. gondii and its inter-relationship with humans has continued to provide a stimulating source of material in many areas of research, resulting in the publication of almost 20,000 papers and a number of books. This flood of diverse information shows no sign of abating, with an average of 10 papers per week appearing in PubMed. Herein, it is impossible to do more than provide a very superficial comment on what has become a massive body of scientific information. T. gondii has many unique features and seems to be the 'exception to almost every rule' thus acting as a focus for research in disciplines from epidemiology to immunology to human behaviour to cell biology to human disease. In this review a number of the historical advances will be mentioned and combined with a description of the basic biology of the parasite.


Disseminated miliary cerebral candidiasis.
We present a case of disseminated intracranial infection by Candida albicans in a 5-year-old girl who had fever and a change of consciousness after surgery for complex congenital heart malformation. MR imaging revealed multiple small ring-enhancing hemorrhagic abscesses. One year after antifungal treatment, the abscesses and ventriculomegaly were almost completely resolved. The patient was discharged in a stable but vegetative condition.


Efficient anti-Stokes generation via intermodal stimulated Raman scattering in gas-filled hollow-core PCF.
A strong anti-Stokes Raman signal, from the vibrational Q(1) transition of hydrogen, is generated in gas-filled hollow-core photonic crystal fiber. To be efficient, this process requires phase-matching, which is not automatically provided since the group velocity dispersion is typically non-zero and--inside a fiber--cannot be compensated for using a crossed-beam geometry. Phase-matching can however be arranged by exploiting the different dispersion profiles of higher-order modes. We demonstrate the generation of first and second anti-Stokes signals in higher-order modes by pumping with an appropriate mixture of fundamental and a higher-order modes, synthesized using a spatial light modulator. Conversion efficiencies as high as 5.3% are achieved from the pump to the first anti-Stokes band.


Selective structure-based virtual screening for full and partial agonists of the beta2 adrenergic receptor.
The recently solved high-resolution X-ray structure of the beta2 adrenergic receptor has been challenged for its ability to discriminate inverse agonists/antagonists from partial/full agonists. Whereas the X-ray structure of the ground state receptor was unsuitable to distinguish true ligands with different functional effects, modifying this structure to reflect early conformational events in receptor activation led to a receptor model able to selectively retrieve full and partial agonists by structure-based virtual screening. The use of a topological scoring function based on molecular interaction fingerprints was shown to be mandatory to properly rank docking poses and achieve acceptable enrichments for partial and full agonists only.


Clinical features of the exploding head syndrome.
Fifty patients suffering from the "exploding head syndrome" are described. This hitherto unreported syndrome is characterised by a sense of an explosive noise in the head usually in the twilight stage of sleep. The associated symptoms are varied, but the benign nature of the condition is emphasised and neither extensive investigation nor treatment are indicated.


Pre-transmembrane sequence of Ebola glycoprotein. Interfacial hydrophobicity distribution and interaction with membranes.
The membrane-interacting domain that precedes the transmembrane anchor of Ebola glycoprotein has been characterized. This aromatic-rich region is predicted to bind the membrane interface adopting an alpha-helical structure. Peptides representing either the Ebola glycoprotein pre-transmembrane sequence, or a 'scrambled' control with a different hydrophobic-at-interface moment, have been studied. Insertion into lipid monolayers, changes in intrinsic fluorescence and in infrared spectra demonstrated that only the wild-type peptide bound the interface under equilibrium conditions and adopted an alpha-helical conformation. The presence of the raft-associated lipid sphingomyelin did not affect membrane insertion, but it stimulated highly the membrane-destabilizing capacity of the pre-transmembrane sequence. A parallel study of the effects of the viral sequence and of melittin suggests that Ebola glycoprotein pre-transmembrane sequence might target membranes inherently prone to destabilization by lytic peptides.


Impact of automated reporting of estimated glomerular filtration rate in the veterans health administration.
Early detection and treatment of chronic kidney disease (CKD) is important for slowing progression to renal failure and preventing cardiovascular events, but CKD is often not recognized and patients are referred to nephrologists too late for timely management. Automated laboratory reporting of estimated glomerular filtration rate (eGFR) has been introduced in many health systems to improve CKD recognition, but its impact on large, US-based health systems remains unclear. Retrospective time-series study examined change in renal care services and CKD recognition across VA health care system facilities in 2000-2009. Hierarchical generalized linear models were used to estimate immediate and long-term impacts of eGFR reporting across facilities on monthly rates of outpatient CKD diagnoses, utilization of CKD diagnostic tests (urine microalbumin and kidney ultrasound), and outpatient nephrology visits. Rates of CKD recognition through diagnoses in patient medical records changed an average of 11.4 additional diagnosed patients per 10,000 in the general outpatient population per month, with sustained long-term increases in CKD diagnoses (P<0.001). Diagnostic microalbumin and kidney ultrasound testing increased significantly, with long-term increases in microalbumin testing (P<0.001) and short-term increases in kidney ultrasound (P=0.01-0.04) rates across the VHA. There was no significant change in nephrology consultation rates. Automated eGFR reporting was associated with moderate system-level improvements in documentation of CKD diagnoses and use of diagnostic tests, but had no impact on nephrology consultation. To effectively reduce the large burden of disease and its associated complications, further strategies are needed to identify and provide timely treatment to those with CKD.


Abdominal lean muscle is associated with lower mortality among kidney waitlist candidates.
Morphometric assessments, such as muscle density and body fat distribution, have emerged as strong predictors of cardiovascular risk and postoperative morbidity and mortality. To date, no study has examined morphometric mortality risk prediction among kidney transplant (KT) candidates. KT candidates, waitlisted 2008-2009, were identified (n=96) and followed to the earliest of transplant, death, or administrative end of study. Morphometric measures, including abdominal adipose tissue, paraspinous and psoas muscle composition, and aortic calcification, were measured from CTs. Risk of waitlist mortality was examined using Cox proportional hazard regression. On adjusted analyses, radiologic measures remained independently and significantly associated with lower waitlist mortality; the addition of radiologic measures significantly improved model predictive ability over models containing traditional risk factors alone (net reclassification index: 0.56, 95% CI: 0.31-0.75). Higher psoas muscle attenuation (indicative of leaner muscle) was associated with decreased risk of death (aHR: 0.93, 95% CI: 0.91-0.96, P<.001), and for each unit increase in lean paraspinous volume, there was an associated 2% decreased risk for death (aHR: 0.98, 95% CI: 0.96-0.99, P=.03). Radiologic measures of lean muscle mass, such as psoas muscle attenuation and paraspinous lean volume, may improve waitlist mortality risk prediction and candidate selection.


Elderly patients with non-Hodgkin lymphoma who receive chemotherapy are at higher risk for osteoporosis and fractures.
To determine risk of osteoporosis and fractures associated with chemotherapy among elderly non-Hodgkin's lymphoma (NHL) patients, a cohort of 13 570 patients aged >/=65 years with incident NHL was identified from SEER-Medicare data with up to 11 years of follow-up. One year prior to the diagnosis, significantly fewer patients had fracture and osteoporosis claims in the chemotherapy group versus no chemotherapy group. However, after NHL diagnosis, patients who received chemotherapy had significantly higher rates of fracture (31% versus 19%, P < 0.001) and osteoporosis (10% versus 8%, P < 0.001), compared with those who did not. The risk of having fracture (odds ratio = 2.24, 95% CI = 2.04 - 2.45) and osteoporosis (odds ratio = 1.27, 95% CI = 1.12 - 1.45) was significantly higher in patients receiving chemotherapy compared with those who did not, after controlling for demographic and tumor factors. In conclusion, use of chemotherapy was significantly associated with increased risk of fracture and osteoporosis in elderly patients with NHL.


Impulse control disorders: updated review of clinical characteristics and pharmacological management.
Impulse control disorders (ICDs) are characterized by urges and behaviors that are excessive and/or harmful to oneself or others and cause significant impairment in social and occupational functioning, as well as legal and financial difficulties. ICDs are relatively common psychiatric conditions, yet are poorly understood by the general public, clinicians, and individuals struggling with the disorder. Although ICD treatment research is limited, studies have shown ICDs may respond well to pharmacological treatment. This article presents a brief overview about the clinical characteristics of ICDs and pharmacological treatment options for individuals with ICDs.


Antioxidant and hepatoprotective properties of Indian Sunderban mangrove Bruguiera gymnorrhiza L. leave.
Bruguiera gymnorrhiza L. (family Rhizophoraceae) is a true mangrove habitat in Indian Sunderban and traditionally uses for liver disorders. The aim was to evaluate antioxidant and hepatoprotective actions of leave extract of B. gymnorrhiza L. Hydro-methanolic extract of mangrove leaves (BR) was standardized using spectrophotometric and high-performance thin layer chromatography methods. Radical scavenging activities were assessed in different in vitro methods, like 1,1-diphenyl-2-picrylhydrazyl, 2,2'-azino-bis-3-ethyl benzthiazoline-6-sulphonic acid (+), superoxides, nitric oxides and hydroxyl radicals. Hepatoprotective efficacy of BR (125 mg/kg and 250 mg/kg, p.o) was measured in D-galactosamine (GalN) induced (200 mg/kg, i.p) hepatitis in Wistar rats. Silymarin (25 mg/kg, p.o) was used as known hepatoprotective agent. Polyphenols such as gallic acid, quercetin, and coumarin obtained from BR exhibited powerful antioxidant properties. Moreover, it produced dose-dependent protection against GalN induced hepatitis in rats. It significantly reduced GalN induced elevation of enzymes (alanine transaminase, aspartate aminotransferase, and alkaline phosphatase) in serum and resist oxidative stress marked by lipid peroxides, glutathione, and catalase in hepatic parenchyma. Polyphenols rich B. gymnorrhiza L. leaves ameliorate hepatic tissue injury through its antioxidant effects.


Comparison of vector velocity imaging and three-dimensional speckle tracking echocardiography for assessment of left ventricular longitudinal strain in hypertrophic cardiomyopathy.
Background: Vector velocity imaging (VVI) is a two-dimensional wall motion tracking method that can measure cardiac mechanics in hypertrophic cardiomyopathy (HCM). 3D-speckle tracking echocardiography (3D-STE) has been proven to be superior to conventional measures in assessment of LV function. The aim of this study was to compare the two technologies in the assessment of LV longitudinal strain (LS) in HCM patients. Methods: A total of 50 patients with HCM were investigated using VVI and 3D-STE in same setting. 3D-STE allows obtaining longitudinal, circumferential, radial and area strains (AS). Values of longitudinal strain (LS) and AS by 3D-STE were compared to VVI- derived analyses. Thereafter, VVI-LS values were correlated with LV phenotype. Last, the variability of VVI versus 3DE strain measurements as well as recorded time of analysis was assessed. Results: The absolute value of 3D-STE LS and AS is significantly higher than VVI-LS (P < 0.0001). VVI provided complete longitudinal LV strain information, similar to 3D-STE. There is excellent agreement between the two technologies-derived values, however, a greater number of segments could be analyzed using VVI (94.7%), compared with 3DE (62.1%). Despite VVI being more time consuming, VVI-LS is more correlated to LV mass index, mitral regurgitation severity and functional class when compared with 3D-STE LS and AS. Conclusions: VVI is a feasible modality for assessing LV longitudinal strain. Although VVI agreed well with 3D-STE for most of regional and global LS, a better correlation was found between VVI-LS and HCM phenotype. It is hypothesized that this discrepancy originates from the inferior imaging quality using 3D tracking algorithms.


Gβ Regulates Coupling between Actin Oscillators for Cell Polarity and Directional Migration.
For directional movement, eukaryotic cells depend on the proper organization of their actin cytoskeleton. This engine of motility is made up of highly dynamic nonequilibrium actin structures such as flashes, oscillations, and traveling waves. In Dictyostelium, oscillatory actin foci interact with signals such as Ras and phosphatidylinositol 3,4,5-trisphosphate (PIP3) to form protrusions. However, how signaling cues tame actin dynamics to produce a pseudopod and guide cellular motility is a critical open question in eukaryotic chemotaxis. Here, we demonstrate that the strength of coupling between individual actin oscillators controls cell polarization and directional movement. We implement an inducible sequestration system to inactivate the heterotrimeric G protein subunit Gβ and find that this acute perturbation triggers persistent, high-amplitude cortical oscillations of F-actin. Actin oscillators that are normally weakly coupled to one another in wild-type cells become strongly synchronized following acute inactivation of Gβ. This global coupling impairs sensing of internal cues during spontaneous polarization and sensing of external cues during directional motility. A simple mathematical model of coupled actin oscillators reveals the importance of appropriate coupling strength for chemotaxis: moderate coupling can increase sensitivity to noisy inputs. Taken together, our data suggest that Gβ regulates the strength of coupling between actin oscillators for efficient polarity and directional migration. As these observations are only possible following acute inhibition of Gβ and are masked by slow compensation in genetic knockouts, our work also shows that acute loss-of-function approaches can complement and extend the reach of classical genetics in Dictyostelium and likely other systems as well.


The role of OIE aquatic standards and OIE Reference Laboratories in aquatic animal disease prevention and control.
The World Organisation for Animal Health (OIE) develops normative documents relating to rules that Member Countries and Territories can use to protect themselves from diseases without setting up unjustified sanitary barriers. For aquatic animal disease, the Aquatic Animal Health Code and the Manual of Diagnostic Tests for Aquatic Animals are prepared by the Aquatic Animal Health Standards Commission, with the assistance of internationally renowned experts, the other Specialist Commissions of the OIE, and in consultation with OIE Members. The role of these standards in aquatic animal disease prevention and control is described in detail. There are currently 27 OIE Reference Laboratories and one Collaborating Centre for aquatic animal diseases, providing a network of expertise in aquatic animal health. These laboratories play a key role in aquatic animal disease prevention and control through providing diagnostic services and expert advice that is particularly useful in emergency situations.


The Normalization of Cannabis Use Among Bangladeshi and Pakistani Youth: A New Frontier for the Normalization Thesis?
The Asian population in Britain has grown, representing the second largest ethnic group; Bangladeshi, Pakistani, and Indian nationalities are prevalent (Jivraj, 2012 ; Office for National Statistics, 2013 ). Yet, we know relatively little about the nature and extent of their substance use. Jayakody et al. ( 2006 ) argue ethnic minority groups may be influenced by the norms and values of the dominant culture. Given recreational drug use has undergone a process of normalization in Britain (Aldridge et al., 2011 ; Parker et al., 1998 , 2002 ), we explore the degree to which this is occurring in a Bangladeshi and Pakistani community of Muslim faith in Northern England; a group typically assumed to reject substance use because of robust religious and cultural values. To examine the extent, frequency, and nature of substance use, and associated attitudes. A cross-sectional study collecting qualitative data from a sample (N = 43) of adolescents accessing a drug service and a range of professionals working with them during 2014. We also present analyses of routinely collected quantitative client data. Adolescent interviewees reported extensive personal experience smoking skunk cannabis, and professionals working in the community confirmed many young Asians smoked it. Its consumption appeared to be accommodated into the daily lives of young people and the supply of it also showed signs of acceptance. Skunk cannabis may be undergoing a process of normalization within some Asian communities in Britain. Our study has significant implications for the normalization thesis, finding evidence for normalization within a subpopulation that is typically perceived to resist this trend.


Loss of p27Kip1 enhances tumor progression in chronic hepatocyte injury-induced liver tumorigenesis with widely ranging effects on Cdk2 or Cdc2 activation.
Effects of p27Kip1 inactivation on tumorigenesis vary from promotion to prevention dependent on the mouse models used. When p27 inactivation has a positive effect on tumorigenesis, de-regulated activation of cyclin-dependent kinases (Cdks) is generally believed to be the underlying mechanism since the function of p27 as an inhibitor of Cdks is firmly established. Here, we determined the effects of p27 inactivation on disease progression and Cdk activation in mouse liver tumorigenesis that originates from hepatocyte regenerative proliferation in response to chronic liver injury, an established etiology in most human liver cancer. Our results show that inactivation of p27 did not affect early-stage hepatocyte regenerative proliferation but promoted tumor cell proliferation and progression in the late stage of the disease. Interestingly, Cdc2 over-expression was observed in all and cyclin E1 was over-expressed in half of the late-stage tumors regardless of p27 status; and p27 inactivation led to significant activation of Cdk2 or Cdc2 only in half of the p27-deficient tumors. These results reveal a tumor suppressor role of p27 in chronic hepatocyte injury-induced liver tumorigenesis and, at the same time, the need to further study the mechanisms for tumor promotion by p27 inactivation.


Do binucleate cardiomyocytes have a role in myocardial repair? Insights using isolated rodent myocytes and cell culture.
Neonatal and adult cardiomyocytes were isolated from rat hearts. Some of the adult myocytes were cultured to allow for cell dedifferentiation, a phenomenon thought to mimic cell changes that occur in stressed myocardium, with myocytes regressing to a fetal pattern of metabolism and stellate neonatal shape.Using fluorescence deconvolution microscopy, cells were probed with fluorescent markers and scanned for a number of proteins associated with ion control, calcium movements and cardiac function. Image analysis of deconvoluted image stacks and sequential real-time image recordings of calcium transients of cells were made.All three myocyte groups were predominantly comprised of binucleate cells. Clustering of proteins to a single nucleus was a common observation, suggesting that one nucleus is active in protein synthesis pathways, while the other nucleus assumes a 'dormant' or different role and that cardiomyocytes might be mitotically active even in late development, or specific protein syntheses could be targeted and regulated for reintroduction into the cell cycle.Such possibilities would extend cardiac disease associated stem cell research and therapy options, while producing valuable insights into developmental and death pathways of binucleate cardiomyocytes (word count 183).


A feedback loop between the liver-enriched transcription factor network and miR-122 controls hepatocyte differentiation.
Hepatocyte differentiation is controlled by liver-enriched transcription factors (LETFs). We investigated whether LETFs control microRNA expression during development and whether this control is required for hepatocyte differentiation. Using in vivo DNA binding assays, we identified miR-122 as a direct target of the LETF hepatocyte nuclear factor (HNF) 6. The role and mechanisms of the HNF6-miR-122 gene cascade in hepatocyte differentiation were studied in vivo and in vitro by gain-of-function and loss-of-function experiments, using developing mice and zebrafish as model organisms. HNF6 and its paralog Onecut2 are strong transcriptional stimulators of miR-122 expression. Specific levels of miR-122 were required for proper progression of hepatocyte differentiation; miR-122 stimulated the expression of hepatocyte-specific genes and most LETFs, including HNF6. This indicates that HNF6 and miR-122 form a positive feedback loop. Stimulation of hepatocyte differentiation by miR-122 was lost in HNF6-null mice, revealing that a transcription factor can mediate microRNA function. All hepatocyte-specific genes whose expression was stimulated by miR-122 bound HNF6 in vivo, confirming their direct regulation by this factor. Hepatocyte differentiation is directed by a positive feedback loop that includes a transcription factor (HNF6) and a microRNA (miR-122) that are specifically expressed in liver. These findings could lead to methods to induce differentiation of hepatocytes in vitro and improve our understanding of liver cell dedifferentiation in pathologic conditions.


Anti-malarial prescription practices among outpatients with laboratory-confirmed malaria in the setting of a health facility-based sentinel site surveillance system in Uganda.
Most African countries have adopted artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. The World Health Organization now recommends limiting anti-malarial treatment to those with a positive malaria test result. Limited data exist on how these policies have affected ACT prescription practices. Data were collected from all outpatients presenting to six public health facilities in Uganda as part of a sentinel site malaria surveillance programme. Training in case management, encouragement of laboratory-based diagnosis of malaria, and regular feedback were provided. Data for this report include patients with laboratory confirmed malaria who were prescribed anti-malarial therapy over a two-year period. Patient visits were analysed in two groups: those considered ACT candidates (defined as uncomplicated malaria with no referral for admission in patients ≥ 4 months of age and ≥ 5 kg in weight) and those who may not have been ACT candidates. Associations between variables of interest and failure to prescribe ACT to patients who were ACT candidates were estimated using multivariable logistic regression. A total of 51,355 patient visits were included in the analysis and 46,265 (90.1%) were classified as ACT candidates. In the ACT candidate group, 94.5% were correctly prescribed ACT. Artemether-lumefantrine made up 97.3% of ACT prescribed. There were significant differences across the sites in the proportion of patients for whom there was a failure to prescribe ACT, ranging from 3.0-9.3%. Young children and woman of childbearing age had higher odds of failure to receive an ACT prescription. Among patients who may not have been ACT candidates, the proportion prescribed quinine versus ACT differed based on if the patient had severe malaria or was referred for admission (93.4% vs 6.5%) or was below age or weight cutoffs for ACT (41.4% vs 57.2%). High rates of compliance with recommended ACT use can be achieved in resource-limited settings. The unique health facility-based malaria surveillance system operating at these clinical sites may provide a framework for improving appropriate ACT use at other sites in sub-Saharan Africa.


Unpacking Care Coordination Through a Multiteam System Lens: A Conceptual Framework and Systematic Review.
The 2016 President's Cancer Panel Connected Health report calls for thoroughly characterizing the team structures and processes involved in coordinating care for people with chronic conditions. We developed a multilevel care coordination framework by integrating existing frameworks from the teams and care coordination literatures, and used it to review evidence examining care coordination processes for patients with cancer, diabetes, cardiovascular disease, and combinations of these conditions. We searched Pubmed/MedLINE, CINAHL Plus, Cochrane, PsycINFO (December 2009-June 2016), and references from previous reviews. Studies describing behavioral markers of coordination between ≥2 US health care providers caring for adults with cancer, chronic heart disease, diabetes, or populations with a combination of these conditions were included. Two investigators screened 4876 records and 180 full-text articles yielding 33 studies. One investigator abstracted data, a second checked abstractions for accuracy. Most studies identified information sharing or monitoring as key coordination processes. To execute these processes, most studies used a designated role (eg, coordinator), objects and representations (eg, survivorship plans), plans and rules (eg, protocols), or routines (eg, meetings). Few examined the integrating conditions. None statistically examined coordination processes or integrating conditions as mediators of relationships between specific coordination mechanisms and patient outcomes. Restricted to United States, English-language studies; heterogeneity in methods and outcomes. Limited research unpacks relationships between care coordination mechanisms, coordination processes, integrating conditions, and patient outcomes suggested by existing theory. The proposed framework offers an organizer for examining behaviors and conditions underlying effective care coordination.


Phylogenetic diversity and microsphere array-based genotyping of human pathogenic Fusaria, including isolates from the multistate contact lens-associated U.S. keratitis outbreaks of 2005 and 2006.
In 2005 and 2006, outbreaks of Fusarium keratitis associated with soft contact lens use occurred in multiple U.S. states and Puerto Rico. A case-control study conducted by the Centers for Disease Control and Prevention (CDC) showed a significant association between infections and the use of one particular brand of lens solution. To characterize the full spectrum of the causal agents involved and their potential sources, partial DNA sequences from three loci (RPB2, EF-1alpha, and nuclear ribosomal rRNA) totaling 3.48 kb were obtained from 91 corneal and 100 isolates from the patient's environment (e.g., contact lens and lens cases). We also sequenced a 1.8-kb region encoding the RNA polymerase II second largest subunit (RPB2) from 126 additional pathogenic isolates to better understand how the keratitis outbreak isolates fit within the full phylogenetic spectrum of clinically important fusaria. These analyses resulted in the most robust phylogenetic framework for Fusarium to date. In addition, RPB2 nucleotide variation within a 72-isolate panel was used to design 34 allele-specific probes to identify representatives of all medically important species complexes and 10 of the most important human pathogenic Fusarium in a single-well diagnostic assay, using flow cytometry and fluorescent microsphere technology. The multilocus data revealed that one haplotype from each of the three most common species comprised 55% of CDC's corneal and environmental isolates and that the corneal isolates comprised 29 haplotypes distributed among 16 species. The high degree of phylogenetic diversity represented among the corneal isolates is consistent with multiple sources of contamination.


Improved quality of life in patients with generalized cardiovascular metabolic disease on a prepared diet.
Current dietary recommendation for cardiovascular disease risk reduction and recommended dietary allowances (RDAs) were used to develop a nutritionally complete prepackaged prepared meal plan specifically designed to reduce the risk of cardiovascular disease. In the current study we tested patient acceptance of the diet as defined by measures of quality of life. In a randomized, parallel-design, multicenter clinical trial, 77 persons with hypertension, diabetes mellitus, dyslipidemia, or a combination of two or more of these conditions were recruited and randomly assigned to either a prepared meal plan (n = 39) or a comparable self-selected diet (n = 38) for 10 wk. The prepared meal plan met both the RDAs for all essential micronutrients and the dietary recommendations of national health organizations for macronutrients, cholesterol, sodium, and fiber. The prescribed self-selected diet was matched for macronutrients. Quality of life, as measured by a battery of instruments, was the major endpoint. Individuals consuming the prepared meal plan had significant improvements in mental health (P < 0.01), general perceived health (P < 0.005), daily activities (P < 0.05), work performance (P < 0.005), affect (P < 0.01), and nutritional health perceptions (P < 0.001), and reductions in nutrition hassles based on a standardized questionnaire (P < 0.001). The self-selected-diet group had significant improvements in nutritional health perceptions (P < 0.001) and affect (P < 0.001). There were significant improvements in weight (P < 0.001), blood pressure (P < 0.001), cholesterol (P < 0.002), low-density lipoproteins (P < 0.001), glucose (P < 0.014), and glycated hemoglobin (Hb A(1c) (P < 0.004) that were comparable in both groups. In summary, this study shows that a nutritionally complete diet, whether prepackaged or self-selected, improves multiple risk factors for cardiovascular disease. The prepackaged prepared meal plan had the added benefit of a greater improvement in quality of life.


Ectopic expression of gamma interferon in the eye protects transgenic mice from intraocular herpes simplex virus type 1 infections.
Transgenic (rho gamma) mice provide a model for studying the influence of gamma interferon (IFN-gamma) produced in the eye on ocular and cerebral viral infection. To establish this model, we injected BALB/c- and C57BL/6-derived transgenic and nontransgenic mice of different ages intravitreally with herpes simplex virus type 1 (HSV-1) strain F. Eye and brain tissues of these mice were assessed for pathological and immunocytochemical changes. HSV-1 infection induced severe retinitis of the injected eyes and infection of the brain in all mice. In transgenic mice inoculated with HSV-1, the left, nontreated eyes were protected from retinitis, whereas nontransgenic mice developed bilateral retinitis. Additional intravitreal injection of IFN-gamma with the virus protected the noninoculated eyes of nontransgenic mice. Three-week-old nontransgenic mice died from HSV-1 infection, whereas transgenic mice of the same age and nontransgenic mice intravitreally treated with IFN-gamma survived. Ocular IFN-gamma production increased the extent of inflammation in transgenic mice but did not have a significant influence on the growth of HSV-1 until day 3 after inoculation and did not influence the neuroinvasion of this virus. Thus, the effects of IFN-gamma were not caused by an early block of viral replication. Possible mechanisms of IFN-gamma action include activation of the immune response, alteration of the properties of the virus, and direct protection of neurons.


Reach, engagement, and effectiveness: a systematic review of evaluation methodologies used in health promotion via social networking sites.
Issue addressed Social networking sites (SNS) are increasingly popular platforms for health promotion. Advancements in SNS health promotion require quality evidence; however, interventions are often not formally evaluated. This study aims to describe evaluation practices used in SNS health promotion. Methods A systematic review was undertaken of Medline, PsycINFO, Scopus, EMBASE, CINAHL Plus, Communication and Mass Media Complete, and Cochrane Library databases. Articles published between 2006 and 2013 describing any health promotion intervention delivered using SNS were included. Results Forty-seven studies were included. There were two main evaluation approaches: closed designs (n=23), which used traditional research designs and formal recruitment procedures; and open designs (n=19), which evaluated the intervention in a real-world setting, allowing unknown SNS users to interact with the content without enrolling in research. Closed designs were unable to assess reach and engagement beyond their research sample. Open designs often relied on weaker study designs with no use of objective outcome measures and yielded low response rates. Conclusions Barriers to evaluation included low participation rates, high attrition, unknown representativeness and lack of comparison groups. Acceptability was typically assessed among those engaged with the intervention, with limited population data available to accurately assess intervention reach. Few studies were able to assess uptake of the intervention in a real-life setting while simultaneously assessing effectiveness of interventions with research rigour. So what? Through use of quasi-experimental or well designed before-after evaluations, in combination with detailed engagement metrics, it is possible to balance assessment of effectiveness and reach to evaluate SNS health promotion.


Expression of interstitial collagenase is restricted to skeletal tissue during mouse embryogenesis.
Collagenases are thought to be involved in physiological and pathological processes that require extracellular matrix remodeling. Using the in situ hybridization technique, we describe the expression of interstitial collagenase gene during mouse embryogenesis between E6.5 and E17. We demonstrate that interstitial collagenase expression is exclusively detected in one event, namely the onset of bone formation. Transcripts accumulate in hypertrophied chondrocytes, found in the mature cartilaginous matrix of long-bone growth plates or ribs, and in osteoblasts and/or in endothelial cells that have migrated into the shafts of developing long bones. The expression of the tissue inhibitor of metalloproteinases (TIMP-2) gene precedes the expression of interstitial collagenase in developing bones. These data suggest that interstitial collagenase plays a specific role in bone development and that the tight regulation of its activity during development is achieved not only by post-translational mechanisms with TIMPs, as previously suggested, but also at the transcriptional level.


Profile of Reproductive Issues Associated with Different Sickle Cell Disease Genotypes.
Purpose To describe the reproductive variables associated with different sickle cell disease (SCD) genotypes and the influence of contraceptive methods on acute painful episodes among the women with the homozygous hemoglobin S (HbSS) genotype. Methods A cross-sectional study was conducted between September of 2015 and April of 2016 on 158 women afflicted with SCD admitted to a hematology center in the Northeast of Brazil. The reproduction-associated variables of different SCD genotypes were assessed using the analysis of variance (ANOVA) test to compare means, and the Kruskal-Wallis test to compare medians. The association between the contraceptive method and the acute painful episodes was evaluated by the Chi-square test. Results The mean age of women with SCD was 28.3 years and 86.6% were mixed or of African-American ethnicity. With respect to the genotypes, 134 women (84.8%) had HbSS genotype, 12 women (7.6%) had hemoglobin SC (HbSC) disease genotype, and 12 (7.6%) were identified with hemoglobinopathy S-beta (S-β) thalassemia. The mean age of HbSS diagnosis was lower than that of HbSC disease, the less severe form of SCD (p < 0.001). The mean age of menarche was 14.8 ± 1.8 years for HbSS and 12.7 ± 1.5 years for HbSC (p < 0.001). Among women with HbSS who used progestin-only contraception, 16.6% had more than 4 acute painful episodes per year. There was no statistically significant difference when compared with other contraceptive methods. Conclusion With respect to reproduction-associated variables, only the age of the menarche showed delay in HbSS when compared with HbSC. The contraceptive method used was not associated with the frequency of acute painful episodes among the HbSS women.


Challenges with health-related quality of life assessment in arthroplasty patients: problems and solutions.
Assessment of health-related quality of life (HRQOL) using patient-reported outcomes in arthroplasty has become popular because it provides a unique perspective on successful elective procedures. However, challenges exist in the assessment of HRQOL in clinical practice and in clinical research. Patient compliance with multiple and sometimes lengthy HRQOL assessments administered at multiple follow-up visits is problematic. Many well-validated HRQOL instruments are available, and progress has been made in defining the minimal clinically important difference in hip and knee arthroplasty that denotes the minimal change perceived to be important by patients. Challenges in understanding the literature are attributable to the use of various HRQOL scales, with different scoring ranges and scoring algorithms, different interpretations of highest score, and differences in the presentation of raw versus transformed scores.


Intraventricular hemorrhage after ventriculoperitoneal shunt revision: a retrospective review.
OBJECT The authors review their ventriculoperitoneal (VP) shunt revisions over a 3-year period to determine the rate of intraventricular hemorrhage (IVH) and subsequent need for re-revision. METHODS Review of medical records identified 35 pediatric patients who underwent 52 VP shunt revisions between 2009 and 2012. The presence and amount of IVH as determined by CT and the time to re-revision were documented. The reason for shunting, catheter position, and time between initial VP shunt placement and subsequent revisions were also recorded. RESULTS After 13 (25%) of the 52 revisions, IVH was evident on postoperative CT scans. The majority of patients had a trace amount of IVH, with only 2% having IVH greater than 5 ml. After 2 (15%) of the 13 revisions associated with IVH, re-revision was required within 1 month. In contrast, the re-revision rate in patients without IVH was 18%. All of the patients who developed IVH had occipital catheters. CONCLUSIONS Some degree of IVH can be expected after approximately one-quarter of all VP shunt revision procedures in pediatric patients, but the rate of significant IVH is low. Furthermore, the presence of IVH does not necessitate an early shunt revision.


Socioeconomic and demographic factors in the diagnosis and treatment of Chiari malformation type I and syringomyelia.
The goal of this study was to assess the social determinants that influence access and outcomes for pediatric neurosurgical care for patients with Chiari malformation type I (CM-I) and syringomyelia (SM). The authors used retro- and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM-I and SM who received surgical treatment and had at least 1 year of follow-up data. Race, ethnicity, and insurance status were used as comparators for preoperative, treatment, and postoperative characteristics and outcomes. A total of 637 patients met inclusion criteria, and race or ethnicity data were available for 603 (94.7%) patients. A total of 463 (76.8%) were non-Hispanic White (NHW) and 140 (23.2%) were non-White. The non-White patients were older at diagnosis (p = 0.002) and were more likely to have an individualized education plan (p < 0.01). More non-White than NHW patients presented with cerebellar and cranial nerve deficits (i.e., gait ataxia [p = 0.028], nystagmus [p = 0.002], dysconjugate gaze [p = 0.03], hearing loss [p = 0.003], gait instability [p = 0.003], tremor [p = 0.021], or dysmetria [p < 0.001]). Non-White patients had higher rates of skull malformation (p = 0.004), platybasia (p = 0.002), and basilar invagination (p = 0.036). Non-White patients were more likely to be treated at low-volume centers than at high-volume centers (38.7% vs 15.2%; p < 0.01). Non-White patients were older at the time of surgery (p = 0.001) and had longer operative times (p < 0.001), higher estimated blood loss (p < 0.001), and a longer hospital stay (p = 0.04). There were no major group differences in terms of treatments performed or complications. The majority of subjects used private insurance (440, 71.5%), whereas 175 (28.5%) were using Medicaid or self-pay. Private insurance was used in 42.2% of non-White patients compared to 79.8% of NHW patients (p < 0.01). There were no major differences in presentation, treatment, or outcome between insurance groups. In multivariate modeling, non-White patients were more likely to present at an older age after controlling for sex and insurance status (p < 0.01). Non-White and male patients had a longer duration of symptoms before reaching diagnosis (p = 0.033 and 0.004, respectively). Socioeconomic and demographic factors appear to influence the presentation and management of patients with CM-I and SM. Race is associated with age and timing of diagnosis as well as operating room time, estimated blood loss, and length of hospital stay. This exploration of socioeconomic and demographic barriers to care will be useful in understanding how to improve access to pediatric neurosurgical care for patients with CM-I and SM.


Very late results of esophagomyotomy for patients with achalasia: clinical, endoscopic, histologic, manometric, and acid reflux studies in 67 patients for a mean follow-up of 190 months.
Laparoscopic esophagomyotomy is the preferred approach to patients with achalasia of the esophagus, However, there are very few long-term follow-up studies (>10 years) in these patients. To perform a very late subjective and objective follow-up in a group of 67 patients submitted to esophagomyotomy plus a partial antireflux surgery (Dor's technique). In a prospective study that lasted 30 years, 67 patients submitted to surgery were divided into 3 groups: group I followed for 80 to 119 months (15 patients); group II, with follow-up of 120 to 239 months (35 patients); and group III, with follow-up more than 240 months (17 patients). They were submitted to clinical questionnaire, endoscopic evaluation, histologic analysis, radiologic studies, manometric determinations, and 24-hour pH studies late after surgery. Three patients developed a squamous cell esophageal carcinoma 5, 7, and 15 years after surgery. At the late follow-up, Visick III and IV were seen in 7%, 23%, and 35%, according to the length of follow-up of each group. Endoscopic examination revealed a progressive nonsignificant deterioration of esophageal mucosa, histologic analysis distal to squamous-columnar junction showed a significant decrease of fundic mucosa in patients of group III, with increase of intestinal metaplasia, although not significant time. Lower esophageal sphincter showed a significant decrease of resting pressure 1 year after surgery, which remained similar at the late control. There was no return to peristaltic activity. Acid reflux measured by 24-hour pH studies revealed a progressive increase, and the follow-up was longer. Nine patients developed Barrett esophagus: 6 of them a short-segment and 3 a long-segment Barrett esophagus. Final clinical results in all 67 patients demonstrated excellent or good results in 73% of the cases, development of epidermoid carcinoma in 4.5%, and failures in 22.4% of the patients, mainly due to reflux esophagitis. Incomplete myotomy was seen in only 1 case. In patients with achalasia submitted to esophagomyotomy and Dor's antireflux procedure, there is a progressive clinical deterioration of initially good results if a very long follow-up is performed (23 years after surgery), mainly due to an increase in pathologic acid reflux disease and the development of short- or long-segment Barrett esophagus.


Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.
Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12). Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.