Curcumin activation of a bacterial mechanosensitive channel underlies its membrane permeability and adjuvant properties.
Curcumin, a natural compound isolated from the rhizome of turmeric, has been shown to have antibacterial properties. It has several physiological effects on bacteria including an apoptosis-like response involving RecA, membrane permeabilization, inhibiting septation, and it can also work synergistically with other antibiotics. The mechanism by which curcumin permeabilizes the bacterial membrane has been unclear. Most bacterial species contain a Mechanosensitive channel of large conductance, MscL, which serves the function of a biological emergency release valve; these large-pore channels open in response to membrane tension from osmotic shifts and, to avoid cell lysis, allow the release of solutes from the cytoplasm. Here we show that the MscL channel underlies the membrane permeabilization by curcumin as well as its synergistic properties with other antibiotics, by allowing access of antibiotics to the cytoplasm; MscL also appears to have an inhibitory role in septation, which is enhanced when activated by curcumin.


The reaction of formaldehyde carbonyl oxide with the methyl peroxy radical and its relevance in the chemistry of the atmosphere.
The reaction of formaldehyde carbonyl oxide (H2COO) with the methyl peroxy radical (CH3OO), a prototype of the reactions of carbonyl oxides with alkyl peroxy radicals of potential interest in atmospheric chemistry, has been investigated by means of quantum-mechanical electronic structure methods (CASSCF, CASPT2, UQCISD, and UCCSD(T)) and DFT functionals (B3LYP, BH&HLYP, M05 and M06-2X). Two reaction paths have been found for the lowest-barrier reaction, namely the CH3OO radical addition to the carbon atom of H2COO leading to the formation of the CH3OOCH2OO radical adduct. Both pathways begin with the formation of a pre-reactive complex with binding energies of 5.39 and 5.13 kcal mol(-1). The corresponding transition states are predicted to lie 2.64 and 0.25 kcal mol(-1), respectively, below the energy of the reactants and the rate constant of the global reaction is calculated to be 3.74 × 10(-12) cm(3) molecules(-1) s(-1) at 298 K. Since the CH3OOCH2OO radical adduct is formed with an internal energy excess of about 45 kcal mol(-1), it can decompose unimolecularly into formaldehyde and the CH2(O)OOCH radical. This unimolecular decomposition involves an intramolecular H-atom transfer followed by the decomposition of the CH2OOCH2OOH radical intermediate. Kinetic calculations based on the collision-reaction master equation employing the MultiWell Program Suite reveal that the CH3OOCH2OO radical adduct is stabilized in 86.9%, whereas 13.10% of the reaction corresponds to the formation of H2CO plus the CH2(O)OOH radical. It is concluded that the methyl peroxy radical addition to substituted carbonyl oxides might be the source of low volatility oligomers observed in secondary organic aerosols in chamber studies.


Biliary excretion of radioactivity after intravenous administration of 3H-1,25-dihydroxyvitamin D3 in man.
Biliary radioactivity excretion was studied in 10 patients with postcholecystectomy T-tube drainage after intravenous administration of 3H-1,25-dihydroxyvitamin D3. The mean +/- SD radioactivity excreted in T-tube bile expressed as a percentage of the administered dose was 18.9 +/- 10.7% per 24 hours. After correction for incomplete bile collection the value obtained was 28.8 +/- 12.8%. The mean chloroform solubility of the biliary radioactivity increased from 17.0 +/- 8.4% to 69.4 +/- 15.1% after incubation with beta-glucuronidase. High performance liquid chromatography of chloroform extracts of bile revealed that most of the eluted radioactivity was more polar than 1,25(OH)2D3. The percentage radioactivity eluting as 3H-1,25(OH)2D3 increased from approximately 2.4 +/- 1.9 to 16.2 +/- 8.0 after incubation with beta-glucuronidase. We conclude that significant amounts of intravenously administered 3H-1,25(OH)2D3 are excreted in bile, mostly as more polar metabolites. The increase in free 3H-1,25(OH)2D3 after incubation with beta-glucuronidase indicates that glucuronides of 1,25(OH)2D3 are present in bile.


Efficient priming of simian/human immunodeficiency virus (SHIV)-specific T-cell responses with DNA encoding hybrid SHIV/hepatitis B surface antigen particles.
Recent efforts to design an human immunodeficiency virus type 1 (HIV-1) vaccine candidate have focused on means of eliciting anti-viral T-cell responses. We tried to improve the immunogenicity of DNA vaccines by designing hybrid DNA constructs encoding hepatitis B surface antigen (HBsAg) fused to antigenic domains of simian/human immunodeficiency virus (SHIV 89.6P). Immunisation with hybrid DNA induced both effector and long-lasting precursor T-cells. Following boosting with a recombinant modified vaccinia Ankara (rMVA) producing full-length SIV and HIV antigens, it appeared that priming with hybrid DNA had increased virus-specific T-cell responses in terms of both the number of virus-specific IFN-gamma-secreting T-cells and virus-specific lymphoproliferation. After intrarectal challenge with SHIV 89.6P, immunised animals demonstrated early control of SHIV 89.6P replication and stable CD4+ T-cell counts.


Cryopreservation of caprine beta-lactoglobulin transgenic mouse embryos.
As an economical and safer alternative to the maintenance of transgenic animals as live stocks, transgenic embryo cryobanks can be generated and maintained indefinitely. Two-cell embryos obtained from four lines of caprine beta-lactoglobulin transgenic mice homozygous for the transgene were cryopreserved, and their response to cryopreservation-related stress was investigated. Significant differences between transgenic lines were found in the viability of frozen/thawed transgenic embryos and also in two-cell embryo production after superovulatory treatment of transgenic females. The results of this study suggest that cryopreservation protocols should be assessed on each transgenic line before the generation of transgenic embryo banks.


Is a biomarker-based diagnostic strategy for invasive aspergillosis cost effective in high-risk haematology patients?
Empirical antifungal therapy is frequently used in hematology patients at high risk of invasive aspergillosis (IA), with substantial cost and toxicity. Biomarkers for IA aim for earlier and more accurate diagnosis and targeted treatment. However, data on the cost-effectiveness of a biomarker-based diagnostic strategy (BDS) are limited. We evaluated the cost effectiveness of BDS using results from a randomized controlled trial (RCT) and individual patient costing data. Data inputs derived from a published RCT were used to construct a decision-analytic model to compare BDS (Aspergillus galactomannan and PCR on blood) with standard diagnostic strategy (SDS) of culture and histology in terms of total costs, length of stay, IA incidence, mortality, and years of life saved. Costs were estimated for each patient using hospital costing data to day 180 and follow-up for survival was modeled to five years using a Gompertz survival model. Treatment costs were determined for 137 adults undergoing allogeneic hematopoietic stem cell transplant or receiving chemotherapy for acute leukemia in four Australian centers (2005-2009). Median total costs at 180 days were similar between groups (US$78,774 for SDS [IQR US$50,808-123,476] and US$81,279 for BDS [IQR US$59,221-123,242], P = .49). All-cause mortality was 14.7% (10/68) for SDS and 10.1% (7/69) for BDS, (P = .573). The costs per life-year saved were US$325,448, US$81,966, and US$3,670 at 180 days, one year and five years, respectively. BDS is not cost-sparing but is cost-effective if a survival benefit is maintained over several years. An individualized institutional approach to diagnostic strategies may maximize utility and cost-effectiveness.


Nuclear magnetic resonance imaging of the brain in children.
A preliminary study of nuclear magnetic resonance imaging of the brains of four normal children (36 weeks' postmenstrual age to 5 years) showed long T(1) areas in the periventricular region of the neonate as well as evidence of progressive myelinisation with increasing age. Study of 18 patients of 40 weeks' postmenstrual age to 4 years showed an apparent deficit in myelinisation in an infant with probable rubella embryopathy and another with ventricular dilatation of unknown cause. Abnormal scans were obtained in an infant with congenital muscular dystrophy, and abnormalities were visualised at the lateral ventricular margins in a case of acute hydrocephalus after shunt blockage. Periventricular regions of increased T(2) were seen in a term infant aged 4 days after severe birth asphyxia and convulsions.Nuclear magnetic resonance imaging appears to provide a unique demonstration of myelinisation in vivo and shows changes in pathological processes of importance in paediatric practice.


Changes in HOXB6 homeodomain protein structure and localization during human epidermal development and differentiation.
HOX homeodomain proteins are master developmental regulators, which are now thought to function as transcription factors by forming cooperative DNA binding complexes with PBX or other protein partners. Although PBX proteins exhibit regulated subcellular localization and function in the nucleus in other tissues, little data exists on HOX and PBX protein localization during skin development. We now show that the HOXB6 protein is expressed in the suprabasal layer of the early developing epidermis and throughout the upper layers of late fetal and adult human skin. HOXB6 signal is cytoplasmic throughout fetal epidermal development, but substantially nuclear in normal adult skin. HOXB6 protein is also partially nuclear in hyperproliferative skin conditions, but appears to be cytoplasmic in basal and squamous cell carcinomas. Although all three PBX genes are expressed in fetal epidermis, none of the three PBX proteins exhibit nuclear co-localization with HOXB6 in either fetal or adult epidermis. RNA and protein data suggest that a truncated HOXB6 protein, lacking the homeodomain, is expressed in undifferentiated keratinocytes and that the full-length protein is induced by differentiation. GFP-fusion proteins were used to demonstrate that the full-length HOXB6 protein is localized to the nucleus while the truncated protein is largely cytoplasmic. Taken together, these data suggest that during epidermal development the truncated HOXB6 isoform may function by a mechanism other than as DNA binding protein, and that most of the nuclear, homeodomain-containing HOXB6 protein does not utilize PBX proteins as DNA binding partners in the skin. Published 2000 Wiley-Liss, Inc.


Temperature and Precipitation Associate With Ischemic Stroke Outcomes in the United States.
Background There is disagreement in the literature about the relationship between strokes and seasonal conditions. We sought to (1) describe seasonal patterns of stroke in the United States, and (2) determine the relationship between weather variables and stroke outcomes. Methods and Results We performed a cross-sectional study using Get With The Guidelines-Stroke data from 896 hospitals across the continental United States. We examined effects of season, climate region, and climate variables on stroke outcomes. We identified 457 638 patients admitted from 2011 to 2015 with ischemic stroke. There was a higher frequency of admissions in winter (116 862 in winter versus 113 689 in spring, 113 569 in summer, and 113 518 in fall; P<0.0001). Winter was associated with higher odds of in-hospital mortality (odds ratio [OR] 1.08 relative to spring, confidence interval [ CI ] 1.04-1.13, P=0.0004) and lower odds of discharge home ( OR 0.92, CI 0.91-0.94, P<0.0001) or independent ambulation at discharge ( OR 0.96, CI 0.94-0.98, P=0.0006). These differences were attenuated after adjusting for climate region and case mix and became inconsistent after controlling for weather variables. Temperature and precipitation were independently associated with outcome after multivariable analysis, with increases in temperature and precipitation associated with lower odds of mortality ( OR 0.95, CI 0.93-0.97, P<0.0001 and OR 0.95, CI 0.90-1.00, P=0.035, respectively). Conclusions Admissions for ischemic stroke were more frequent in the winter. Warmer and wetter weather conditions were independently associated with better outcomes. Further studies should aim to identify sensitive populations and inform public health measures aimed at resource allocation, readiness, and adaptive strategies.


Error-free DNA damage tolerance and sister chromatid proximity during DNA replication rely on the Polα/Primase/Ctf4 Complex.
Chromosomal replication is entwined with DNA damage tolerance (DDT) and chromatin structure establishment via elusive mechanisms. Here we examined how specific replication conditions affecting replisome architecture and repriming impact on DDT. We show that Saccharomyces cerevisiae Polα/Primase/Ctf4 mutants, proficient in bulk DNA replication, are defective in recombination-mediated damage-bypass by template switching (TS) and have reduced sister chromatid cohesion. The decrease in error-free DDT is accompanied by increased usage of mutagenic DDT, fork reversal, and higher rates of genome rearrangements mediated by faulty strand annealing. Notably, the DDT defects of Polα/Primase/Ctf4 mutants are not the consequence of increased sister chromatid distance, but are instead caused by altered single-stranded DNA metabolism and abnormal replication fork topology. We propose that error-free TS is driven by timely replicative helicase-coupled re-priming. Defects in this event impact on replication fork architecture and sister chromatid proximity, and represent a frequent source of chromosome lesions upon replication dysfunctions.


Expression of beta-catenin in normal breast tissue and breast carcinoma: a comparative study with epithelial cadherin and alpha-catenin.
Expression of beta-catenin was investigated in normal breast tissue and 66 breast carcinomas in conjunction with expression of epithelial cadherin (E-CD) and alpha-catenin. In normal mammary ducts and acini, intense beta-catenin immunoreactivity was present at the basolateral surfaces of luminal epithelium and weak immunoreactivity was observed at the lateral borders of myoepithelial cells. No beta-catenin was revealed at the myoepithelial basal surface. The intercellular expression of beta-catenin, as well as of E-CD and alpha-catenin, was also observed in carcinoma tissues with varying staining intensity. Almost all of 10 intraductal carcinomas and approximately 70% of 41 invasive ductal carcinomas expressed the three molecules at the same level as in normal glands, whereas approximately 80% of 13 invasive lobular carcinomas showed severe deficiency of them. Two lobular carcinomas in situ showed complete absence of all of the proteins. Some of these findings were confirmed biochemically by immunoblotting analysis. In invasive ductal carcinomas, alpha-catenin was reduced more frequently in diffuse than in solid type tumours, whereas the level of expression of beta-catenin and E-CD was unchanged between them. No correlation was present between reduced expression of the adhesion molecules and lymph node metastasis.


Characterization of variable regions in the envelope and S3 open reading frame of equine infectious anemia virus.
The polymerase chain reaction was used to amplify and clone parts of the envelope gene and overlapping S3 open reading frame, thought to encode rev, of the virulent in vivo-derived Th-1 isolate of equine infectious anemia virus (EIAV). The results indicated that EIAV consists of a heterogeneous mixture of genotypes present at the first febrile cycle after initial infection. We showed that the Th-1 isolate apparently contains nondefective genotypes as well as types which have transmembrane protein truncations or are rev deficient. Furthermore, we could confirm the presence of a hypervariable region in the gp90 envelope glycoprotein. Taken together with earlier data on the heterogeneity of the regulatory motifs present in the long terminal repeat sequences of viruses from the same in vivo isolate (S. Carpenter, S. Alexandersen, M. J. Long, S. Perryman, and B. Chesebro, J. Virol. 65:1605-1610, 1991), our findings indicate that EIAV uses a complex system of diversity in biological phenotypes together with variation in regulatory and antigenic makeup to evade host response and to cause persistent infection and recurrent chronic disease.


Orthostatic hypotension for the cardiologist.
Orthostatic hypotension is a phenomenon commonly encountered in a cardiologist's clinical practice that has significant diagnostic and prognostic value for a cardiologist. Given the mounting evidence associating cardiovascular morbidity and mortality with orthostatic hypotension, cardiologists will play an increasing role in treating and managing patients with orthostatic hypotension. The American College of Cardiology, American Heart Association, and Heart Rhythm Society recently published consensus guidelines on the diagnosis, treatment, and management of syncope and their instigators, including orthostatic hypotension. Additionally, consensus guidelines have also been recently updated, reinforcing the universal definition orthostatic hypotension and its closely associated pathologies. Finally, the United States Food and Drug Administration (FDA) recently approved droxidopa, a synthetic oral norepinephrine prodrug, in 2014 for the treatment of neurogenic orthostatic hypotension (nOH), and it represents a well tolerated, effective, and easy to use intervention for nOH. This represents only the second drug approved by the FDA for orthostatic hypotension, the first being midodrine in 1986. A handful of smaller head-to-head studies have pitted not only pharmacologic agents to one another but also nonpharmacologic interventions to pharmacologic agents. Additionally, recent studies have also reported on more convenient screening tools for orthostatic hypotension. Though there have been many advances in the management of orthostatic hypotension, nOH remains a chronic, debilitating, and often progressively fatal condition. Cardiologists can play a very important role in optimizing hemodynamics in this patient population to improve quality of life and minimize cardiovascular risk.


Progress report on the evaluation of the efficacy of infection surveillance and control programs.
The main objective of the Study on the Efficacy of Nosocomial Infection Control (SENIC Project) is to determine whether infection surveillance and control programs have reduced the rates of nosocomial infection in United States hospitals. To study this question, we stratified all hospitals in the SENIC target population into 16 design strata defined by categories of a surveillance and a control index derived from hospitals' responses to a preliminary screening questionnaire, and estimated the nosocomial infection rates among 339,044 randomly selected patients admitted in 1970 and 1975 through 1976 to 338 hospitals selected randomly from the 16 design strata. Finding that the over-all infection rates, standardized for important confounding variables or covariates, in hospitals with higher intensity programs had increased less from 1970 to 1975-1976 than those of hospitals with low intensity programs would indicate the efficacy of these programs. Potentially important confounding variables and covariates being studied include individual patient risk factors, hospital characteristics and the completeness of hospitals' medical records. Since only the first has been explored sufficiently, no conclusions on efficacy can yet be drawn. The analytic techniques were illustrated with preliminary data on infection rates at the four individual sites of infection.


Functional real-time optoacoustic imaging of middle cerebral artery occlusion in mice.
Longitudinal functional imaging studies of stroke are key in identifying the disease progression and possible therapeutic interventions. Here we investigate the applicability of real-time functional optoacoustic imaging for monitoring of stroke progression in the whole brain of living animals. The middle cerebral artery occlusion (MCAO) was used to model stroke in mice, which were imaged preoperatively and the occlusion was kept in place for 60 minutes, after which optoacoustic scans were taken at several time points. Post ischemia an asymmetry of deoxygenated hemoglobin in the brain was observed as a region of hypoxia in the hemisphere affected by the ischemic event. Furthermore, we were able to visualize the penumbra in-vivo as a localized hemodynamically-compromised area adjacent to the region of stroke-induced perfusion deficit. The intrinsic sensitivity of the new imaging approach to functional blood parameters, in combination with real time operation and high spatial resolution in deep living tissues, may see it become a valuable and unique tool in the development and monitoring of treatments aimed at suspending the spread of an infarct area.


Physiological significance of a peripheral tissue circadian clock.
Mammals have circadian clocks in peripheral tissues, but there is no direct evidence of their physiological importance. Unlike the suprachiasmatic nucleus clock that is set by light and drives rest-activity and fasting-feeding cycles, peripheral clocks are set by daily feeding, suggesting that at least some contribute metabolic regulation. The liver plays a well known role in glucose homeostasis, and we report here that mice with a liver-specific deletion of Bmal1, an essential clock component, exhibited hypoglycemia restricted to the fasting phase of the daily feeding cycle, exaggerated glucose clearance, and loss of rhythmic expression of hepatic glucose regulatory genes. We conclude that the liver clock is important for buffering circulating glucose in a time-of-day-dependent manner. Our findings suggest that the liver clock contributes to homeostasis by driving a daily rhythm of hepatic glucose export that counterbalances the daily cycle of glucose ingestion resulting from the fasting-feeding cycle.


Shikonin sensitizes wild‑type EGFR NSCLC cells to erlotinib and gefitinib therapy.
As patients with non‑small cell lung cancer (NSCLC) and wild‑type epidermal growth factor receptor (EGFR) are resistant to treatment with erlotinib or gefitinib, potential chemosensitizers are required to potentiate wild‑type EGFR NSCLC cells to erlotinib/gefitinib treatment. The present study reported that shikonin could sensitize the anticancer activity of erlotinib/gefitinib in wild‑type EGFR NSCLC cells. Furthermore, shikonin could potentiate mitochondrial‑mediated apoptosis induced by erlotinib/gefitinib in wild‑type EGFR NSCLC cells. In addition, the present study demonstrated that shikonin could induce apoptosis by activating reactive oxygen species (ROS)‑mediated endoplasmic reticulum (ER) stress, and that erlotinib/gefitinib may also induce ER stress in wild‑type EGFR NSCLC cells; however, shikonin plus erlotinib/gefitinib was more effective in activating ER stress than either agent alone. This indicated that ROS‑mediated ER stress may be associated with enhanced mitochondrial apoptosis induced by shikonin plus erlotinib/gefitinib. In addition, shikonin may promote the transition of cytoprotective ER stress‑inducing EGFR‑tyrosine kinase inhibitor tolerance to apoptosis‑promoting ER stress. Furthermore, shikonin may enhance the anti‑NSCLC activity of erlotinib/gefitinib in vivo. The data of the present study indicated that shikonin may be a potential sensitizer to enhance the anti‑cancer efficacy of erlotinib/gefitinib in wild‑type EGFR NSCLC cells resistant to erlotinib/gefitinib treatment.


Short- and long-term variability of selected indices related to nutritional status. II. Vitamins, lipids, and protein indices.
Five free-living women (ages 23-38 years) who consumed a self-selected diet and five women (ages 23-44 years) residing in a metabolic unit who were fed constant diet were assessed for variation in vitamin and general chemistry indices. Blood was drawn from these women once a month for five months, once a week for five weeks, and once a day for five days to assess analytical and biological variability of the indices. Analytical variability was determined by concurrently analyzing control samples prepared from plasma and serum pools. All samples were analyzed in duplicate. Of the measured indices, vitamins and lipids seemed to be the most variable. Diet had a significant effect only on ascorbic acid. We were unable to show any seasonal change for these analytes. Estimations of analytical variability, along with estimates of biological variability, and knowledge of dietary practices are essential when interpreting differences in analytes.


Epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China: a hospital-based retrospective study.
Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, -0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (-4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals' ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.


Software for the estimation of foetal radiation dose to patients and staff in diagnostic radiology.
Occasionally, it is clinically necessary to perform a radiological examination(s) on a woman who is known to be pregnant or an examination is performed on a woman who subsequently discovers that she was pregnant at the time. In radiological examinations, especially of the lower abdomen and pelvis area, the foetus is directly irradiated. It is therefore important to be able to determine the absorbed dose to the foetus in diagnostic radiology for pregnant patients as well as the foetal dose from occupational exposure of the pregnant worker. The determination of the absorbed dose to the unborn child in diagnostic radiology is of interest as a basis for risk estimates from medical exposure of the pregnant patient and occupational exposure of the pregnant worker. In this paper we describe a simple computer program, FetDose, which calculates the dose to the foetus from both medical and occupational exposures of the pregnant woman. It also calculates the risks of in utero exposure, compares calculated doses with published data in the literature and provides information on the natural spontaneous risks. The program will be a useful tool for the medical and paramedical personnel who are involved with foetal dose (and hence risks) calculations and counselling of pregnant women who may be concerned about in utero exposure of their foetuses.


Purification of the vertebrate nuclear pore complex by biochemical criteria.
The nuclear pore is a large and complex biological machine, mediating all signal-directed transport between the nucleus and the cytoplasm. The vertebrate pore has a mass of approximately 120 million daltons or 30 times the size of a ribosome. The large size of the pore, coupled to its tight integration in the nuclear lamina, has hampered the isolation of pore complexes from vertebrate sources. We have now developed a strategy for the purification of nuclear pores from in vitro assembled annulate lamellae (AL), a cytoplasmic mimic of the nuclear envelope that lacks a lamina, nuclear matrix, and chromatin-associated proteins. We find that purified pore complexes from annulate lamellae contain every nuclear pore protein tested. In addition, immunoblotting reveals the presence of soluble transport receptors and factors known to play important roles in the transport of macromolecules through the pore. While transport factors such as Ran and NTF2 show only transient interaction with the pores, a number of soluble transport receptors, including importin beta, show a tight association with the purified pores. In summary, we report that we have purified the vertebrate pore by biochemical criteria; silver staining reveals approximately 40-50 distinct protein bands.


Tolerance to MHC class II disparate allografts through genetic modification of bone marrow.
Induction of molecular chimerism through genetic modification of bone marrow is a powerful tool for the induction of tolerance. Here, we demonstrate for the first time that expression of an allogeneic MHC class II gene in autologous bone marrow cells, resulting in a state of molecular chimerism, induces tolerance to MHC class II mismatched skin grafts, a stringent test of transplant tolerance. Reconstitution of recipients with syngeneic bone marrow transduced with retrovirus encoding H-2I-A(b) (I-A(b)) resulted the long-term expression of the retroviral gene product on the surface of MHC class II-expressing bone marrow-derived cell types. Mechanistically, tolerance was maintained by the presence of regulatory T cells, which prevented proliferation and cytokine production by alloreactive host T cells. Thus, the introduction of MHC class II genes into bone marrow-derived cells through genetic engineering results in tolerance. These results have the potential to extend the clinical applicability of molecular chimerism for tolerance induction.


Greater pQCT Calf Muscle Density Is Associated with Lower Fracture Risk, Independent of FRAX, Falls and BMD: A Meta-Analysis in the Osteoporotic Fractures in Men (MrOS) Study.
We investigated the predictive performance of peripheral quantitative computed tomography (pQCT) measures of both calf muscle density (an established surrogate for muscle adiposity, with higher values indicating lower muscle adiposity and higher muscle quality) and size (cross-sectional area [CSA]) for incident fracture. pQCT (Stratec XCT2000/3000) measurements at the tibia were undertaken in Osteoporotic Fractures in Men (MrOS) United States (US), Hong Kong (HK), and Swedish (SW) cohorts. Analyses were by cohort and synthesized by meta-analysis. The predictive value for incident fracture outcomes, illustrated here for hip fracture (HF), using an extension of Poisson regression adjusted for age and follow-up time, was expressed as hazard ratio (HR) per standard deviation (SD) increase in exposure (HR/SD). Further analyses adjusted for femoral neck (fn) bone mineral density (BMD) T-score, Fracture Risk Assessment Tool (FRAX) 10-year fracture probability (major osteoporotic fracture) and prior falls. We studied 991 (US), 1662 (HK), and 1521 (SW) men, mean ± SD age 77.0 ± 5.1, 73.9 ± 4.9, 80 ± 3.4 years, followed for a mean ± SD 7.8 ± 2.2, 8.1 ± 2.3, 5.3 ± 2.0 years, with 31, 47, and 78 incident HFs, respectively. Both greater muscle CSA and greater muscle density were associated with a lower risk of incident HF [HR/SD: 0.84; 95% confidence interval [CI], 0.72-1.0 and 0.78; 95% CI, 0.66-0.91, respectively]. The pattern of associations was not materially changed by adjustment for prior falls or FRAX probability. In contrast, after inclusion of fn BMD T-score, the association for muscle CSA was no longer apparent (1.04; 95% CI, 0.88-1.24), whereas that for muscle density was not materially changed (0.69; 95% CI, 0.59-0.82). Findings were similar for osteoporotic fractures. pQCT measures of greater calf muscle density and CSA were both associated with lower incidence of fractures in older men, but only muscle density remained an independent risk factor for fracture after accounting for fn BMD. These findings demonstrate a complex interplay between measures of bone, muscle size, and quality, in determining fracture risk. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.


Diosgenin prevents bone loss on retinoic acid-induced osteoporosis in rats.
To observe the preventive and therapeutic effects of diosgenin on retinoic acid-induced osteoporosis in rats. A total 50 Sprague-Dawley rats were randomly divided into 5 groups: control group, model group (osteoporosis rats), low (10 mg kg(-1)), middle (30 mg kg(-1)), and high-dose diosgenin (90 mg kg(-1))-treated groups. The osteoporosis rats model was induced by retinoic acid. The BMD and physical parameters of femoral including length, wet weight, and dry weight in each group were measured. The hematoxylin-eosin staining was used for bone histomorphology analysis. Besides, the bone calcium (Ca) and phosphorus (P) contents were measured. In order to detect the biochemical index in different treatment groups, the serum tartrate-resistant acid phosphatase (TRAP), alkaline phosphatase (ALP), estradiol, and osteocalcin were compared among different groups. The osteoporosis rat model was successfully induced by retinoic acid. Compared with the model group, the lessening of femoral length and weight and the loss of BMD were significantly improved in diosgenin groups. Both contents of Ca and P were much more increased when induced by retinoic acid (p < 0.05). The estradiol and osteocalcin levels in the middle and high-dose treatment groups were significantly higher than that of the model group, while the ALP and TRAP levels were much lower than the model group (p < 0.05). Diosgenin can prevent the loss of bone in experimental rats. The mechanism may be that it improves the level of estrogenic hormone of estradiol and inhibits the high bone turnover.


Impaired dynamic cerebral autoregulation measured in the middle cerebral artery in patients with vertebrobasilar ischemia is associated with autonomic failure.
To assess whether vertebrobasilar artery ischemia (VBI) affects cortical cerebral blood flow (CBF) regulation. 107 consecutive patients (mean age 65 ± 15 years; women 21) with VBI underwent structured stroke care with assessment of dynamic cerebral autoregulation (dCA) in both middle cerebral arteries (MCAs) by transfer function analysis using spontaneous oscillations of blood pressure (BP) and CBF velocity that yields by extraction of phase and gain information in the very low (0.02-0.07 Hz), low (0.07-0.15 Hz) and high frequency (0.15-0.5 Hz) ranges. Additionally, power spectrum analysis of BP and heart rate variability (HRV) was performed. The control group consists of 29 age- and sex-matched healthy persons. Compared to controls, phase in the VBI patients was significantly reduced and gain increased in the very low frequencies (VLF), in the low (LF), phase was significantly reduced only ipsilaterally. In the high frequencies (HF), phase reduction was only marginally significant. BP power spectral density (PSD) was much higher in the patients than in the controls across all frequencies. In the PSD of heart rate variability the controls but not the patients exhibited a strong peak around 0.11Hz, while the patients, but not the controls, exhibit a strong peak around 0.36 Hz. In regression analysis, patient's phase and gain results were not related to age, sex, arterial hypertension, diabetes mellitus, renal dysfunction, heart failure as indicated by left ventricular ejection fraction, stroke subtype, presence or absence of cerebral small vessel disease. Patients with VBI exhibit bilateral cortical autoregulation impairment in association with an autonomic nervous system disbalance. NCT04611672.


A novel alkaline alpha-galactosidase from melon fruit with a substrate preference for raffinose
The cucurbits translocate the galactosyl-sucrose oligosaccharides raffinose and stachyose, therefore, alpha-galactosidase (alpha-D-galactoside galactohydrolase, EC 220.127.116.11) is expected to function as the initial enzyme of photoassimilate catabolism. However, the previously described alkaline alpha-galactosidase is specific for the tetrasaccharide stachyose, leaving raffinose catabolism in these tissues as an enigma. In this paper we report the partial purification and characterization of three alpha-galactosidases, including a novel alkaline alpha-galactosidase (form I) from melon (Cucumis melo) fruit tissue. The form I enzyme showed preferred activity with raffinose and significant activity with stachyose. Other unique characteristics of this enzyme, such as weak product inhibition by galactose (in contrast to the other alpha-galactosidases, which show stronger product inhibition), also impart physiological significance. Using raffinose and stachyose as substrates in the assays, the activities of the three alpha-galactosidases (alkaline form I, alkaline form II, and the acid form) were measured at different stages of fruit development. The form I enzyme activity increased during the early stages of ovary development and fruit set, in contrast to the other alpha-galactosidase enzymes, both of which declined in activity during this period. In the mature, sucrose-accumulating mesocarp, the alkaline form I enzyme was the major alpha-galactosidase present. We also observed hydrolysis of raffinose at alkaline conditions in enzyme extracts from other cucurbit sink tissues, as well as from young Coleus blumei leaves. Our results suggest different physiological roles for the alpha-galactosidase forms in the developing cucurbit fruit, and show that the newly discovered enzyme plays a physiologically significant role in photoassimilate partitioning in cucurbit sink tissue.


Hematological disturbances in Down syndrome: single centre experience of thirteen years and review of the literature.
Karakurt N, Uslu İ, Aygün C, Albayrak C. Hematological disturbances in Down syndrome: single centre experience of thirteen years and review of the literature. Turk J Pediatr 2019; 61: 664-670. Neonates with Down syndrome (DS) may have hematological abnormalities such as polycythemia, thrombocytopenia and transient leukemia (TL). The primary objective of this study was to report the descriptive data of complete blood counts (CBC) of neonates with DS, which were obtained within first week of life. We wanted to focus on neonates with hematological abnormalities and compare them among those with and without TL. The secondary objective was the description of hematological malignancies in the first six years of life. Medical records of 100 neonates with DS between 2006-2018 were assessed. Hematological abnormalities were present in 73/100. We detected anemia in 16, polycythemia in eight, microcytosis in 10, leukopenia in two, leukocytosis in 11, thrombocytopenia in 26, thrombocytosis in 7 and TL in 11 patients. TL group had higher levels of leukocyte count (115.0±93.0x103/mm3) when compared with neonates without TL (11.7±5.6x103/mm3) (p < 0.001). No other statistically significant difference between groups for hemoglobin, MCV and platelet count levels was detected. In the follow- up period, two patients developed acute lymphoblastic leukemia, one hemophagocytic lymphohistiocytosis and one Burkitt lymphoma. None of the TL survivors developed myeloid leukemia of Down Syndrome (ML-DS). Thrombocytopenia may be detected frequently in DS and it may not be a part of TL. We suggest that CBC with peripheral blood film should be evaluated for every patient to check for TL and other hematological disturbances. Despite the fact that none of our TL survivors developed overt leukemia (ML-DS), we also suggest that patients with DS be followed due to the risk of developing leukemia.


Advanced methods for perfusion analysis in echocardiography.
It has been shown that besides positron emission tomography, single photon emission computed tomography and magnetic resonance imaging; contrast echocardiography can be used for qualitative and quantitative myocardial perfusion assessment. In this review, the properties of ultrasound contrast agents, imaging techniques and acquisition methods are shortly described and the possibilities of perfusion echocardiography are summarized. The main focus is put on the description of three perfusion models: mathematical models, physical models assuming an ideal inflow and physical models including inflow measurement.


Selenium deficiency with total parenteral nutrition: reversal of biochemical and functional abnormalities by selenium supplementation: a case report.
A patient with multiple intestinal fistulae maintained on total parenteral nutrition for 18 months developed low serum selenium. Erythrocyte glutathione peroxidase activity was 6% of normal. Erythrocytes were not able to metabolize H2O2 as well as those from controls, although the hexose monophosphate shunt itself was intact. Granulocytes from this patient had 15% of the erythrocyte glutathione peroxidase activity found in normals. Patient granulocytes were not able to metabolize H2O2 as well as controls, although the hexose monophosphate shunt was intact. Erythrocyte glutathione peroxidase-deficient granulocytes incubated with a respiratory burst stimulant, phorbol myristate acetate, had only 60% of the hexose monophosphate shunt activity present in control granulocytes. These abnormalities were reversed with selenium supplementation. Bacterial killing of Staphylococcus aureus 502A and cardiac function were not affected by selenium deficiency. Thus, selenium deficiency resulted in biochemical and functional abnormalities of erythrocytes and granulocytes. These abnormalities were reversed with selenium supplementation.


Comparison of clinical, ultrasonographic, and postoperative macroscopic findings in cows with bursitis.
Clinical, ultrasonographic, and macroscopic findings of bursitis in cows were compared to assess the contribution of diagnosis and therapy planning. Sixteen dairy cows with swelling at the carpal (n = 12) or tarsal (n = 4) region were examined clinically and ultrasonographically and the findings were compared. In 10 patients the bursae were removed in toto. According to the duration of the disease (history) and clinical findings nine and seven patients had acute and chronic bursitis, respectively. Six had fluctuation and in 10 the bursa was firm. Contents were serous (n = 3), serofibrinous (n = 4), serohemorrhagic (n = 2), or purulent (n = 1). Sonographically there was fluid in all bursa except one. Capsule echogenicity varied between hypoechoic and hyperechoic and mean capsule thickness was 9.2 +/- 4.1 mm. Fourteen of the bursae contained free-floating particles. The hyperechoic capsules represented fibrous tissue, and the echogenic/hyperechoic free-floating particles were erythrocytes, purulent exudate, or fibrin masses. Capsule thickness and large free-floating particles could not be detected by clinical examination/centesis alone. However, capsule thickness, bursa contents, and the extent of inflammation could be determined ultrasonographically and this made the decision for different invasive/ operative procedures easier.


Lymphatic Changes in Respiratory Diseases: More than Just Remodeling of the Lung?
Advances in our ability to identify lymphatic endothelial cells and differentiate them from blood endothelial cells have led to important progress in the study of lymphatic biology. Over the past decade, preclinical and clinical studies have shown that there are changes to the lymphatic vasculature in nearly all lung diseases. Efforts to understand the contribution of lymphatics and their growth factors to disease initiation, progression, and resolution have led to seminal findings establishing critical roles for lymphatics in lung biology spanning from the first breath after birth to asthma, tuberculosis, and lung transplantation. However, in other diseases, it remains unclear if lymphatics are part of the overall lung remodeling process or real contributors to disease pathogenesis. The goal of this Translational Review is to highlight some of the advances in our understanding of the role(s) of lymphatics in lung disease and shed light on the critical needs and unanswered questions that might lead to novel translational applications.


Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies.
Cancer evolves through the emergence and selection of molecular alterations. Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Here, we designed SELECT, an algorithmic approach to systematically identify evolutionary dependencies from alteration patterns. By analyzing 6,456 genomes from multiple tumor types, we constructed a map of oncogenic dependencies associated with cellular pathways, transcriptional readouts, and therapeutic response. Finally, modeling of cancer evolution shows that alteration dependencies emerge only under conditional selection. These results provide a framework for the design of strategies to predict cancer progression and therapeutic response.


A high-temperature furnace for in situ synchrotron X-ray spectroscopy under controlled atmospheric conditions.
A high-temperature furnace with an induction heater coil has been designed and constructed for in situ X-ray spectroscopic experiments under controlled atmospheric conditions and temperatures up to 3275 K. The multi-purpose chamber design allows working in backscattering and normal fluorescence mode for synchrotron X-ray absorption and emission spectroscopy. The use of the furnace is demonstrated in a study of the in situ formation of Cr oxide between 1823 K and 2023 K at logPO(2) values between -10.0 and -11.3 using X-ray absorption near-edge spectroscopy. The set-up is of particular interest for studying liquid metals, alloys and other electrically conductive materials under extreme conditions.


Novel strategies in feedforward adaptation to a position-dependent perturbation.
To investigate the control mechanisms used in adapting to position-dependent forces, subjects performed 150 horizontal reaching movements over 25 cm in the presence of a position-dependent parabolic force field (PF). The PF acted only over the first 10 cm of the movement. On every fifth trial, a virtual mechanical guide (double wall) constrained subjects to move along a straight-line path between the start and target positions. Its purpose was to register lateral force to track formation of an internal model of the force field, and to look for evidence of possible alternative adaptive strategies. The force field produced a force to the right, which initially caused subjects to deviate in that direction. They reacted by producing deviations to the left, "into" the force field, as early as the second trial. Further adaptation resulted in rapid exponential reduction of kinematic error in the latter portion of the movement, where the greatest perturbation to the handpath was initially observed, whereas there was little modification of the handpath in the region where the PF was active. Significant force directed to counteract the PF was measured on the first guided trial, and was modified during the first half of the learning set. The total force impulse in the region of the PF increased throughout the learning trials, but it always remained less than that produced by the PF. The force profile did not resemble a mirror image of the PF in that it tended to be more trapezoidal than parabolic in shape. As in previous studies of force-field adaptation, we found that changes in muscle activation involved a general increase in the activity of all muscles, which increased arm stiffness, and selectively-greater increases in the activation of muscles which counteracted the PF. With training, activation was exponentially reduced, albeit more slowly than kinematic error. Progressive changes in kinematics and EMG occurred predominantly in the region of the workspace beyond the force field. We suggest that constraints on muscle mechanics limit the ability of the central nervous system to employ an inverse dynamics model to nullify impulse-like forces by generating mirror-image forces. Consequently, subjects adopted a strategy of slightly overcompensating for the first half of the force field, then allowing the force field to push them in the opposite direction. Muscle activity patterns in the region beyond the boundary of the force field were subsequently adjusted because of the relatively-slow response of the second-order mechanics of muscle impedance to the force impulse.


Improved costs and outcomes with conscious sedation vs general anesthesia in TAVR patients: Time to wake up?
Transcatheter aortic valve replacement (TAVR) has become a commonplace procedure for the treatment of aortic stenosis in higher risk surgical patients. With the high cost and steadily increasing number of patients receiving TAVR, emphasis has been placed on optimizing outcomes as well as resource utilization. Recently, studies have demonstrated the feasibility of conscious sedation in lieu of general anesthesia for TAVR. This study aimed to investigate the clinical as well as cost outcomes associated with conscious sedation in comparison to general anesthesia in TAVR. Records for all adult patients undergoing TAVR at our institution between August 2012 and June 2016 were included using our institutional Society of Thoracic Surgeons (STS) and American College of Cardiology (ACC) registries. Cost data was gathered using the BIOME database. Patients were stratified into two groups according to whether they received general anesthesia (GA) or conscious sedation (CS) during the procedure. No-replacement propensity score matching was done using the validated STS predicted risk of mortality (PROM) as a propensity score. Primary outcome measure with survival to discharge and several secondary outcome measures were also included in analysis. According to our institution's data reporting guidelines, all cost data is presented as a percentage of the general anesthesia control group cost. Of the 231 patients initially identified, 225 (157 GA, 68 CS) were included for analysis. After no-replacement propensity score matching, 196 patients (147 GA, 49 CS) remained. Overall mortality was 1.5% in the matched population with a trend towards lower mortality in the CS group. Conscious sedation was associated with significantly fewer ICU hours (30 vs 96 hours, p = <0.001) and total hospital days (4.9 vs 10.4, p<0.001). Additionally, there was a 28% decrease in direct cost (p<0.001) as well as significant decreases in all individual all cost categories associated with the use of conscious sedation. There was no difference in composite major adverse events between groups. These trends remained on all subsequent subgroup analyses. Conscious sedation is emerging as a safe and viable option for anesthesia in patients undergoing transcatheter aortic valve replacement. The use of conscious sedation was not only associated with similar rates of adverse events, but also shortened ICU and overall hospital stays. Finally, there were significant decreases in all cost categories when compared to a propensity matched cohort receiving general anesthesia.


Influence and predicting variables of obstructive sleep apnea on cardiac function and remodeling in patients without congestive heart failure.
Obstructive sleep apnea syndrome (OSAS) has been considered to be an important predisposing factor for cardiovascular disease. This study aims to investigate the impact of OSAS on cardiac function and remodeling in patients without congestive heart failure. A total of 79 patients with sleep disordered breathing, preserved systolic function, and normal pro-brain natriuretic peptide level were enrolled. Sixty-five patients were classified to have moderate to severe OSAS (apnea-hypopnea index [AHI] ≥ 15/h), while the other 14 patients with mild or no OSAS (AHI < 15/h) served as control subjects. Baseline clinical and polysomnographic variables as well as tissue Doppler imaging and three-dimensional echocardiographic parameters were obtained. The body mass index, neck circumference, Epworth Sleepiness Scale, desaturation index, arousal index, and snoring index were significantly higher in patients with moderate to severe OSAS than those without (p < 0.05). The left atrial size, mitral A-wave velocity, and left ventricular end-diastolic volume were significantly larger, while E/A ratio was lower in patients with moderate to severe OSAS than those without (p < 0.05). Notably, AHI in REM sleep was significantly correlated with the aortic root size, E/A ratio, left ventricular volume, and stroke volume. In addition, the area under the receiver operator characteristic curve for AHI in REM sleep ≥ 32.3/h was 0.647 (95% CI [0.525, 0.769]) in predicting the development of left ventricular diastolic dysfunction. AHI in REM sleep ≥ 32.3/h was the only independent variant in predicting diastolic dysfunction after adjusting the variables including age, gender, hypertension, and body mass index. Patients with moderate to severe OSAS tend to have cardiac dysfunction revealed by echocardiography. High AHI in REM sleep is significantly associated with cardiovascular remodeling and ventricular diastolic dysfunction, and may be a potential variable to predict cardiac dysfunction.


Transcriptome profiling of granulosa cells of bovine ovarian follicles during growth from small to large antral sizes.
At later stages of folliculogenesis, the mammalian ovarian follicle contains layers of epithelial granulosa cells surrounding an antral cavity. During follicle development granulosa cells replicate, secrete hormones and support the growth of the oocyte. In cattle, the follicle needs to grow > 10 mm in diameter to allow an oocyte to ovulate, following which the granulosa cells cease dividing and differentiate into the specialised cells of the corpus luteum. To better understand the molecular basis of follicular growth and granulosa cell maturation, we undertook transcriptome profiling of granulosa cells from small (< 5 mm; n = 10) and large (> 10 mm, n = 4) healthy bovine follicles using Affymetrix microarrays (24,128 probe sets). Principal component analysis for the first two components and hierarchical clustering showed clustering into two groups, small and large, with the former being more heterogeneous. Size-frequency distributions of the coefficient of variation of the signal intensities of each probe set also revealed that small follicles were more heterogeneous than the large. IPA and GO enrichment analyses revealed that processes of axonal guidance, immune signalling and cell rearrangement were most affected in large follicles. The most important networks were associated with: (A) Notch, SLIT/ROBO and PI3K signalling, and (B) ITGB5 and extracellular matrix signalling through extracellular signal related kinases (ERKs). Upstream regulator genes which were predicted to be active in large follicles included STAT and XBP1. By comparison, developmental processes such as those stimulated by KIT, IHH and MEST were most active in small follicles. MGEA5 was identified as an upstream regulator in small follicles. It encodes an enzyme that modifies the activity of many target proteins, including those involved in energy sensing, by removal of N-acetylglucosamine from serine and threonine residues. Our data suggest that as follicles enlarge more genes and/or pathways are activated than are inactivated, and gene expression becomes more uniform. These findings could be interpreted that either the cells in large follicles are more uniform in their gene expression, or that follicles are more uniform or a combination of both and that additional factors, such as LH, are additionally controlling the granulosa cells.


Co-occurrence of IgE and IgG autoantibodies in patients with chronic spontaneous urticaria.
Chronic spontaneous urticaria (CSU) pathogenesis shows a complex and still unclear interplay between immunoglobulin (Ig)G- and IgE-mediated autoimmunity, leading to mast cell and basophil degranulation and wheal formation. The objective of this study was to evaluate at the same time IgE- and IgG-reactivity to well recognized and recently reported autoantigens in CSU patients, and to assess the effects of such reactivity on response to the anti-IgE monoclonal antibody omalizumab. Twenty CSU patients underwent omalizumab treatment. Urticaria activity score 7 (UAS7) was recorded at baseline and at different drug administration time-points for categorizing early-, late- or non-responders. At baseline, sera from the 20 patients and from 20 controls were tested for IgE and IgG autoantibodies to high- and low-affinity IgE receptors (FcεRI and FcεRII), tissue factor (TF) and thyroglobulin (TG) by immunoenzymatic methods. Antibody levels were compared with those of controls and analysed according to response. Eighteen patients were omalizumab responders (11 early and seven late), while two were non-responders. More than 50% of patients had contemporary IgE and IgG to at least to one of the four different autoantigens. Late responders showed higher levels of both anti-TF IgE and IgG than early responders (P = 0·011 and P = 0·035, respectively). Twenty-five per cent of patients had levels of anti-FcεRI IgE, exceeding the upper normal limit, suggesting that it could be a novel auto-allergen in CSU. In CSU, there is an autoimmune milieu characterized by the co-existence of IgE and IgG autoantibodies to the same antigen/allergen, particularly in late responders to omalizumab, possibly explaining the slower response.


The role of the left dorsolateral prefrontal cortex in attentional bias.
The DLPFC is thought to be critically involved in maintaining attention away from behaviourally irrelevant information, and in the establishment of attentional control settings. These play an important role in the phenomenon of top-down bias to features in the visual field - also known as attentional bias. This paper probes the involvement of the left DLPFC in attentional bias by manipulating its cortical excitability via tDCS and then analysing these effects following an induced attentional bias towards the colour green. Although both anodal and cathodal tDCS over the left DLPFC decrease distractibility caused by biased but irrelevant objects, further interrogation of our data reveals theoretically differential mechanisms for each type of stimulation. Anodal tDCS appears to increase cognitive control over attentional bias-related items that are behaviourally irrelevant, allowing for their efficient disregard. In contrast, cathodal tDCS appears to lessen the overall effect of the induced attentional bias, potentially by reducing the influence of top-down modulated attentional control settings thus preventing the implementation of the control setting favouring green items. These results suggest a potential causal role of the left DLPFC in the cognitive mechanism underlying attentional bias.


Evidence that G(z)-proteins couple to hypothalamic 5-HT(1A) receptors in vivo.
Using in situ hybridization and immunoblot analysis, the present studies identified G(z) mRNA and G(z)-protein in the hypothalamic paraventricular nucleus. The role of G(z)-proteins in hypothalamic 5-HT(1A) receptor signaling was examined in vivo. Activation of 5-HT(1A) receptors increases the secretion of oxytocin and ACTH, but not prolactin. Intracerebroventricular infusion (3-4 d) of G(z) antisense oligodeoxynucleotides, with different sequences and different phosphorothioate modification patterns, reduced the levels of G(z)-protein in the hypothalamic paraventricular nucleus, whereas missense oligodeoxynucleotides had no effect. Neither antisense nor missense oligodeoxynucleotide treatment altered basal plasma levels of ACTH, oxytocin, or prolactin, when compared with untreated controls. An antisense-induced decrease in hypothalamic G(z)-protein levels was paralleled by a significant decrease in the oxytocin and ACTH responses to the 5-HT(1A) agonist 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT). In contrast, the prolactin response to 8-OH-DPAT (which cannot be blocked by 5-HT(1A) antagonists) was not inhibited by G(z) antisense oligodeoxynucleotides. G(z)-proteins are the only members of the G(i)/G(o)-protein family that are not inactivated by pertussis toxin. In a control experiment, pertussis toxin treatment (1 microgram/5 microliter, i.c.v.; 48 hr before the 8-OH-DPAT challenge) did not inhibit the ACTH response, potentiated the oxytocin response, and eliminated the prolactin response to 8-OH-DPAT. Thus, pertussis toxin-sensitive G(i)/G(o)-proteins do not mediate the 5-HT(1A) receptor-mediated increase in ACTH and oxytocin secretion. Combined, these studies provide the first in vivo evidence for a key role of G(z)-proteins in coupling hypothalamic 5-HT(1A) receptors to effector mechanisms.


Alternative decision analysis modeling in the economic evaluation of tumor necrosis factor inhibitors for rheumatoid arthritis.
To provide a review of the studies that use decision models in the economic evaluation of tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) and to address some important issues surrounding the choice of such modeling techniques in these economic evaluations. A systematic literature search was conducted by 1 author from the literature published from January 1996 to March 2005 through Medline, Embase, and Cochrane library databases. The review yielded 29 studies that used decision models. Only 10 studies used a decision model in the economic analysis of the TNF inhibitors and were included in the final review. Decision model types included the following in the review articles: decision tree (2), Markov model (7), and discrete event simulation (1). These models vary in complexity and their choice depends on the course of disease, the impact of treatment, and the available data. Based on the results derived from alternative modeling techniques, it is safe to say that all methods can provide useful information with regard to economic evaluations of TNF inhibitors. Even though different modeling techniques provide an appropriate representation of available data, their results should be interpreted contingent on the input data, assumptions, sensitivity analyses, and other alternative scenario analyses. The transparency in the models will encourage end users such as policymakers and prescribers to make informed judgments regarding the appropriateness of the methods and the validity of the results.


Cutaneous Feedback of Fingertip Deformation and Vibration for Palpation in Robotic Surgery.
Despite its expected clinical benefits, current teleoperated surgical robots do not provide the surgeon with haptic feedback largely because grounded forces can destabilize the system's closed-loop controller. This paper presents an alternative approach that enables the surgeon to feel fingertip contact deformations and vibrations while guaranteeing the teleoperator's stability. We implemented our cutaneous feedback solution on an Intuitive Surgical da Vinci Standard robot by mounting a SynTouch BioTac tactile sensor to the distal end of a surgical instrument and a custom cutaneous display to the corresponding master controller. As the user probes the remote environment, the contact deformations, dc pressure, and ac pressure (vibrations) sensed by the BioTac are directly mapped to input commands for the cutaneous device's motors using a model-free algorithm based on look-up tables. The cutaneous display continually moves, tilts, and vibrates a flat plate at the operator's fingertip to optimally reproduce the tactile sensations experienced by the BioTac. We tested the proposed approach by having eighteen subjects use the augmented da Vinci robot to palpate a heart model with no haptic feedback, only deformation feedback, and deformation plus vibration feedback. Fingertip deformation feedback significantly improved palpation performance by reducing the task completion time, the pressure exerted on the heart model, and the subject's absolute error in detecting the orientation of the embedded plastic stick. Vibration feedback significantly improved palpation performance only for the seven subjects who dragged the BioTac across the model, rather than pressing straight into it.


[Variability of psychological diagnosis in patients with psychogenic excoriation].
Among psychiatric dermatoses, the psychogenic excoriation is characterized by patient's confession to provoking the lesions, without presenting any dermatological underlying pathology. This topic has been rarely approached in the literature, focusing on the diversity of psychological diagnoses. Epidemiological data indicated that prevalence varies from 2 to 3% in the general population, 2% among dermatological patients and 9% in patients with itching, with significant prevalence in women. The present article report three Brazilian cases and discusses the therapeutic plan based on multidisciplinary teamwork,including indications of psychotherapy and specific drug therapy to each case.


Reducing unhealthy weight gain in Fijian adolescents: results of the Healthy Youth Healthy Communities study.
Obesity is a significant problem among adolescents in Pacific populations. This paper reports on the outcomes of a 3-year obesity prevention study, Healthy Youth Healthy Communities, which was part of the Pacific Obesity Prevention in Communities project, undertaken with Fijian adolescents. The intervention was developed with schools and comprised social marketing, nutrition and physical activity initiatives and capacity building designed to reduce unhealthy weight, and the individual exposure period was just over 2-year duration. The evaluation incorporated a quasi-experimental, longitudinal design in seven intervention secondary schools near Suva (n=874) and a matched sample of 11 comparison secondary schools from western Viti Levu (n=2,062). There were significant differences between groups at baseline; the intervention group was shorter, weighed less, had a higher proportion of underweight and lower proportion of overweight, and better quality of life (Pediatric Quality of Life Inventory only). At follow-up, the intervention group had lower percentage body fat (-1.17) but also a lower increase in quality of life (Assessment of Quality of Life instrument: -0.02; Pediatric Quality of Life Inventory: -1.94) than the comparison group. There were no other differences in anthropometry, and behaviours' changes showed a mixed pattern. In conclusion, this school-based health promotion programme lowered percentage body fat but did not reduce unhealthy weight gain or influence most obesity-promoting behaviours among Fijian adolescents. Despite growing evidence supporting the efficacy of community-based approaches to reduce obesity among children of European descent, findings from this study failed to demonstrate the efficacy of a community capacity-building approach among an adolescent sample drawn from a different sociocultural, economic and geographical context. Additional 'top-down' or other innovative approaches may be needed to reduce adolescent obesity in the Pacific.


OSHA criteria for laboratory proficiency in blood lead analysis.
The OSHA lead standard, 29 CFR 1910.1025, was established to protect the health of workers exposed to the hazards of lead. The standard lists specific requirements to ensure that blood lead analyses--critical indicators of workers at risk--be performed reliably by laboratories. Employers must be laboratories that meet OSHA performance criteria in blood lead proficiency testing programs monitored by the Centers for Disease Control and certain States. This proficiency testing requires that, as a minimum, laboratories must report the equivalent of eight out of nine samples within acceptable limits for the most recent three quarters or similar period. For compliance purposes, OSHA circulates to its staff a "List of Laboratories Approved for Blood Lead Analysis" each quarter.


Stigmatizing experiences of parents of children with a new diagnosis of ADHD.
The experiences of parents of a child who received an initial diagnosis of attention-deficit hyperactivity disorder (ADHD) were examined to determine the ways in which they may have encountered stigmatizing situations. Forty-eight parents of children aged six to 18 years were interviewed about their experiences leading up to their child's ADHD diagnosis, including their decisions to seek treatment. All interviews were recorded, transcribed, and analyzed using grounded theory methods. Codes were identified using a constant comparative approach, which led to theoretically defined thematic constructs of stigma. Stigmatizing experiences were noted by 77% of the sample. Nearly half (N=21, 44%) were concerned about how society would label their child, 40% (N=19) felt social isolation and rejection, and 21% (N=10) perceived health care professionals and school personnel as being dismissive of their concerns. Parents' own attitudes about ADHD treatment were shaped by their exposure to negative media (N=10, 21%), their mistrust of medical assessments (N=8, 17%), and the influence of general public views (N=3, 6%). These stigmatizing views were related to parental concerns about the impact that diagnosis and treatment would have on their child's self-esteem and opportunities for future success. The range of ways in which parents in the study experienced stigma highlights the need for multiple perspectives for community outreach and public health programs that are aimed at addressing and eliminating mental health stigma. Even though stigma is a well-established barrier to mental health service use, the anticipated benefits of treatment may outweigh parents' experiences with stigma.


Managers' perceptions of the effects of a national mandatory accreditation program in Danish hospitals. A cross-sectional survey.
This study aimed to examine and compare middle and senior hospital managers' perceptions of the effects of a mandatory accreditation program in Denmark, the Danish Healthcare Quality Program (Den Danske Kvalitetsmodel [DDKM]) after it was terminated in 2015. A cross-sectional online questionnaire survey. All 26 somatic and psychiatric public hospitals in Denmark. All senior and middle managers. A questionnaire with open and closed response (five-point Likert scale) questions. Quantitative data were analyzed descriptively and through ordered logistic regression by management level. Qualitative data were subjected to a software-assisted content analysis. The response rate was 49% (533/1059). In both the qualitative and quantitative data sets, participants perceived the DDKM as having: led to an increased focus on registration, documentation and additional and unnecessary procedures. While the DDKM was perceived as increasing a focus on quality, the time required for accreditation was at the expense of patient care. There were significant differences by management level, with middle managers having more negative perceptions of the DDKM related to time spent on documentation and registration. While the DDKM had some perceived benefits for quality improvement, it was ultimately considered time-consuming and outdated or having served its purpose. Including managers, particularly middle managers, in refinements to the new quality improvement model could capitalize on the benefits while redressing the problems with the terminated accreditation program.


Recommendations on prevention and screening for breast cancer in Hong Kong.
In Hong Kong, breast cancer is the most common cancer among women and poses a significant health care burden. The Cancer Expert Working Group on Cancer Prevention and Screening (CEWG) was set up in 2002 by the Cancer Coordinating Committee to review and assess local and international scientific evidence, and to formulate recommendations for cancer prevention and screening. After considering the local epidemiology, emerging scientific evidence, and local and overseas screening practices, the CEWG concluded that it was unclear whether population-based breast cancer screening did more harm than good in local asymptomatic women at average risk. The CEWG considers that there is insufficient evidence to recommend for or against population-based mammography screening for such individuals. Women who consider breast cancer screening should be adequately informed about the benefits and harms. The CEWG recommends that all women adopt primary preventive measures, be breast aware, and seek timely medical attention for suspicious symptoms. For women at high risk of breast cancer, such as carriers of confirmed BRCA1/2 deleterious mutations and those with a family history of breast cancer, the CEWG recommends that they seek doctor's advice for annual mammography screening and the age at which the process should commence. Additional annual screening by magnetic resonance imaging is recommended for confirmed BRCA1/2 mutation carriers or women who have undergone radiation therapy to the chest between the age of 10 and 30 years. Women at moderate risk of breast cancer should discuss with doctors the pros and cons of breast cancer screening before making an informed decision about mammography screening every 2 to 3 years.


[Comparison of the therapeutic results of bromocriptine treatment of prolactin microadenoma and macroadenoma].
26 infertile women with prolactinomas were treated by bromocriptine, 24 of them (92%) became pregnant. All of 11 cases with microadenoma restored fertility, 13 out of 15 patients with macroadenomas became fertile. The total is 32 pregnancies. 4 of 32 pregnancies developed spontaneous abortion or fetal death in uterus. In all the women with microadenomas and 11 cases with macroadenomas there were no symptom of enlargement of pituitary tumor, 2 patients with macroadenomas developed visual field defect or paralysis of left oculomotor nerves. 22 patients continued bromocriptine medication for 4.6 +/- 3.6 months and in 6 patients took bromocriptine until delivery. No congenital malformation were found, the development and intelligence were normal in their children. 4 women with microadenomas restored menses at postpartum without taking bromocriptine. The other patients still suffered amenorrhea and galactorrhea after delivery. 8 patients breast-feed their infants for 17.9 +/- 9.5 (7-33) months, no harmful effect on prolactinomas was found. Our data suggest: (1) The pregnancy rate in women with prolactinomas treated with bromocriptine was 92%. (2) Women with microprolactinomas who became pregnant appear to have a very low risk for developing complications and women with macroprolactinomas should be followed closely throughout pregnancy for pituitary tumors enlargement. (3) Bromocriptine therapy do not increase the risk of spontaneous abortion in women with prolactinoma and congenital anomalies of their offspring during pregnancy.


Characterization of the microanatomy and histopathology of placentas from aborted, stillborn, and normally delivered alpacas (Vicugna pacos) and llamas (Lama glama).
From 2002 to 2007, 101 camelid abortions and stillbirths were submitted to the Veterinary Diagnostic Laboratory at Oregon State University (84 alpacas [Vicugna pacos], 13 llamas [Lama glama], 4 unknown). For most cases (n = 67), a cause was not determined by routine testing. Eighty-five submissions included placenta for microscopic examination, of which 55 were from abortions to unknown causes (idiopathic). Microscopic features of placentas from abortion/stillbirth were compared with those from 19 camelids delivered normally (6 alpacas, 12 llamas, 1 unknown) and with those from 4 alpaca fetuses of known gestational age collected during the dam's necropsy. The most common microscopic findings in abortion/stillbirth placentas were mineralization (n = 57) and mucinous edema (n = 27) of the chorioallantoic stroma. One or more of these features were also observed in 22 of 23 placentas from normal pregnancies/deliveries and therefore interpreted as incidental findings. The comparison of alpaca placentas after matching for gestational parameters (crown-rump length, weight, days of gestation; n = 41) revealed hypoplasia of placental villi in 5 of 22 idiopathic abortions and in 1 abortion due to umbilical torsion; hypoplasia was further suspected in an additional 6 abortions of unknown cause and 2 abortions of known cause. The identified villous hypoplasia is assumed to have resulted in placental insufficiency. When placental insufficiency is included as cause, idiopathic abortions are reduced from 66.2 to 47.9% of alpaca cases with histopathologic examination of placenta and from 66.3 to 52.5% of alpaca and llama abortions overall. This study also permitted the generation of a linear regression curve correlating alpaca fetal crown-rump length with fetal age.


Metabolite measurements in the caudate nucleus, anterior cingulate cortex and hippocampus among patients with mitochondrial disorders: a case-control study using proton magnetic resonance spectroscopy.
Mitochondrial disorders are clinical syndromes associated with mutations in the mitochondrial or nuclear genome that result in impaired oxidative phosphorylation and deficient energy production. Metabolic abnormalities in brain areas associated with cognitive functions could give rise to neuropsychiatric symptomatology. The aim of this study was to use single-voxel proton magnetic resonance spectroscopy to identify metabolic abnormalities in regions implicated in neuropsychiatric symptoms in patients with mitochondrial disorders. N-acetyl-aspartate and creatine levels were measured in the caudate nucleus, anterior cingulate cortex and hippocampus in 15 patients with mitochondrial disorders compared with 15 healthy controls matched for age and sex. N-acetyl-aspartate levels were significantly lower in the caudate nucleus among patients with mitochondrial disorders (mean 7.04 ± 1.19 standard deviation [SD] institutional units) compared with healthy controls (mean 8.19 ± 1.18 SD institutional units; p = 0.02). Creatine levels were lower in the caudate nucleus among patients compared with controls (patients: mean 6.84 ± 1.42 SD institutional units; controls: mean 7.52 ± 0.76 SD institutional units; p = 0.03), but the results were no longer significant after correction for multiple comparisons. There were no significant differences in metabolite measurements between patients and controls in the anterior cingulate cortex and the hippocampus. Metabolic abnormalities were identified exclusively in the caudate nucleus, with significantly lower N-acetyl-aspartate levels among patients compared with controls. These results suggest that the corpus striatum may be highly susceptible to mitochondrial oxidative phosphorylation defects and resultant cell loss. Given the role of the caudate nucleus in cognitive and executive functions, our findings raise the possibility that metabolic abnormalities in the caudate nucleus may contribute to cognitive impairment and neuropsychiatric symptoms in patients with mitochondrial disorders, which could be investigated in future studies.


Progression of hepatic stellate cell activation is associated with the level of oxidative stress rather than cytokines during CCl4-induced fibrogenesis.
In order to identify a fibrogenic factor associated with the potential of hepatic stellate cells (HSC) activation that arises during the CCl4-induced fibrogenic process, the relationship between the activation of HSC and levels of several fibrogenic factors were investigated. After isolation of HSC from the liver at different stages of CCl4 intoxication, the activation of HSC was assessed by the expression of alpha-smooth muscle actin. Levels of cytokines and oxidative stress in liver homogenates and plasma were measured by enzyme linked immunosorbent assay and the colorimetric method. In primary culture, HSC isolated from a rat liver were gradually activated in a time-dependent manner according to CCl4 administration. The progression of HSC activation was closely correlated with parameters related to oxidative stress in liver homogenates rather than the tissue levels of several cytokines. Also, the levels of antioxidants and arginase activity were inversely correlated with HSC activation. In plasma, the levels of oxidative stress and cytokines in CCl4-treated rat livers were not associated with the activation of HSC found during the CCl4-induced fibrogenic process. The relationship between HSC activation and oxidative stress was also confirmed through several factor-treated HSC cultures. In conclusion, the activation of HSC was accelerated according to CCl4 administration, and the progression of HSC activation is absolutely related to the oxidative stress. These results show that enhanced oxidative stress is an important signal for activation of HSC in experimental liver fibrogenesis.


A case report: Giant cystic parathyroid adenoma presenting with parathyroid crisis after Vitamin D replacement.
Parathyroid adenoma with cystic degeneration is a rare cause of primary hyperparathyroidism. The clinical and biochemical presentation may mimic parathyroid carcinoma. We report the case of a 55 year old lady, who had longstanding history of depression and acid peptic disease. Serum calcium eight months prior to presentation was slightly high, but she was never worked up. She was found to be Vitamin D deficient while being investigated for generalized body aches. A month after she was replaced with Vitamin D, she presented to us with parathyroid crisis. Her corrected serum calcium was 23.0 mg/dL. She had severe gastrointestinal symptoms and acute kidney injury. She had unexplained consistent hypokalemia until surgery. Neck ultrasound and CT scan revealed giant parathyroid cyst extending into the mediastinum. After initial medical management for parathyroid crisis, parathyroid cystic adenoma was surgically excised. Her serum calcium, intact parathyroid hormone, creatinine and potassium levels normalized after surgery. This case of parathyroid crisis, with very high serum calcium and parathyroid hormone levels, is a rare presentation of parathyroid adenoma with cystic degeneration. This case also highlights that Vitamin D replacement may unmask subclinical hyperparathyroidism. Consistent hypokalemia until surgery merits research into its association with hypercalcemia.


Atlanto-axial rotatory subluxations in postmortem CT: radiologists be aware of a common pitfall.
The aim of the present study was to determine the frequency of atlanto-axial rotatory subluxations (AARS) in multi detector computed tomography (MDCT) performed on human corpses for forensic purposes and to investigate whether these are a physiological postmortem finding or indicate a trauma to the neck region. 80 forensic cases examined with MDCT from November 2003 to March 2007 were included in the study. The study was approved by the regional ethics committee. For each case volumes were rendered and investigated with reference to suspected AARS and any other anomalies of the head and neck region. The rotation of the head as well as in the atlanto-axial joint were measured and occurring AARS were judged according Fielding's classification. The finding of AARS was correlated to case criteria such as postmortem head rotation, sex, age, cause of death, time since death and further autopsy results. Statistical analysis was performed using Fisher's exact test, Wilcoxon's rank sums test and Chi-square test with Pearson approximation. 70% (n=56) of the cases included in the study presented with an AARS. A strong correlation (P<.0001) between suspected AARS and postmortem head rotation was found. Two cases presented with an atlanto-axial rotation greater than the head rotation. One showed an undiscovered lateral dislocation of the atlas, and one an unfused atlas-ring. There was no correlation to any further investigated case criteria. Ipsilateral AARS with head rotation alone does not indicate trauma to the neck. PmCT can substantially support forensic examinations of the skeleton, especially in body regions, which are elaborate to access at autopsy, such as the cervical spine. Isolated AARS (Fielding type I) on pmCT is usually a normal finding associated with ipsilateral head rotation.


Lateralized Hemispheric Mechanisms and the Antidepressant Effects of Right and Left Unilateral ECT.
This article critically reviews the six controlled studies of the antidepressant effects of right unilateral versus left unilateral ECT (R-ECT, L-ECT), contrasting them with results recently obtained in double-blind, random assignment comparison of the two methods, using a square-wave stimulus, widely spaced temporoparietal electrode placement, and markedly supra-threshold stimulus charge. The author challenges the prevalent belief in a therapeutic advantage of R-ECT versus L-ECT, proposing instead the contrary case for a therapeutic advantage of L-ECT, based on the interaction of a hypothesized interhemispheric seizure threshold difference and a maximally efficient method of stimulus delivery.


[Treatment of patients with Wegener's granulomatosis or ANCA-associated vasculitis].
Standard therapy of Wegener's granulomatosis is prednisolone in combination with cyclophosphamide. Cyclophosphamide is continued for 15-18 months after diagnosis. During therapy 26% of the patients have severe or life-threatening side effects, mostly infections. Furthermore, there are multiple long-term side effects such as an increased incidence of malignancies, especially bladder carcinoma. During the last 10 years the European vasculitis study group (www.vasculitis.org) organized several randomized clinical trials to determine optimal treatment. Recently, it was demonstrated in one of these trials that in patients with generalized ANCA-associated vasculitis (vasculitis associated with antineutrophil cytoplasmic autoantibodies) withdrawal of cyclophosphamide and substitution by azathioprine after remission did not increase the rate of relapse and was safe. Wegner's granulomatosis is not a fatal disease anymore. Sometimes, however, patients lose their job. Fortunately, this occurs only in a small percentage of patients.


Effect of epinephrine on PO2 in anterior chamber.
A polarographic oxygen electrode was inserted through the cornea into the middle of the anterior chamber, and the aqueous humor PO2 was continuously monitored. Epinephrine hydrochloride applied topically to the cornea (1% Epifrin: 0.05 to 0.1 mL) or injected into the anterior chamber (Adrenalin Chloride: 1 mg/mL, 0.05 mL) caused a marked decrease in the anterior chamber PO2. This drop in anterior chamber PO2 was not simply due to mydriasis, since atropine sulfate administered in a similar fashion did not cause a notable drop in anterior chamber PO2, and epinephrine applied to eyes with the pupils previously dilated with atropine still caused the typical drop in anterior chamber PO2. The hypoxic effects of epinephrine were reversed by injection of an alpha-adrenergic blocker, phentolamine mesylate (5 mg/mL, 0.05 mL), into the anterior chamber.


Magnesium sulphate improves pulmonary function after video-assisted thoracoscopic surgery: A randomised double-blind placebo-controlled study.
Reduced lung volumes are unavoidable after lung resection surgery. Magnesium sulphate (MgSO4) administration has been reported to reduce the requirement for neuromuscular blocking drugs and postoperative analgesics in surgical patients. To investigate the effect of MgSO4 on pulmonary function after video-assisted thoracoscopic surgery (VATS). A randomised, double-blind, placebo-controlled trial. A university tertiary care centre. Sixty-six patients scheduled for pulmonary lobectomy or segmentectomy via VATS. Patients were allocated to one of two groups: the Mg (MgSO4 50 mg kg intravenously for 10 min, followed by a continuous infusion of 15 mg kg h during surgery) or the control (same volume of 0.9% saline). Pulmonary function tests [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow rate] were measured before surgery and at three time points after surgery (2, 24 and 48 h postoperatively) using a portable spirometer. Twelve months after surgery, pulmonary function test values were repeated at a regular outpatient follow-up visit. FEV1 at 24 (1.7 ± 0.6 vs. 1.3 ± 0.5 l, P = 0.033) and 48 h (1.7 ± 0.6 vs. 1.4 ± 0.5 l, P = 0.021) and FVC at 24 (2.0 ± 0.8 vs. 1.6 ± 0.6 l, P = 0.038) and 48 h (2.2 ± 0.8 vs. 1.7 ± 0.7 l, P = 0.008) after surgery were significantly greater in the Mg group. Patients in the Mg group required less rocuronium than those in the control group (64.2 ± 19.9 vs. 74.9 ± 20.3 mg, respectively; P = 0.041). Consumption of postoperative patient-controlled analgesia was also significantly less at 24 and 48 h after surgery in the Mg group (P = 0.022 and 0.015, respectively), although pain scores and rescue analgesics were comparable. Five patients in the control group were diagnosed with postoperative pneumonia using clinical and radiological criteria before discharge. FEV1 and FVC at 12 months after surgery were not different between the two groups. Intraoperative administration of MgSO4 improved pulmonary function and reduced the need for rocuronium and postoperative analgesics in patients who underwent VATS. cris.nih.go.kr identifier: KCT0001410.


Digital Phenotype for Childhood Internalizing Disorders: Less Positive Play and Promise for a Brief Assessment Battery.
Childhood internalizing disorders, like anxiety and depression, are common, impairing, and difficult to detect. Universal childhood mental health screening has been recommended, but new technologies are needed to provide objective detection. Instrumented mood induction tasks, designed to press children for specific behavioral responses, have emerged as means for detecting childhood internalizing psychopathology. In our previous work, we leveraged machine learning to identify digital phenotypes of childhood internalizing psychopathology from movement and voice data collected during negative valence tasks (pressing for anxiety and fear). In this work, we develop a digital phenotype for childhood internalizing disorders based on wearable inertial sensor data recorded from a Positive Valence task during which a child plays with bubbles. We find that a phenotype derived from features that capture reward responsiveness is able to accurately detect children with underlying internalizing psychopathology (AUC = 0.81). In so doing, we explore the impact of a variety of feature sets computed from wearable sensors deployed to two body locations on phenotype performance across two phases of the task. We further consider this novel digital phenotype in the context of our previous Negative Valence digital phenotypes and find that each task brings unique information to the problem of detecting childhood internalizing psychopathology, capturing different problems and disorder subtypes. Collectively, these results provide preliminary evidence for a mood induction task battery to develop a novel diagnostic for childhood internalizing disorders.


Cricoarytenoid subluxation presenting as vocal cord palsy following endotracheal intubation - A case report.
Airway interventions commonly present with self-limiting throat pain and hoarseness of voice. Persistent hoarseness is rare and should be evaluated for serious complications. Cricoarytenoid injuries may present as vocal cord palsies which need careful evaluation. We encountered a case of intubation-related cricoarytenoid subluxation in a 49-year-old diabetic female with a past history of pulmonary tuberculosis was planned for a modified radical mastectomy after a course of neoadjuvant chemotherapy. During intubation by a third-year resident, Cormack Lehane's grade was 3, and bougie-guided railroading of 7 mm endotracheal tube was done blindly. The patient developed haemoptysis and desaturation following intubation and was on ventilator support for 24 hours. Following extubation, the patient had throat pain and hoarseness in voice for more than 2 days. Fibreoptic laryngoscopy revealed right vocal cord palsy. A detailed evaluation revealed right cricoarytenoid subluxation which was treated successfully by closed reduction after 1 week. Cricoarytenoid subluxation, though rare is a serious complication after interventional airway procedures. According to the literature, unfavourable intubating conditions, predisposing patient factors and inadequate experience of the anaesthesiologist are the major contributors to this complication. Injury may produce submucosal haemorrhage and haemarthrosis, which cause adhesions and scarring leading to fixing of vocal cord in abnormal position and permanent disability. Early diagnosis by fibreoptic laryngoscopy and CT imaging and prompt interventions like closed reduction or laryngoplasty should be done to restore vocal cord function.


Demonstrating the fibular collateral ligament.
A posture is described which allows palpation of the fibular collateral ligament of the knee as an isolated structure. Visual identification is also possible. This is of interest to the clinician and student of surface anatomy.


Antibody response to pneumococcal vaccination in children with chronic or recurrent rhinosinusitis.
Although chronic and recurrent rhinosinusitis is prevalent in children, little is known about its causes. Here, we investigated the humoral immunity in children with chronic or recurrent rhinosinusitis. We examined 16 children attending the outpatient clinic at the CHA Bundang Medical Center including 11 boys and 5 girls, aged 3.11 years (mean age, 5.6 years), who had rhinosinusitis for >3 months or >3 times per year. The complete blood count with differential and total serum concentrations of Immunoglobulin (Ig) E, IgA, IgD, IgM, IgG, and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) of all children were measured. All subjects received 23-polysaccharide pneumococcal vaccination (PPV), and the levels of antibodies to 5 serologic types (4, 6B, 14, 18C, and 23F) of pneumococcal capsular polysaccharide antigens were measured before and after vaccination. Post-PPV antibody titers ≥0.35 µg/mL or with a ≥4-fold increase were considered as positive responses. The titers of IgG, IgA, IgD, and IgM were within normal range in all 16 children, whereas the total IgE concentration was higher than normal in 2 children. IgG1 deficiency was observed in 1 patient and IgG3 deficiency in 3. After PPV, 1 patient failed to respond to all 5 serologic types, 2 failed to respond to 4 serologic types, and 2 failed to respond to 3 serologic types. Clinicians should consider the evaluation of humoral immune functions in children with chronic or recurrent rhinosinusitis who do not respond to prolonged antibiotic treatment.


Quantitative risk of positive family history in developing colorectal cancer: A meta-analysis.
Positive family history is a risk factor for development of colorectal cancer. Despite numerous studies on the topic, the absolute risk in patients with a positive family history remains unclear and therefore studies are lacking to validate non-invasive screening methods in individuals with positive family history. To quantify the risk of colorectal cancer in individuals with a positive family history. A comprehensive electronic literature search was performed using PubMed from January 1955 until November 2017, EMBASE from 1947 until 2018, and Cochrane Library without date restrictions. Two independent reviewers conducted study selection, data extraction and quality assessment. A meta-analysis of Mantel-Haenzel relative risks was performed using the random effects model. Newcastle-Ottawa scale was used to score the quality of selected papers. Funnel plot and Egger's regression test was performed to detect publication bias. Subgroup analysis was performed comparing Asian and non-Asian studies. Sensitivity analyses were performed to rule out the effect of the timing of the study, overall quality, the main outcome and the effect of each individual study in overall result. Forty-six out of 3390 studies, including 906981 patients were included in the final analysis. 41 of the included studies were case-control and 5 were cohort. A positive family history of colorectal cancer in first-degree relatives was associated with significantly increased risk of colorectal cancer with a relative risk of 1.87 (95%CI: 1.68-2.09; P < 0.00001). Cochrane Q test was significant (P < 0.00001, I 2 = 90%). Egger's regression test showed asymmetry in the funnel plot and therefore the Trim and Fill method was used which confirmed the validity of the results. There was no difference between Asian versus non-Asian studies. Results remained robust in sensitivity analyses. Individuals with a positive family history of colorectal cancer are 1.87 times more likely to develop colorectal cancer. Screening guidelines should pay specific attention to individuals with positive family history and further studies need to be done on validating current screening methods or developing new modalities in this high-risk population.