HSP70, adiponectin, leptin, pro-inflammatory cytokines and metabolic hormones of heat-stressed broilers fed herbal supplements.
Global warming undoubtedly is a serious challenge facing poultry production especially in tropical climate, which subject animals to heat-stressed conditions leading to multiple physiological alterations. An investigation was conducted to determine the role of herbal supplements on adipokines, pro-inflammatory cytokines and metabolic hormones of broilers exposed to heat stress. 200 a day-old broiler chicks were randomly allotted to standard diets; diet 1 without leaf meal (T1), diet 2 with 5% Moringa oleifera (T2), diet 3 with 5% Phyllanthus amarus (T3) and diet 4 with 5% mistletoe; Viscum album (T4) in a 49-day feed trial during the peak of thermal discomfort in Southern Nigeria, to assess hormones, adipokines and cytokines using standard procedures. Results obtained shows that triiodothyronine of birds fed phyllanthus and mistletoe were significantly (p < 0.05) higher than birds on basal diet. Corticosterone of birds fed mistletoe and phyllanthus were significantly (p < 0.05) lower than those obtained in birds on basal diet. Heat shock protein of birds fed on moringa supplements were significantly (p < 0.05) lower than those in birds on basal diet. The adiponectin of birds fed on basal diet were statistically (p < 0.05) higher than other treatments. Interleukin 6 of birds on phyllanthus and mistletoe supplements were not significantly (p > 0.05) different from birds on basal diet. Interleukin 1β of birds fed basal diet was significantly (p < 0.05) higher than birds fed moringa supplements and the significantly (p < 0.05) least values obtained in those of birds fed phyllanthus supplement. Tumor necrosis factor α of birds fed on phyllanthus and mistletoe were significantly (p < 0.05) higher than birds fed basal diet and the significantly (p < 0.05) least values were obtained in birds fed moringa supplement. In conclusion, three herbal supplements decreased the HSP 70, leptin and adiponectin of broilers exposed to heat stress and moringa supplements lower pro-inflammatory cytokine expression in heat stress birds.


Machine Learning Methods for Endocrine Disrupting Potential Identification Based on Single-Cell Data.
Humans are continuously exposed to a variety of toxicants and chemicals which is exacerbated during and after environmental catastrophes such as floods, earthquakes, and hurricanes. The hazardous chemical mixtures generated during these events threaten the health and safety of humans and other living organisms. This necessitates the development of rapid decision-making tools to facilitate mitigating the adverse effects of exposure on the key modulators of the endocrine system, such as the estrogen receptor alpha (ERα), for example. The mechanistic stages of the estrogenic transcriptional activity can be measured with high content/high throughput microscopy-based biosensor assays at the single-cell level, which generates millions of object-based minable data points. By combining computational modeling and experimental analysis, we built a highly accurate data-driven classification framework to assess the endocrine disrupting potential of environmental compounds. The effects of these compounds on the ERα pathway are predicted as being receptor agonists or antagonists using the principal component analysis (PCA) projections of high throughput, high content image analysis descriptors. The framework also combines rigorous preprocessing steps and nonlinear machine learning algorithms, such as the Support Vector Machines and Random Forest classifiers, to develop highly accurate mathematical representations of the separation between ERα agonists and antagonists. The results show that Support Vector Machines classify the unseen chemicals correctly with more than 96% accuracy using the proposed framework, where the preprocessing and the PCA steps play a key role in suppressing experimental noise and unraveling hidden patterns in the dataset.


Autoimmune Hepatitis: Diagnostic Dilemma When It Is Disguised as Iron Overload Syndrome.
Elevated serum ferritin level is a common finding in iron overload syndrome, autoimmune and viral hepatitis, alcoholic and nonalcoholic fatty liver diseases. High transferrin saturation is not a common finding in above diseases except for iron overload syndrome. We encountered a challenging case of 73-year-old female who presented with yellowish discoloration of skin, dark color urine and dull abdominal pain. Initial laboratory tests reported mild anemia; elevated bilirubin, liver enzymes, and transferrin saturation. We came to the final diagnosis of autoimmune hepatitis after extensive workups. Autoimmune hepatitis is a rare disease, and the diagnosis can be further complicated by a similar presentation of iron overload syndrome. Markedly elevated transferrin saturation can simulate iron overload syndrome, but a liver biopsy can guide physicians to navigate the diagnosis.


Total femoral allograft with simultaneous revision total hip and knee arthroplasty: 18 year follow-up.
Massive allograft can be a useful option in revision total joint arthroplasty for treatment of significant bone loss. In rare cases, revision hip and knee arthroplasty procedures can be performed simultaneously using massive allograft-prosthetic composites. We present an 18 year follow up of a patient who received a simultaneous revision hip and knee total femoral allograft and discuss recent literature as it relates to this case.


Quinidine-induced potentiation of cardiovascular effects of nitrendipine: functional aspects and possible molecular mechanisms.
The functional interaction between the dihydropyridine calcium channel blocker nitrendipine and quinidine was studied in isolated preparations from guinea-pig cardiac ventricle and in mesenteric arterial segments under a variety of experimental conditions. The negative inotropic potency of nitrendipine is clearly enhanced by quinidine (3 x 10(-6)-10(-4) mol/l) by up to two orders of magnitude, i.e. cardiac nitrendipine effects are potentiated. Vasorelaxant effects, however, remain largely unaffected (nitrendipine potency is increased by half an order of magnitude maximally). To elucidate the mechanism of this interaction, the ability of quinidine to potentiate the negative inotropic effect of a series of 12 dihydropyridines was compared with their voltage-dependence of action in guinea-pig left atria. No significant correlation is found (r = 0.18). Furthermore, quinidine inhibits rather than stimulates binding of tritiated nitrendipine, nimodipine or (S)-isradipine to isolated cardiac membranes. Therefore, the mechanism of the quinidine-nitrendipine interaction differs from those previously proposed for modulation of dihydropyridine binding by other drugs. We hypothesize that quinidine-occupied calcium channels adopt an intermediate affinity for nitrendipine, higher than in resting channels, but lower than the high affinity present with inactivated channels. Model calculations which are based on this assumption are able to reproduce all experimental findings of this study.


Head-group conformation in phospholipids: a phosphorus-31 nuclear magnetic resonance study of oriented monodomain dipalmitoylphosphatidylcholine bilayers.
Angular-dependent 31P NMR spectra of oriented biaxial monodomain DPPC.H2O multilayers are employed to study head-group conformation in this phospholipid. The results indicate that the O-P-O plane of the phosphate, where the O's are the nonesterified oxygens of the phosphodiester, is tilted at 47 +/- 5 degrees with respect to the bilayer normal. This PO4 orientation could result in the choline moiety being extended parallel to the bilayer plane, and it will explain the breadth of the axially symmetric 31P powder spectrum observed for DPPC in excess water. This work is the first direct observation of this conformation for lecithins and it illustrates the utility of high-resolution solid-state NMR in structural studies of disordered systems.


Medical Students and Staff Physicians: The Question of Social Media.
Social media's prevalence among the professional world is rapidly increasing. Its use among medical personnel-specifically, medical students, resident physicians, and staff physicians-could compromise personal-professional boundaries. Could the acceptance or lack of acceptance of a friend request bias the medical student application process? If friend requests are accepted, then medical students, resident physicians, and staff physicians are provided access to very personal aspects of one another's lives, which may not have been the intent. The question remains whether the separation of one's personal life from work is necessary. Should medical students restrict social media relationships with residents and staff physicians to professional social media networks? The suitability and opportunities of social media among medical professionals is an ongoing issue for research that needs continued evaluation.


Refractory supra-ventricular tachyarrhythmias due to early posterior pericardial effusion following open-heart surgery.
Three cases are presented of supra-ventricular tachyarrhythmias following open heart surgery refractory to direct current cardioversion and pharmacological treatment. Echocardiography demonstrated a moderate to large posterior pericardial effusion in each case. Surgical evacuation of the effusion was followed by reversion to sinus rhythm.


Autophagy collaborates with apoptosis pathways to control oligodendrocyte number.
Oligodendrocytes are the sole myelin-producing cells in the central nervous system. Oligodendrocyte number is tightly controlled across diverse brain regions to match local axon type and number, yet the underlying mechanisms remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under physiological conditions, elicits premyelinating oligodendrocyte apoptosis during development. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy functions cell autonomously in the premyelinating oligodendrocyte to trigger cell apoptosis, and it genetically interacts with the TFEB pathway to limit oligodendrocyte number across diverse brain regions. Our results provide in vivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrogenesis.


Changes in nitrogen related functional genes along soil pH, C and nutrient gradients in the charosphere.
The interface between biochar and soil differs from both the bulk soil and the biochar itself, and has been termed the "charosphere". However, a complete definition of the charosphere, including aspects of size, properties, functional reach and effects on soil processes, is still required. In this study, the distributions of functional genes related to the soil N cycle within the charosphere were investigated over a multi-sectional gradient. We found that concentrations of dissolved organic carbon (DOC), available phosphorus and exchangeable cations (Ca2+, Mg2+, K+) increased with proximity to the biochar surface (termed the 'near charosphere'). Similarly, the abundance of bacterial amoA was greater in the near charosphere, while archaeal amoA abundance was relatively homogenous. This taxonomic asymmetry resulted in a shift in the predominant ammonia-oxidizers from ammonia-oxidizing bacteria (AOB) to ammonia-oxidizing archaea (AOA) in the far charosphere. This was associated with other factors such as decreasing pH and carbon availability with increasing distance from the biochar. Moreover, the ratio of nosZ/(nirS + nirK) genes also showed functionally asymmetry in the charosphere: increasing with increasing distance from the biochar. This is the first study to map spatial distributions of a set functional genes related to soil N cycling in the soil around biochar. This exploration into the underlying heterogeneity of biochar-affected mechanisms of N transformation provides new insight into the functional geometry of the charosphere.


Safety and efficacy of preoperative chemotherapy for muscle-invasive bladder cancer in elderly patients.
This study aimed at describing the feasibility and oncological outcomes of standard cisplatin-based neoadjuvant chemotherapy (C-NAC) for muscle-invasive bladder cancer (MIBC) in patients aged ≥ 75 and assess the impact of baseline geriatric parameters. This retrospective study included patients with stage cT2-4NanyM0 MIBC aged 75 and older treated with ≥ 1 cycle of C-NAC from 2011 to 2021 at a high-volume academic center. Primary outcome was overall survival (OS). Secondary outcomes were chemotherapy feasibility (administration of ≥ 4 cycles), safety, and pathological downstaging. Fifty-six patients were included. Median age was 79 (range 75-90). C-NAC regimen was ddMVAC in 41 patients and GC in 15. Seventy-three percent of patients received ≥ 4 cycles of C-NAC. Grade ≥ 3 toxicity was observed in 55% of patients. The febrile neutropenia rate was 7%. Thirty patients underwent cystectomy, and 13 underwent chemoradiotherapy. Three-year OS was 63%. Geriatric parameters polypharmacy, undernutrition, and age-adjusted Charlson comorbidity index ≥ 8 predicted worse OS. Standard-of-care C-NAC and local treatments are feasible in selected elderly MIBC patients, with efficacy and safety findings similar to that observed in pivotal trials with younger patients. The prognostic impact of geriatric parameters underlines the need for specialized evaluation before treatment initiation.


The Mentor's Role in Fostering Research Integrity Standards Among New Generations of Researchers: A Review of Empirical Studies.
Promoting research integrity practices among doctoral candidates and early career researchers is important for creating a stable and healthy research environment. In addition to teaching specific technical skills and knowledge, research supervisors and mentors inevitably convey research practices, both directly and indirectly. We conducted a scoping review to summarise the role of mentors in fostering research integrity practices, mentors' responsibilities and the role that institutions have in supporting good mentorship. We searched five different databases and included studies that used an empirical methodology. After searching, a total of 1199 articles were retrieved, of which 24 were eligible for analysis. After snowballing, a total of 35 empirical articles were selected. The review discusses various themes such as the importance of good mentorship, poor mentorship practices, virtues and qualities of mentors, responsibilities and activities of mentors, group mentoring and responsibilities of the institution in supporting good mentorship. This review demonstrates the importance of mentors instilling responsible research practices and attitudes, and promoting research integrity among their mentees. Mentors are responsible for providing explicit guidance and for acting as good role models. The review highlights how poor mentorship can have a bad impact on the research climate. In addition, the review highlights the important influence that institutions can have in supporting mentorship.


Synthesis of PAF-acether and blood volume changes in gram-negative sepsis.
Gram-negative sepsis was induced in rats by intraperitoneal injection of Escherichia coli. The development of bacterial peritonitis and septicemia was monitored by counting the number of peritoneal cells and by performing cultures of blood samples. Mortality reached a 50% rate when rats were injected with 2 X 10(8) colony-forming units. Rats injected with the doses of bacteria which induced mortality showed a time- and dose-dependent increase of vascular permeability as judged by the presence of abundant peritoneal exudate and by the depletion of the circulating volume. In order to know whether the generation of PAF-acether could be involved in the development of the permeability changes, the formation of this mediator was measured in the peritoneal cells and spleen of animals at different times and in response to different doses of E. coli. Significant amounts of PAF-acether could be obtained preceding the development of blood volume depletion in response to the injection of doses of E. coli which induced both mortality and the development of permeability. These data suggest that PAF-acether might be one of the inflammatory mediators involved in the pathogenesis of the hemodynamic changes observed in endotoxemia.


Mucosal Leishmaniasis of the lip: Report of an Exuberant case in a Young man.
Leishmaniasis is a tropical disease caused by protozoan parasites of the genus Leishmania. Mucosal leishmaniasis has been described as secondary to the cutaneous form; however, isolated mucosal involvement can also occur. Specifically, mucosal leishmaniasis of the lip is poorly described and its diagnosis challenges clinicians. We herein report a case of mucosal leishmaniasis affecting the lower lip without cutaneous involvement in a 20-year-old Venezuelan man. The patient had no relevant past medical history. Clinically, a mass-like lesion with ulcerations and crusts was observed. Microscopically, the lesion was composed of granulomatous inflammation along with macrophages containing intracytoplasmic inclusions similar to round-shaped Leishmania. The species Leishmania (Viannia) braziliensis was confirmed. Treatment with meglumine antimonate was effective. The lesion healed satisfactorily, and no side effects or recurrences were observed. Clinicians should be aware of isolated forms of mucosal leishmaniasis of the lip, even in cases where the cutaneous lesion is undetected or clinically manifests as self-limiting. Knowing the endemic areas in the scenario of the dynamics of the ecoepidemiology of leishmaniasis is also essential for surveillance and counselling of the population.


Prevalence of Balance Impairment Among Stroke Survivors Undergoing Neurorehabilitation in Nigeria.
Poststroke balance impairment adversely affects stroke outcomes and addressing the impairment is expected to constitute an important focus of neurorehabilitation. To examine the prevalence and factors associated with balance impairment after stroke. Ninety-five stroke survivors undergoing neurorehabilitation at 2 government hospitals in Northern Nigeria participated in this cross-sectional study. Berg Balance Scale (BBS) was used to assess the presence of balance impairment (BBS score of 0-20). Prevalence of balance impairment was presented as frequency and percentage while demographic and stroke-related determinants of balance impairments were identified using logistic regression analysis. Thirty-five (36.8%) stroke survivors had balance impairment, and age, gender, and poststroke duration were statistically significant determinants. Stroke survivors aged less than 40 years (odds ratio [OR] = .14 [confidence interval [CI] = .20-.94]) and 40-59 years (OR = .23 [CI = .06-.81]) had a lower likelihood of having balance impairment compared to stroke survivors aged 60 years and above. Similarly, males had a lower likelihood of having balance impairment (OR = 1.60 [CI = .05-.55]) compared to females while those in the acute/subacute phase of stroke had a 7-fold likelihood of having balance impairment (OR = 7.74 [CI = 2.63-22.79]) compared to those with chronic stroke. Poststroke balance impairment appears to be significantly influenced by stroke survivors' age, gender, and poststroke duration. Hence, these variables should be considered when planning rehabilitation strategies for improving balance after stroke.


Correction: Multidrug resistance transporter profile reveals MDR3 as a marker for stratification of blastemal Wilms tumour patients.
[This corrects the article DOI: 10.18632/oncotarget.14491.].


Tetracycline double-labeling of iliac trabecular bone in 41 normal adults.
A histomorphometric evaluation of the iliac crest trabecular bone remodeling was performed after tetracycline double-labeling in 41 normal Danes (12 males and 29 females) aged 19 to 56 years. The fraction of formative (osteoid covered) and resorptive surfaces was unrelated to age but higher in males than in females (P less than 0.02 and P less than 0.05, respectively). The appositional rate (0.65 +/- 0.12 micrometer/day) was unrelated to age and sex, whereas the fractional labeled surfaces were higher (P less than 0.01) in the males (0.18 +/- 0.08 micrometer2/micrometer2) than in the females (0.12 +/- 0.05 micrometer2/micrometer2), and among the females inversely related to age (R = -0.38, P less than 0.05). The bone formation rate at BMU level (0.50 +/- 0.20 micrometer3/micrometer2/day) was unrelated to sex, but among the females inversely related to age R = -0.49, P less than 0.01). The bone formation rate at tissue level was higher (P less than 0.02) in the males (0.13 +/- 0.07 micrometer3/micrometer2/day) than in the females (0.07 +/- 0.03 micrometer3/micrometer2/day) and among the females inversely correlated to age (R = -0.43, P less than 0.05). the age- and sex-dependent variations in the dynamic parameters underline the importance of a more elaborated normal material.


Machine Learning Applications to Resting-State Functional MR Imaging Analysis.
Machine learning is one of the most exciting and rapidly expanding fields within computer science. Academic and commercial research entities are investing in machine learning methods, especially in personalized medicine via patient-level classification. There is great promise that machine learning methods combined with resting state functional MR imaging will aid in diagnosis of disease and guide potential treatment for conditions thought to be impossible to identify based on imaging alone, such as psychiatric disorders. We discuss machine learning methods and explore recent advances.


Phytochemical profiling of five medicinally active constituents across 14 Eutrema species.
Wasabi or Japanese horseradish (Eutrema japonicum) is both a traditional condiment and a medicinally important plant with diverse uses. Its medicinally active constituents appear to include five isothiocyanates, but their spatial variations in naturally occurring congeners are unknown. Thus, in this study we measured concentrations of these five active constituents in 20 populations of 14 species of Eutrema and one related species, Yinshania sinuata. Three to five of these constituents were detected in each of the examined species, at concentrations that varied greatly between sampled species and populations of the same species. However, two species, Eutrema tenue and Eutrema deltoideum, had higher total concentrations of the five isothiocyanates and substantially higher concentrations of one or two, than the widely cultivated E. japonicum. Thus, both of these species could be important wild resources for artificial cultivation, in addition to the currently widely cultivated E. japonicum.


Treating unexplained recurrent pregnancy loss based on lessons learned from obstetric antiphospholipid syndrome and inherited thrombophilia: A propensity-score adjusted retrospective study.
The efficacy of low molecular weight heparin (LMWH) is well-established in patients with obstetric antiphospholipid syndrome (O-APS). Their role in women with unexplained recurrent pregnancy loss (U-RPL) and late obstetrical complications (intrauterine growth restriction, IUGR and preeclampsia) is controversial. Here we compared rates of miscarriage and late obstetrical complications in RPL patients diagnosed with O-APS (n = 57) or hereditary thrombophilia (n = 25) (both assuming LMWH from the beginning of pregnancy) and in patients with a history of U-RPL (n = 118), assuming or not LMWH, followed at the 'Pregnancy at risk' and 'Recurrent pregnancy loss' outpatient clinics at the San Raffaele Hospital from April 2010 to April 2020. Patients with systemic autoimmune diseases other than primary O-APS were excluded. We tested for bivariate or multivariate associations among adverse pregnancy outcomes, the presence of thrombophilia and LMWH use by using chi-square test, Anova, propensity score adjusted univariate logistic regression and multivariate analysis as appropriate. U-RPL patients assuming LMWH from the beginning of pregnancy (group A) had a significantly lower rate of miscarriage compared to U-RPL patients who were not treated with LMWH (group B) (13 % vs. 41 % respectively, p 0.001) and similar pregnancy rates compared to both O-APS patients with a history of RPL taking LMWH (group C, 18 %) and RPL patients with thrombophilia and treated with LMWH (group D, 16 %). Our data highlight a protective effect of LMWH on miscarriage in patients with a history of U-RPL. In these patients, LMWH seems as effective as in O-APS and hereditary thrombophilia in reducing RPL.


Sustained and stable hematopoietic donor-recipient mixed chimerism after unrelated cord blood transplantation for adult patients with severe aplastic anemia.
We evaluated the engraftment of donor cells from unrelated cord blood into adult patients with severe aplastic anemia (SAA) and the outcome of allo-CBSCT (cord blood stem cell transplantation). Nine patients were conditioned with decreased dosage of immunosuppressive agents of CTX (60 mg/kg) and ALG (120 mg/kg). The prophylaxis of GVHD consisted of standard CsA and MTX. Patients have a media age of 25.3 yr (range: 15-37), and a median weight of 57.2 kg (range: 52.5-60) at the time of transplantation. Cord blood searches were all conducted at Guangzhou Cord Blood Bank. The engraftment state of the donor cells into recipients was confirmed by microsatellite DNA fingerprinting and fluorescent quantitative PCR analysis. Engrafted evidence has been found in seven patients involved by biomolecular analyses showing donor-recipient mixed chimerism post-transplant which was stable and persistent. After a median follow up of 32.2 months (range: 4-69), seven patients were alive and disease free. This study shows that durable donor-recipient stable mixed chimerism can be achieved by unrelated CBSCT in patients with SAA. Umbilical cord blood could be employed as a source of hematopoietic stem cell for adult transplantation.


Determination of kinetic parameters in the pyrolysis operation and thermal behavior of Prosopis juliflora using thermogravimetric analysis.
This paper deals with the pyrolysis of Prosopis juliflora fuelwood using thermogravimetric analysis to determine the kinetic parameters at six different heating rates of 2, 5, 10, 15, 20 and 25°C/min. The activation energy of pyrolysis was calculated using different methods, namely Kissinger, Kissinger-Akahira-Sunose, Ozawa-Flynn-Wall and Friedman model and corresponding calculated activation energy were found to be 164.6, 204, 203.2, and 219.3kJ/mol, respectively for each method. The three-pseudo component model was applied to calculate the following three kinetic parameters: activation energy, pre-exponential factor and order of reaction. The experimental results were validated with model prediction for all the six heating rates. The three-pseudo component model is able to predict experimental results much accurately while considering variable order reaction model (n≠1).


Structural and functional synthesis of the continuous wave NQR temperature sensor with increased conversion linearity.
The paper describes development of the detailed structure and circuit diagrams of the continuous wave NQR temperature sensor with increased conversion linearity. It is experimentally established that at amplitude modulation of 40% and change of input voltage in the range of 20-1000 mV, the circuit of a symmetric marginal oscillator with a linear active demodulator provides better linearity of transfer characteristic than the circuits of asymmetric marginal oscillators with JFET or diode detectors. As a thermometric substance of the proposed NQR sensor, copper oxide Cu2O was used, which is characterized by a strong temperature dependence of the resonance frequency of 63Cu NQR. In contrast to 35Cl NQR in KClO3, for cuprous oxide the temperature dependence of 63Сu NQR frequency in the frequency range 26.621-25.658 MHz is linear in the temperature range 100-390 K. It is experimentally confirmed that the use of a low mass sample (less than 200 mg) as a thermometric substance of the proposed NQR sensor is quite sufficient for successfully observation of the resonance line at the SNR equal to 9.1 dB.


Rare SUZ12 variants commonly cause an overgrowth phenotype.
The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.


Non-mitochondrial aconitase regulates the expression of iron-uptake genes by controlling the RNA turnover process in fission yeast.
Aconitase, a highly conserved protein across all domains of life, functions in converting citrate to isocitrate in the tricarboxylic acid cycle. Cytosolic aconitase is also known to act as an iron regulatory protein in mammals, binding to the RNA hairpin structures known as iron-responsive elements within the untranslated regions of specific RNAs. Aconitase-2 (Aco2) in fission yeast is a fusion protein consisting of an aconitase and a mitochondrial ribosomal protein, bL21, residing not only in mitochondria but also in cytosol and the nucleus. To investigate the role of Aco2 in the nucleus and cytoplasm of fission yeast, we analyzed the transcriptome of aco2ΔN mutant that is deleted of nuclear localization signal (NLS). RNA sequencing revealed that the aco2ΔN mutation caused increase in mRNAs encoding iron uptake transporters, such as Str1, Str3, and Shu1. The half-lives of mRNAs for these genes were found to be significantly longer in the aco2ΔN mutant than the wild-type strain, suggesting the role of Aco2 in mRNA turnover. The three conserved cysteines required for the catalytic activity of aconitase were not necessary for this role. The UV cross-linking RNA immunoprecipitation analysis revealed that Aco2 directly bound to the mRNAs of iron uptake transporters. Aco2-mediated degradation of iron-uptake mRNAs appears to utilize exoribonuclease pathway that involves Rrp6 as evidenced by genetic interactions. These results reveal a novel role of non-mitochondrial aconitase protein in the mRNA turnover in fission yeast to fine-tune iron homeostasis, independent of regulation by transcriptional repressor Fep1.


Childhood sequelae of infant lung disease: exercise and pulmonary function abnormalities after bronchopulmonary dysplasia.
To determine the long-term pulmonary sequelae and effect on exercise tolerance of bronchopulmonary dysplasia (BPD), we studied 10 children at a mean age of 10.4 years, who had been born prematurely, survived respiratory distress syndrome, and subsequently developed BPD, and compared them with eight age-matched normal children born at term. Pulmonary function tests and graded exercise stress tests were performed. Residual volume, the ratio between residual volume and total lung capacity, vital capacity, forced expiratory volume in 1 second, forced expiratory flow between 25% and 75% of vital capacity, and maximal expiratory flows at 80%, 70%, and 60% of total lung capacity were all abnormal (P less than 0.02) in the children with BPD, compared with control values. Pre-exercise transcutaneous CO2 tension was higher (P less than 0.05) in the BPD group than in the control group. At maximal workload, tcPCO2 remained high in patients with BPD compared with control values (P less than 0.05). Arterial oxygen saturation at maximal workload fell below pre-exercise levels in the BPD group (P less than 0.05) but not in control children. There were no differences in maximal oxygen consumption between the BPD group and control children. Exercise-induced bronchospasm occurred in 50% of the BPD group, but not in the control group. We conclude that long-term survivors of BPD have evidence of airway obstruction, hyperinflation, and airway hyperreactivity, compared with a control group. Aerobic fitness was not significantly different in the BPD and control groups, but was achieved in the BPD group at the expense of a fall in SaO2 and a rise in tcPCO2.


The impact of lesion length and reference vessel diameter on angiographic restenosis and target vessel revascularization in treating in-stent restenosis with radiation.
The study assessed the influence of lesion length and reference vessel diameter (RVD) on recurrent restenosis after gamma intracoronary radiation therapy (ICRT) for in-stent restenosis (IRS). Intracoronary radiation therapy reduces angiographic and clinical restenosis in patients with ISR. The impact of ICRT on challenging subgroups, such as long lesions and small vessels, has not been established. Six-month quantitative coronary angiography and clinical follow-up were conducted to evaluate the influence of lesion length and RVD in patients with ISR treated with ICRT who were enrolled in gamma radiation trials. Angiographic binary restenosis (>50% diameter stenosis) and clinical events were assessed in 311 patients treated with gamma ICRT and 105 patients who received placebo. Baseline demographic, angiographic and procedural details were similar in the two treatment groups. The ICRT group had reduced binary restenosis in vessels of all sizes (30% vs. 66%, p < 0.001), with the most benefit seen in small vessels. A trend toward reduced restenosis with ICRT was found across all lesion lengths. At six months, major adverse cardiac events (MACE) were reduced in the ICRT group compared to placebo (34% vs. 71%, p < 0.0001), driven by reduced target vessel revascularization (27% vs. 71%, p < 0.0001). The independent predictors of angiographic restenosis include ICRT (OR [odds ratio] 0.16; CI [confidence interval] 0.10 to 0.28, p < 0.001), lesion length (OR 1.03; CI 1.01 to 1.05, p = 0.004) and RVD (OR 0.40; CI 0.23 to 0.67, p < 0.001). Intracoronary radiation therapy, compared to placebo, results in a significant reduction of angiographic restenosis across all vessel sizes, with a trend toward reduction of angiographic restenosis across all lesion lengths; this effect is seen predominantly in small vessels and diffuse lesions.


Chronic Oral L-Carnitine Supplementation Drives Marked Plasma TMAO Elevations in Patients with Organic Acidemias Despite Dietary Meat Restrictions.
Recent studies have implicated trimethylamine N-oxide (TMAO) in atherosclerosis, raising concern about L-carnitine, a common supplement for patients with inborn errors of metabolism (IEMs) and a TMAO precursor metabolized, in part, by intestinal microbes. Dietary meat restriction attenuates carnitine-to-TMAO conversion, suggesting that TMAO production may not occur in meat-restricted individuals taking supplemental L-carnitine, but this has not been tested. Here, we mine a metabolomic dataset to assess TMAO levels in patients with diverse IEMs, including organic acidemias. These data were correlated with clinical information and confirmed using a quantitative TMAO assay. Marked plasma TMAO elevations were detected in patients treated with supplemental L-carnitine, including those on a meat-free diet. On average, patients with an organic acidemia had ~45-fold elevated [TMAO], as compared to the reference population. This effect was mitigated by metronidazole therapy lasting 7 days each month. Collectively, our data show that TMAO production occurs at high levels in patients with IEMs receiving oral L-carnitine. Further studies are needed to determine the long-term safety and efficacy of chronic oral L-carnitine supplementation and whether suppression or circumvention of intestinal bacteria may improve L-carnitine therapy.


The Effect of Night Float Rotation on Resident Sleep, Activity, and Well-Being.
Night float call systems are becoming increasingly common at training programs with the goal of reducing fatigue related to sleep deprivation and sleep disturbance. Previous studies have shown that trainees obtain less sleep during the night float rotation and have decreased sleep efficiency for several days after the rotation. The impact on physical and emotional well-being has not been documented. Twenty-seven anesthesia residents were enrolled in a study using wearable sleep and activity trackers and National Institutes of Health Patient-Reported Outcome Measurement Information System (NIH PROMIS) surveys for sleep disturbance, fatigue, and positive affect to record data the week before ("baseline"), during ("night float"), and 1 week after ("recovery") their night float rotation. Each subject's data during the night float week and recovery week were compared to his or her own baseline week data using a paired, nonparametric analysis. The primary outcome variable was the change in average daily sleep hours during the night float week compared to the baseline week. Average daily rapid eye movement (REM) sleep, daily steps, and NIH PROMIS scores comparing night float and recovery weeks to baseline week were prespecified secondary outcomes. NIH PROMIS scores range from 0 to 100 with 50 as the national mean and more of the construct having a higher score. There was no difference in average daily sleep hours between the night float and the baseline weeks (6.7 [5.9-7.8] vs 6.7 [5.5-7.7] hours, median [interquartile range]; P = .20). Residents had less REM sleep during the night float compared to the baseline weeks (1.1 [0.7-1.5] vs 1.4 [1.1-1.9] hours, P = .002). NIH PROMIS fatigue scores were higher during the night float than the baseline week (58.8 [54.6-65.1] vs 48.6 [46.0-55.1], P = .0004) and did not return to baseline during the recovery week (51.0 [48.6-58.8], P = .029 compared to baseline). Sleep disturbance was not different among the weeks. Positive affect was reduced after night float compared to baseline (39.6 [35.0-43.5] vs 44.8 [40.1-49.6], P = .0009), but returned to baseline during the recovery week (43.6 [39.6-48.2], P = .38). The residents slept the same number of total hours during their night float week but had less REM sleep, were more fatigued, and had less positive affect. All of these resolved to baseline except fatigue, that was still greater than the baseline week. This methodology appears to robustly capture psychophysiological data that might be useful for quality initiatives.


Centrally administered orexin A increases motivation for sweet pellets in rats.
Centrally administered orexin A induces both feeding and locomotion in rats. Thus, the feeding response following orexin A administration may be secondary to general increases in activity rather than a specific motivation to eat. The aim of the study is to determine whether orexin A increases the motivation to eat. The effect of orexin A (0, 31.25, 62.5, 125, 250, and 500 pmol) on breakpoint was determined in male Sprague-Dawley rats with rostro-lateral hypothalamic cannulae under a progressive ratio of five schedule (PR5). The effect of orexin A (0, 31.25, 125, and 500 pmol) on pressing rate under a fixed ratio (20) schedule was obtained to analyze the time course of orexin-A-induced pressing. The effect of 24-h food deprivation on breakpoint under PR5 and the effect of orexin A (125 pmol) on free feeding (sweet pellets) and on open-field locomotor activity (0, 100, 500, and 1,000 pmol) were also tested. Orexin A significantly augmented free feeding of sweet pellets, open-field locomotor activity, rate of pressing (FR20 schedule), and breakpoint (PR5 schedule), although compared to 24-h deprivation, the effect of orexin A on breakpoint was mild. However, there was a differential dose response relationship and time course of stimulation between orexin A's effects on locomotion and lever pressing. These data indicate that infusion of orexin A enhances free feeding by enhancing and possibly prolonging motivation to eat.


Anterior cruciate ligament reconstruction, rehabilitation, and return to play: 2015 update.
Anatomical discoveries and a growing appreciation of the knee as a complex organ are driving innovations in patient care decision-making following anterior cruciate ligament (ACL) injury. Surgeons are increasing their efforts to restore combined mechanical-neurosensory ACL function and placing more consideration on when to reconstruct versus repair native anatomical structures. Surgical options now include primary repair with or without reinforcing the injured ACL with suture-based internal bracing, and growing evidence supports biological augmentation using platelet-rich plasma and mesenchymal stem cells to enhance tissue healing. Physical therapists and athletic trainers are increasing their efforts to facilitate greater athlete cognitive engagement during therapeutic exercise performance to better restore nonimpaired neuromuscular control activation amplitude and timing. Knee brace design and use needs to evolve to better match these innovations and their influence on the rehabilitation plan timetable. There is a growing appreciation for the multifaceted characteristics of the rehabilitation process and how they influence neuromuscular, educational, and psychobehavioral treatment goal achievement. Multiple sources may influence the athlete during the return to sports process and clinical outcome measures need to be refined to better evaluate these influences. This update summarizes contemporary ACL surgical, medical, and rehabilitation interventions and future trends.


Surveillance for hepatocellular carcinoma: development and validation of an algorithm to classify tests in administrative and laboratory data.
The purpose of alpha-fetoprotein (AFP) and abdominal ultrasound (US) cannot be discerned in administrative data. We developed an algorithm to identify AFP and US used as surveillance tests for hepatocellular carcinoma (HCC). We evaluated 300 AFP and 301 US tests from a VA database. Surveillance predictors in the administrative files (diagnoses, labs) were examined in logistic regression models. We calculated model-based probabilities of HCC surveillance status, and developed classification procedures using single and multiple imputation methods. The predictors of surveillance intent for AFP were absence of alcoholism, abdominal pain, ascites, diabetes and high AST levels. For US, the predictors of surveillance were prior AFP testing and HIV status and absence of abdominal pain, ascites, or drug dependence. For AFP classification, single imputation compared favorably with multiple imputation, both showing robustness in discrimination and calibration. For US both approaches were less robust in discrimination and calibration which was more moderate in multiple imputation than single imputation. Predictive algorithms in administrative files can be used to identify AFP performed for HCC surveillance, however, the intent of US is more difficult to identify.


Biceps Transposition for Biological Superior Capsular Reconstruction.
Reconstruction of the superior capsule is a valuable intervention for some patients in whom massive, irreparable posterosuperior rotator cuff tears are identified. Superior capsular reconstruction techniques most commonly use either tensor fascia lata autograft or dermal allograft. As an alternative to more traditional superior capsular reconstruction, we commonly transpose and incorporate the biceps tendon into the rotator cuff repair construct in such patients instead. This biological superior capsular reconstruction biceps transposition technique ("bio-SCR"), described herein, provides increased structural integrity and supplemental tendon graft using viable cells while potentially serving the role of the superior capsule. As such, transposition of the biceps tendon may offer unique and significant advantages over other techniques and can be an effective and valuable alternative in appropriate cases.


Activation of autophagy contributes to the renoprotective effect of postconditioning on acute kidney injury and renal fibrosis.
Ischemia/Reperfusion injury contributes to acute kidney injury (AKI) and subsequent chronic kidney disease (CKD) including renal fibrosis. Autophagy is a cytoplasmic components degradation pathway that has complex function in the development of various diseases such as fibrosis in kidney. Our previous work demonstrated that postconditioning (POC) showed excellent therapeutic effect on renal fibrosis via inhibiting the overproduction of reactive oxygen species (ROS) after reperfusion. But the connection of autophagy and POC in the renoprotective effect remains unclear. Here, we defined the relevance of autophagy and POC in the protective effect on AKI and subsequent renal fibrosis. We found that at two days after I/R injury, POC largely reduced renal tubular epithelial cell apoptosis and improved renal function; autophagy was significantly activated in kidneys of the POC rats. At two months after reperfusion, the I/R injury rats displayed severe renal fibrosis and epithelial-mesenchymal transition (EMT), whereas these were remarkably attenuated in the POC treated rats. Overall, our results demonstrated that POC could reduce renal damage and attenuate the degree of EMT after I/R injury via enhanced activation of autophagy.


Mercury assisted fluorescent supramolecular assembly of hexaphenylbenzene derivative for femtogram detection of picric acid.
Aggregates of hexaphenylbenzene derivatives 3, having pyrene groups form network of fluorescent nanofibres in presence of mercury ions. Further, fluorescent nanofibres of 3-Hg(2+) supramolecular ensemble exhibit sensitive and pronounced response towards the picric acid. In addition, the solution coated paper strips of 3-Hg(2+) supramolecular ensemble can detect picric acid in the range of 2.29 fg/cm(2), thus, providing a simple, portable and low cost method for detection of picric acid in solution and in contact mode.


Paracoccidioides brasiliensis 87-kilodalton antigen, a heat shock protein useful in diagnosis: characterization, purification, and detection in biopsy material via immunohistochemistry.
The 87-kDa antigen derived from the fungal pathogen Paracoccidioides brasiliensis can be detected in the sera of infected patients, and its levels have been shown to correlate well with response to treatment and with clinical cure. Despite its potential importance, the antigen has been poorly characterized. The 87-kDa antigen was purified to homogeneity via preparative gel electrophoresis; N-terminal amino acid sequencing revealed substantial homology with heat shock proteins (hsps) from a variety of organisms. A monoclonal antibody (MAb) raised against a Histoplasma capsulatum 80-kDa hsp showed cross-reactivity to the purified 87-kDa antigen via Western blotting, and the 87-kDa-specific MAb P1B demonstrated that the antigen was expressed at higher levels in yeast than in mycelia by the same technique. Enzyme-linked immunosorbent assay and immunofluorescence reactivity using P1B confirmed increased expression of the 87-kDa antigen during the temperature-induced transformation of mycelia to yeast. Yeast-to-mycelium transformation was accompanied by a fall in expression, although the 87-kDa antigen was clearly constitutively expressed in both phases. Immunochemical staining of tissues from patients with MAb P1B who were infected with P. brasiliensis confirmed in vivo expression of the 87-kDa antigen by yeasts, and identification of this antigen via this method appears to be a useful adjunct to other methods used to diagnose paracoccidioidomycosis.


Community-based care models for arterial hypertension management in non-pregnant adults in sub-Saharan Africa: a literature scoping review and framework for designing chronic services.
Arterial hypertension (aHT) is the leading cardiovascular disease (CVD) risk factor in sub-Saharan Africa; it remains, however, underdiagnosed, and undertreated. Community-based care services could potentially expand access to aHT diagnosis and treatment in underserved communities. In this scoping review, we catalogued, described, and appraised community-based care models for aHT in sub-Saharan Africa, considering their acceptability, engagement in care and clinical outcomes. Additionally, we developed a framework to design and describe service delivery models for long-term aHT care. We searched relevant references in Embase Elsevier, MEDLINE Ovid, CINAHL EBSCOhost and Scopus. Included studies described models where substantial care occurred outside a formal health facility and reported on acceptability, blood pressure (BP) control, engagement in care, or end-organ damage. We summarized the interventions' characteristics, effectiveness, and evaluated the quality of included studies. Considering the common integrating elements of aHT care services, we conceptualized a general framework to guide the design of service models for aHT. We identified 18,695 records, screened 4,954 and included twelve studies. Four types of aHT care models were identified: services provided at community pharmacies, out-of-facility, household services, and aHT treatment groups. Two studies reported on acceptability, eleven on BP control, ten on engagement in care and one on end-organ damage. Most studies reported significant reductions in BP values and improved access to comprehensive CVDs services through task-sharing. Major reported shortcomings included high attrition rates and their nature as parallel, non-integrated models of care. The overall quality of the studies was low, with high risk of bias, and most of the studies did not include comparisons with routine facility-based care. The overall quality of available evidence on community-based aHT care is low. Published models of care are very heterogeneous and available evidence is insufficient to recommend or refute further scale up in sub-Sahara Africa. We propose that future projects and studies implementing and assessing community-based models for aHT care are designed and described according to six building blocks: providers, target groups, components, location, time of service delivery, and their use of information systems.


Variability associated with assessing changes in position of a canine uncemented femoral stem prosthesis.
Evaluate variability associated with assessing changes in the position of uncemented femoral stems. Stem level, canal fill, stem angle, and version angle were measured on craniocaudal horizontal beam (CCHB) and open leg lateral (OLL) radiographic projections of the femur of 20 dogs that had uncemented total hip replacement. Intraobserver and interobserver repeatability were determined on immediate postoperative (PO) images. Differences in position were calculated between the first (3 months - R1) and second (6 months - R2) re-evaluation (R1-R2) time points, and between PO and R1. The measurement process was very repeatable. For R1-R2, the stem appeared to subside 0.8 ± 1.4 mm for measurements based on the greater trochanter on the CCHB images, but there was a wide range (-3.9 to 2 mm; positive values indicate proximad movement). Measurements based on the intertrochanteric crest on the OLL images had the same mean, and also a wide range (-4.4 to 2.1 mm; negative values indicate proximad movement). For PO-R1, the stem appeared to subside 1.8 ± 2.0 mm (CCHB, based on the greater trochanter, range -7.7 to 2.2 mm), 1.6 ± 1.5 mm (CCHB, based on the intertrochanteric crest, range -0.7 to 4.3 mm); and 2.1 ± 2.1 mm (OLL, based on the intertrochanteric crest, range -1.6 to 6.8 mm). The position of a stable stem can appear different on subsequent re-evaluations, but this may be due to variability associated with inconsistency of positioning of the patient and limb. Documenting subsidence in individual patients should not rely on calculations based on a single measurement.


Inherited genetic susceptibility to breast cancer: the beginning of the end or the end of the beginning?
Genome-wide association studies have identified 72 loci associated with breast cancer susceptibility. Seventeen of these are known to predispose to other cancers. High-penetrance susceptibility loci for breast cancer usually result from coding alterations, principally in genes involved in DNA repair, whereas almost all of the associations identified through genome-wide association studies are found in noncoding regions of the genome and are likely to involve regulation of genes in multiple pathways. However, the genes underlying most associations are not yet known. In this review, we summarize the findings from genome-wide association studies in breast cancer and describe the genes and mechanisms that are likely to be involved in the tumorigenesis process. We also discuss approaches to fine-scale mapping of susceptibility regions used to identify the likely causal variant(s) underlying the associations, a major challenge in genetic epidemiology. Finally, we discuss the potential impact of such findings on personalized medicine and future avenues for screening, prediction, and prevention programs.


Decreased volume and increased asymmetry of the anterior limb of the internal capsule in patients with schizophrenia.
The anterior limb of the internal capsule (ALIC) contains the anterior thalamic peduncle connecting the medial and anterior thalamic nuclei with the prefrontal cortex and the cingulate gyrus. The purpose of this study was to detect the volumetric changes in the ALIC in view of the putative abnormal frontothalamic connectivity in schizophrenia. High-resolution, three-dimensional magnetic resonance imaging was acquired from 53 schizophrenia patients and 48 age- and gender-matched control subjects. Volumetric analysis was performed using consecutive 1-mm-thick coronal slices rostral to the anterior commissure, on the ALIC, caudate nucleus, and lentiform nucleus. White matter concentration over the whole brain was compared using the voxel-based morphometry (VBM) with Statistical Parametric Mapping 99. The patients had significantly decreased volumes in the bilateral ALIC and showed significantly increased right-greater-than-left asymmetry of the ALIC; VBM revealed a reduction in white matter concentration of the bilateral internal capsule in patients. No volumetric difference was found in the rostral part of the caudate and lentiform nucleus between groups. Decreased volume found in the ALIC supports the hypothesis of abnormal frontothalamic connectivity in schizophrenia. Increased asymmetry of the internal capsule seems consistent with the notion of predominantly left-side pathology of schizophrenia.


Forms or Free-Text? Measuring Advance Care Planning Activity Using Electronic Health Records.
Advance care planning (ACP) discussions seek to guide future serious illness care. These discussions may be recorded in the electronic health record by documentation in clinical notes, structured forms and directives, and physician orders. Yet, most studies of ACP prevalence have only examined structured electronic health record elements and ignored data existing in notes. We sought to investigate the relative comprehensiveness and accuracy of ACP documentation from structured and unstructured electronic health record data sources. We evaluated structured and unstructured ACP documentation present in the electronic health records of 435 patients with cancer drawn from three separate healthcare systems. We extracted structured ACP documentation by manually annotating written documents and forms scanned into the electronic health record. We coded unstructured ACP documentation using a rule-based natural language processing software that identified ACP keywords within clinical notes and was subsequently reviewed for accuracy. The unstructured approach identified more instances of ACP documentation (238, 54.7% of patients) than the structured ACP approach (187, 42.9% of patients). Additionally, 16.6% of all patients with structured ACP documentation only had documents that were judged as misclassified, incomplete, blank, unavailable, or a duplicate of a previously entered erroneous document. ACP documents scanned into electronic health records represent a limited view of ACP activity. Research and measures of clinical practice with ACP should incorporate information from unstructured data.


Retrograde regulation of synaptic vesicle endocytosis and recycling.
Sustained release of neurotransmitter depends upon the recycling of synaptic vesicles. Until now, it has been assumed that vesicle recycling is regulated by signals from the presynaptic bouton alone, but results from rat hippocampal neurons reported here indicate that this need not be the case. Fluorescence imaging and pharmacological analysis show that a nitric oxide (NO) signal generated postsynaptically can regulate endocytosis and at least one later step in synaptic vesicle recycling. The proposed retrograde pathway involves an NMDA receptor (NMDAR)-dependent postsynaptic production of NO, diffusion of NO to a presynaptic site, and a cGMP-dependent increase in presynaptic phosphatidylinositol 4,5-biphosphate (PIP2). These results indicate that the regulation of synaptic vesicle recycling may integrate a much broader range of neural activity signals than previously recognized, including postsynaptic depolarization and the activation of NMDARs at both immediate and nearby postsynaptic active zones.


Flash visual evoked potentials are unreliable as markers of ICP due to high variability in normal subjects.
Previous publications have suggested a high correlation between flash visual evoked potential (F-VEP) N2 peak latency and intracranial pressure. This would enable F-VEP to be used as a non-invasive and inexpensive method to estimate ICP in a number of settings. However, basic knowledge about variability across subjects and test-retest properties of the F-VEP is lacking. Fifteen healthy adult subjects were tested on three different occasions. F-VEP responses were recorded using international standards. For the tested population, mean N2 latency was 65.7 ms (SD 10.7 ms) and the range was 48-110 ms. Intra-individual variability was high, in four of the 15 subjects more than 15 ms between testing sessions. The same was found for P2 latency and for N2 and P2 amplitudes. The response waveform was very variable and unambiguous marking of peaks was often difficult. One out of the 15 subjects had a very poorly developed F-VEP response, but a normal pattern-reversal VEP response. F-VEP has a wide range of latency, amplitude and waveform across normal subjects. A large proportion of subjects also had a high intra-individual variability over time. This variability makes F-VEPs unreliable as a marker for intracranial pressure, and caution in interpreting F-VEP changes in clinical work is advised.


Influence of factors regulating bone formation and remodeling on bone quality in osteonecrosis of the femoral head.
Osteonecrosis of the femoral head (ONFH) usually affects young individuals and has a major impact on lifestyle. Notably, the pathogenetic mechanisms of osteonecrosis are unresolved and no effective treatment exists. The objective of this study was to assess the gene expression levels of factors regulating bone formation and remodeling (bone morphogenetic protein [BMP]-2, BMP-7, Runx2, osteocalcin, osteoprotegerin [OPG]) in patients with ONFH and to compare them to those of patients with primary osteoarthritis (OA). The cellular and macromolecular composition of the bone matrix was assessed by osteocalcin immunohistochemistry, and the three-dimensional organization of trabecular bone was characterized by micro-computed tomographic analysis. Our results demonstrate that gene expression of BMP-2, BMP-7, and Runx2 is elevated in patients with ONFH. We observed increased extracellular osteocalcin deposition, presumably caused by a higher number of osteoblasts in concordance with increased activity of Runx2. Constant gene expression level of OPG implies an unchanged osteoclast differentiation rate in ONFH bone. We found no significant change in bone volume, connectivity, and structural model index; further, no significant differences were detected for trabecular properties in ONFH bone. In conclusion, we have shown increased gene expression of factors regulating bone formation and remodeling in the femoral head and/or neck of patients with ONFH. Further, we observed an increase in osteocalcin immunoreactivity and osteoblast/osteocyte cell number, while no significant changes in trabecular microarchitecture were detected. This study increases our understanding of the pathophysiology and repair process following ONFH and might help in the development of new treatment strategies in the future.


DNA hybridization as a guide to phylogeny: chemical and physical limits.
The technique of forming interspecific DNA heteroduplexes and estimating phylogenetic distances from the depression in their duplex melting temperature has several physical and chemical constraints. These constraints determine the maximum phylogenetic distance that may be estimated by this technique and the most appropriate method of analyzing that distance. Melting curves of self-renatured single copy primate DNAs reveal the presence of components absent from the renaturation products of exactly paired sequences. This observation, which confirms existing literature, challenges a fundamental assumption: that orthologous (i.e., corresponding) DNA sequences in the divergent species are being compared in DNA heteroduplex melting experiments. As a model system, the thermal stabilities of heteroduplexes formed between a human alpha-globin cDNA and four alpha-like globin genes isolated from chimpanzee are qualitatively compared. The results of this comparison show that the cross-hybrids of imperfectly matched gene duplicates from divergent species can contribute to the additional components that are present in renatured single copy DNAs. Single copy DNA, as usually defined, includes sequence duplicates that will obscure phylogenetic comparisons in a mass hybridization of genomes.


Fabrication of cell-containing hydrogel microstructures inside microfluidic devices that can be used as cell-based biosensors.
This paper describes microfluidic systems containing immobilized hydrogel-encapsulated mammalian cells that can be used as cell-based biosensors. Mammalian cells were encapsulated in three-dimensional poly(ethylene glycol)(PEG) hydrogel microstructures which were photolithographically polymerized in microfluidic devices and grown under static culture conditions. The encapsulated cells remained viable for a week and were able to carry out enzymatic reactions inside the microfluidic devices. Cytotoxicity assays proved that small molecular weight toxins such as sodium azide could easily diffuse into the hydrogel microstructures and kill the encapsulated cells, which resulted in decreased viability. Furthermore, heterogeneous hydrogel microstructures encapsulating two different phenotypes in discrete spatial locations were also successfully fabricated inside microchannels.


The effect of transcutaneous electrical nerve stimulation (TENS) on chronic subjective tinnitus.
Chronic Subjective Tinnitus is a very highly prevalent disorder worldwide. There is no definitive treatment. The aim of this study is to investigate the efficacy of transcutaneous electrical nerve stimulation (TENS) applied to the auricula for treating tinnitus using the Depression Anxiety Stress Scales (DASS) and Tinnitus Handicap Inventory (THI). The 60 patients were randomly divided into 3 groups of 20 patients. The first group (A) had one ear stimulated with TENS, and the second group (B) had both ears stimulated. Group C (placebo group) received no electrical or sound stimulation. All group patients received total of 10 sessions with a maximum of 4 days between the sessions. The THI and DASS scores decreased significantly after the treatment (p < 0.05). A significant difference was also observed between the groups after treatment (p < 0.05). While there was no difference between group A and B, it was shown that group C's post-treatment score was significantly higher than those of both groups (p < 0.05.) CONCLUSION: It is important to note that TENS has a therapeutic effect on subjective chronic tinnitus as well as a placebo effect.


Thermal behaviour of procaine and benzocaine Part II: compatibility study with some pharmaceutical excipients used in solid dosage forms.
The compatibility study of active substances with excipients finds an important role in the domain of pharmaceutical research, being known the fact that final formulation is the one administered to the patient. In order to evaluate the compatibility between active substance and excipients, different analytical techniques can be used, based on their accuracy, reproducibility and fastness. Compatibility study of two well-known active substances, procaine and benzocaine, with four commonly used excipients, was carried out employing thermal analysis (TG/DTG/HF) and Fourier Transform Infrared Spectroscopy (UATR-FT-IR). The selected excipients were microcrystalline cellulose, lactose monohydrate, magnesium stearate and talc. Equal proportion of active substance and excipients (w/w) was utilized in the interaction study. The absolute value of the difference between the melting point peak of active substances and the one corresponding for the active substances in the analysed mixture, as well the absolute value of the difference between the enthalpy of the pure active ingredient melting peak and that of its melting peak in the different analysed mixtures were chosen as indexes of the drug-excipient interaction degree. All the results obtained through thermal analysis were also sustained by FT-IR spectroscopy. The corroboration of data obtained by thermal analysis with the ones from FT-IR spectroscopy indicated that no interaction occurs between procaine and benzocaine, with microcrystalline cellulose and talc, as well for the benzocaine-lactose mixture. Interactions were confirmed between procaine and benzocaine respectively and magnesium stearate, and for procaine and lactose.


Chondrocyte-seeded hydroxyapatite for repair of large articular cartilage defects. A pilot study in the goat.
The aim of this study was to evaluate the potential for restoration of a large cartilage defect in the goat knee with hydroxyapatite (HA) loaded with chondrocytes. Isolated chondrocytes were suspended in fibrin glue, seeded on top of the HA, and then the composite graft was implanted in the defect. After transplantation, cell behaviour, newly synthesised matrix and the HA-glue interface were assessed histologically after 2, 4, 12, 26 and 52 weeks. Special attention was paid to the incorporation process of HA in the subchondral bone and interactions between this biomaterial and the fibrin-glue-chondrocyte suspension. Chondrocytes in the glue proved to survive the transplantation procedure and produced new metachromatically stained matrix two weeks after implantation. The glue-cell suspension had penetrated the superficial porous structure of the HA. Four weeks after surgery, islands of hyaline-like cartilage were observed at the HA-glue interface. A layer of fibrous tissue was formed surrounding the HA graft, resulting in a relatively instable fixation of the HA in the defect. This instability of the graft in the defect, possibly together with early weight bearing, resulted in a gradual loss of the newly formed hyaline cartilage-like repair tissue. Progressive resorption of the HA occurred without any sign of active bone remodelling from the host site. One year after surgery part of the defect which extended down to the cancellous bone had been predominantly restored with newly formed lamellar bone. Only small HA remnants were still present at the bottom of the original defect. Resurfacing of the joint had occurred with fibrocartilaginous repair tissue. The absence of adequate fixation capacity of the HA near the joint space resulted in a relative instability of the graft with progressive resorption. Therefore, HA is not a suitable biomaterial to facilitate the repair of large articular cartilage defects.


A LASSO-derived clinical score to predict severe acute kidney injury in the cardiac surgery recovery unit: a large retrospective cohort study using the MIMIC database.
We aimed to develop an effective tool for predicting severe acute kidney injury (AKI) in patients admitted to the cardiac surgery recovery unit (CSRU). A retrospective cohort study. Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-III database, consisting of critically ill participants between 2001 and 2012 in the USA. A total of 6271 patients admitted to the CSRU were enrolled from the MIMIC-III database. Stages 2-3 AKI. As identified by least absolute shrinkage and selection operator (LASSO) and logistic regression, risk factors for AKI included age, sex, weight, respiratory rate, systolic blood pressure, diastolic blood pressure, central venous pressure, urine output, partial pressure of oxygen, sedative use, furosemide use, atrial fibrillation, congestive heart failure and left heart catheterisation, all of which were used to establish a clinical score. The areas under the receiver operating characteristic curve of the model were 0.779 (95% CI: 0.766 to 0.793) for the primary cohort and 0.778 (95% CI: 0.757 to 0.799) for the validation cohort. The calibration curves showed good agreement between the predictions and observations. Decision curve analysis demonstrated that the model could achieve a net benefit. A clinical score built by using LASSO regression and logistic regression to screen multiple clinical risk factors was established to estimate the probability of severe AKI in CSRU patients. This may be an intuitive and practical tool for severe AKI prediction in the CSRU.


Genomic analyses indicate the North American Ap-ha variant of the tick-vectored bacterium Anaplasma phagocytophilum was introduced from Europe.
Anaplasma phagocytophilum is a tick-vectored, obligately intracellular bacterium that infects a diversity of vertebrate hosts. In North America, the Ap-ha variant of A. phagocytophilum can cause dangerous infections in humans, whereas symptomatic human infections in Europe are rare. Conversely, the European host-generalist ecotype of A. phagocytophilum frequently causes illness in domestic ruminants while no comparable infections have been recorded from North America. Despite these differences in pathogenicity, the Ap-ha variant is closely aligned phylogenetically with the European host-generalist ecotype. Furthermore, North American populations of A. phagocytophilum are less genetically diverse than those in Europe. Taken together, these observations suggest that the North American Ap-ha variant may represent an introduced population of this bacterium. Data from publicly available whole genomes of A. phagocytophilum were used to compare phylogeographic patterns and the extent of genetic divergence between the North American Ap-ha variant and the European host-generalist ecotype. The results confirm that North American Ap-ha samples are phylogenetically nested within the diversity of the European host-generalist ecotype, and that Ap-ha likely radiated within the last 100 years. As expected, the Ap-ha variant also exhibited relatively low genetic diversity levels compared to the European host-generalist ecotype. Finally, North American Ap-ha harbored significantly more derived alleles than the European host-generalist A. phagocytophilum population. Collectively, these results support the hypothesis that the Ap-ha variant was recently introduced to North America from Europe and underwent a strong genetic bottleneck during this process (i.e. a 'founder event'). Adaptation to novel vectors may have also played a role in shaping genetic diversity and divergence patterns in these pathogenic bacteria. These findings have implications for future studies aimed at understanding evolutionary patterns and pathogenicity variation within A. phagocytophilum.


Bacterial and viral fecal indicator predictive modeling at three Great Lakes recreational beach sites.
Coliphage are viruses that infect Escherichia coli (E. coli) and may indicate the presence of enteric viral pathogens in recreational waters. There is an increasing interest in using these viruses for water quality monitoring and forecasting; however, the ability to use statistical models to predict the concentrations of coliphage, as often done for cultured fecal indicator bacteria (FIB) such as enterococci and E. coli, has not been widely assessed. The same can be said for FIB genetic markers measured using quantitative polymerase chain reaction (qPCR) methods. Here we institute least-angle regression (LARS) modeling of previously published concentrations of cultured FIB (E. coli, enterococci) and coliphage (F+, somatic), along with newly reported genetic concentrations measured via qPCR for E. coli, enterococci, and general Bacteroidales. We develop site-specific models from measures taken at three beach sites on the Great Lakes (Grant Park, South Milwaukee, WI; Edgewater Beach, Cleveland, OH; Washington Park, Michigan City, IN) to investigate the efficacy of a statistical predictive modeling approach. Microbial indicator concentrations were measured in composite water samples collected five days per week over a beach season (∼15 weeks). Model predictive performance (cross-validated standardized root mean squared error of prediction [SRMSEP] and R2PRED) were examined for seven microbial indicators (using log10 concentrations) and water/beach parameters collected concurrently with water samples. Highest predictive performance was seen for qPCR-based enterococci and Bacteroidales models, with F+ coliphage consistently yielding poor performing models. Influential covariates varied by microbial indicator and site. Antecedent rainfall, bird abundance, wave height, and wind speed/direction were most influential across all models. Findings suggest that some fecal indicators may be more suitable for water quality forecasting than others at Great Lakes beaches.


Comparison of the hydroxyacids from the epidermis and from the sebaceous glands of the horse.
The acylglucosylceramides were isolated from the polar lipids of horse epidermis and examined to determine whether the component omega-hydroxyacids are straight chained as in the corresponding lipids from pig epidermis or branched as in horse sebum. The hydroxyacids from horse epidermis were found to be almost entirely straight chained compounds. The results indicate that sebaceous glands, although derived from epidermal cells, have evolved independent pathways of lipid metabolism.


Amino acid deprivation-induced stress response in the bovine renal epithelial cell line NBL-1: induction of HSP 70 by phenylalanine.
Amino acid deprivation of the bovine renal epithelial cell line NBL-1 led to a range of responses by the heat shock and glucose regulated stress proteins. The classic heat shock induction of HSP 72 was found to be mimicked, without prior heat stress, by phenylalanine addition to cells simultaneously deprived of all other amino acids. Co-inclusion of alanine prevented the HSP 72 induction by phenylalanine but not that caused by heat stress. Phenylalanine also increased expression of HSP 70 mRNA in cells simultaneously deprived of other amino acids. The glucose regulated protein GRP 75 was increased upon amino acid deprivation. GRP94 was detectable in a 50 kDa form in control cells but was detected as a 94 kDa form upon amino acid deprivation which was further enhanced upon inclusion of phenylalanine. Addition of alanine to the starvation medium led to detection of the 50 kDa form only. Amino acid deprivation appears to mimic the glucose deprivation stress response. Inclusion of phenylalanine during amino acid deprivation leads to a stress response similar to that of heat shock in terms of HSP 72 induction. However, the two inducers are sensitive to different repression signals since only the phenylalanine-signal was subject to nihilation by alanine co-inclusion.


Tangential orientation and spatial order in dendrites of cat auditory cortex: a computer microscope study of Golgi-impregnated material.
In the tangential plane (parallel to the pial surface) dendrites in the primary auditory cortex (A1) of cat were found to exhibit preferentially oriented growth. This was shown by means of a computer microscope study of Golgi-Cox stained neurons as seen in 100 micrometers and 300 micrometers thick tangential sections. Two techniques were used to represent the 3-dimensional structure of dendrites: the "dendritic stick" and the "dendritic trumpet". The former dismembers a dendrite into its individual segments; the latter considers a dendrite as an entity and represents it by its centroid, its moments and the spatial dispersionof its branches. Both statistical and Fourier analyses of the data show that within the tangential plane there is a significant and consistent orientation of the dendritic sticks in a dorso-ventral direction which seems correlated with the cortical isofrequency contours observed in electrophysiological maps of the A1 region. The dendritic trumpet analyses also show a distinctly non-random vertical distribution of pyramidal cell basal dendrites but not of stellate cell dendrites.


Causes of symptoms in chronic congestive heart failure and implications for treatment.
The most common symptoms of patients with heart failure are shortness of breath and fatigue. The causes of these symptoms may be different in various entities encompassed by the general term heart failure, such as acute pulmonary edema, circulatory collapse and chronic heart failure. In patients with acute heart failure, shortness of breath is closely related to left atrial pressure. In patients with chronic heart failure, optimally treated with diuretics, the body fluid compartments are usually of normal size. Recent work strongly suggests that, in such patients, central hemodynamic abnormalities are not the sole determinants of symptoms. Impaired vasodilation and altered metabolism in skeletal muscle, circulating metabolites and pulmonary ventilation-perfusion mismatch with consequent increased physiologic dead space may all contribute to the genesis of symptoms. Consequently, it may be possible to alleviate symptoms by treatments that are not aimed directly at improving central hemodynamics. Whether such an approach could also modify prognosis is unknown.


Isolation and analysis of genes mainly expressed in adult mouse heart using subtractive hybridization cDNA library.
Subtractive hybridization cDNA library (SHL) is one of the powerful approaches for isolating differentially expressed genes. Using this technique between mouse heart and skeletal muscle (skm) tissues, we aimed to construct a cDNA-library that was specific to heart tissue and to identify the potential candidate genes that might be responsible for the development of cardiac diseases or related pathophysiological conditions. In the first step of the study, we created a cDNA-library between mouse heart and skm tissues. The homologies of the randomly selected 215 clones were analyzed and then classified by function. A total of 146 genes were analyzed for their expression profiles in the heart and skm tissues in published mouse microarray dataset. In the second step, we analyzed the expression patterns of the selected genes by Northern blot and RNA in situ hybridization (RISH). In Northern blot analyses, the expression levels of Myl3, Myl2, Mfn2, Dcn, Pdlim4, mt-Co3, mt-Co1, Atpase6 and Tsc22d1 genes were higher in heart than skm. For first time with this study, expression patterns of Pdlim4 and Tsc22d1 genes in mouse heart and skm were shown by RISH. In the last step, 43 genes in this library were identified to have relationships mostly with cardiac diseases and/or related phenotypes. This is the first study reporting differentially expressed genes in healthy mouse heart using SHL technique. This study confirms our hypothesis that tissue-specific genes are most likely to have a disease association, if they possess mutations.


The influence of cold and compression on lymph flow at the ankle.
To investigate the effects of cold application with different temperatures on lymph flow in healthy persons and to examine the effects of the combination of cold and compression on lymph vessels. Thirty-nine healthy persons were included in the study, and each served as his or her own control. Water bags (1 degree, 15 degrees, and 32 degrees) with or without 25 mm Hg pressure were applied to the experimental legs for 30 minutes. Cold, pressure, or both were administered by an Aircast-Cryo-cuff (Aircast Europe GMBH, Rosenheim, Germany). Skin temperature was measured with a TESTO 901 (Testoterm GMBH, Leuven, Belgium) precision thermometer. Lymph flow was recorded continuously using lymphoscintigraphy. MANOVA with repeated measures was used for data analysis. As expected, skin temperature dropped relative to the temperature of the water. The migration of the tracer was comparable in both ankles during the first 30 minutes of the experiment (rest). When the water bag was applied, lymph flow increased significantly (p < 0.01). The application of water of 1 degree C without pressure influenced lymph evacuation significantly differently from the other temperatures. The application of pressure of 25 mm Hg influenced lymph evacuation significantly at 1 degree C and 32 degrees C. These results indicate that lymph evacuation at the ankle is influenced significantly when cold water is applied with or without pressure. When pressure is added to the application of water of 32 degrees C, lymph flow will also increase significantly, indicating the importance of pressure in lymph evacuation.


Prospective study of nasogastric feeding via East Grinstead or Viomedex tubes compared with oral dietary supplementation in patients with cirrhosis.
Forty-seven patients with alcoholic hepatitis and/or cirrhosis were randomised to receive nutritional supplementation by oral sip feeding or by nasogastric infusion administered via either an East Grinstead or a Viomedex nasoenteric tube. The three groups were well matched for severity and complications of liver disease. Patients fed by the nasogastric route attained their daily target dietary intake significantly more often than did those supplemented orally, but the consequent improvement in their nitrogen balance was not significant. There were no significant differences between nasogastric and sip feeding, or between the types of tube studied, in the frequency with which vomiting, diarrhoea or variceal bleeding occurred, but Viomedex tubes required reinsertion significantly less frequently than did the East Grinstead type.


[Chronic pain impairs spatial learning and memory ability and down-regulates Bcl-2 and BDNF mRNA expression in hippocampus of neonatal rats].
To investigate the effect and possible mechanism of complete Freund's adjuvant induced chronic pain on later function of learning and memory in neonatal rats. Sixty Sprague-Dewley rat pups (10 litters of 6 pups) were randomly divided into control group and chronic pain group (n = 30 in each group). In the chronic pain group, left hind paws of the rats were treated with subcutaneous injection of 20 microl of CFA on postnatal day-2. The control rat pups received normal saline. The hippocampus of rats were separated on postnatal days 10 and 21 (one rat in each group from every litter, n = 10). The expression of Bcl-2 and BDNF mRNA were investigated by RT-PCR. Morris water maze tests were performed on day 21 (one rat in each group from every litter, n = 10). In hidden-platform training of Morris water maze, the mean escape latency of rats in the chronic pain group were longer than that of the control rats. In spatial probe tests, the average percentages of the swimming time and distances in the platform quadrant in the pain group rats were less than those in the control group. There was no significant difference in visible-platform training between the two groups. The Bcl-2 and BDNF mRNA expressions in hippocampus of the pain group rats were lower than those in the control at day 10, but no significant difference at day 21. Chronic pain stress induced by CFA impairs the spatial learning and memory function in neonatal rats. These effects might exert through down-regulating Bcl-2 and BDNF mRNA expression in the hippocampus.


Synthesis of a Highly Selective Scavenger of Precious Metals from a Printed Circuit Board Based on Cellulose Filter Paper Functionalized with a Grafted Polymer Chain Bearing N-Methyl-2-hydroxyethylcarbamothioate Moieties.
We report the synthesis and practical application of a novel scavenger for precious metals. The scavenger was prepared from cellulose filter paper with grafted chains of poly(glycidyl methacrylate) modified with a novel ligand group of N-methyl-2-hydroxyethylcarbamothioate moieties, introduced by the reaction with O-1-mercapto-3-phenoxypropan-2-yl N-methyl-2-hydroxyethylcarbamothioate. Batch experiments were performed to evaluate the capability of the scavenger in ranges of pH and acid concentration as well as to determine the kinetics and isotherm models. The scavenger was found to adsorb only Ag(I), Pd(II), and Au(III) from an aqueous media in the presence of coexisting ions of different bases and precious metals at wide ranges of pH and acid concentration. The adsorption rates fit a pseudo-second-order kinetic equation, and the adsorption reached equilibrium within 60 min. The isotherm studies indicated that the obtained data were a good fit with the Langmuir model. The maximum adsorption capacities of Ag(I), Pd(II), and Au(III) were 126.95, 124.67, and 230.67 mg g-1, respectively. Regeneration experiments indicated that the adsorbent maintained 97% of its initial efficiency even after five adsorption/desorption cycles. The scavenger was effectively utilized to recover Ag(I), Pd(II), and Au(III) from an aqua regia solution of waste printed circuit boards.


Towards rapidly quantifying and visualizing starch content of sweet potato [Ipomoea batatas (L.) Lam] based on NIR spectral and image data fusion.
This study aimed to achieve the rapid quantification and visualization of the starch content in sweet potato via near-infrared (NIR) spectral and image data fusion. The hyperspectral images of the sweet potato samples containing 900-1700 nm spectral information within every pixel were collected. The spectra were preprocessed, analyzed and the 18 informative wavelengths were finally extracted to relate to the measured starch content using the multiple linear regression (MLR) algorithm, producing a good quantitative prediction accuracy with a correlation coefficient of prediction (rP) of 0.970 and a root-mean-square error of prediction (RMSEP) of 0.874 g/100 g by an external validation using a set of dependent samples. The MLR model was further verified in terms of soundness and predictive validity via F-test and t-test, and then transferred to each pixel of the original two dimensional images with the help of a developed algorithm, generating color distribution maps to achieve the vivid visualization of the starch distribution. The study demonstrated that the fusion of the NIR spectral and image data provided a good strategy for the rapidly and nondestructively monitoring the starch content of sweet potato. This technique can be applied to industrial use in the future.


Evidence for the beneficial effect of perceptual grouping on visual working memory: an empirical study on illusory contour and a meta-analytic study.
The capacity of visual working memory (VWM) is found to be extremely limited. Past research shows that VWM can be facilitated by Gestalt principles of grouping, however, it remains controversial whether factors like the type of Gestalt principles, the characteristics of stimuli and the nature of experimental design could affect the beneficial effect of grouping. In particular, studies have shown that perceptual grouping could improve memory performance for a feature that is relevant for grouping, but it is unclear whether the same improvement exists for a feature that is irrelevant for grouping. In this article, an empirical study and a meta-analytic study were conducted to investigate the effect of perceptual grouping on VWM. In the empirical study, we examined the grouping effect by employing a Kanizsa illusion in which memory items were grouped by illusory contour. We found that the memory performance was improved for the grouped items even though the tested feature was grouping irrelevant, and the improvement was not significantly different from the effect of grouping by physical connectedness or by solid occlusion. In the meta-analytic study, we systematically and quantitatively examined the effect of perceptual grouping on VWM by pulling the results from all eligible studies, and found that the beneficial grouping effect was robust but the magnitude of the effect can be affected by several moderators. Factors like the types of grouping methods, the duration and the layout of the memory display, and the characteristics of the tested feature moderated the grouping effect, whereas whether employing a cue or a verbal suppression task did not. Our study suggests that the underlying mechanism of the grouping benefit may be distinct with regard to grouping relevancy of the to-be-stored feature. The grouping effect on VWM may be independent of attention for a grouping relevant feature, but may rely on attentional prioritization for a grouping irrelevant feature.


The murine whey acidic protein promoter directs expression to human mammary tumors after retroviral transduction.
The whey acidic protein (WAP) promoter is known to be active in pregnant and lactating mammary epithelial cells as well as mammary tumors of mice. Here we show that a proximal fragment of the murine WAP promoter, including most elements postulated as being responsible for mammary-specific regulation, confers mammary-specific expression upon a marker gene in transgenic mice even though the distal promoter region, known to be important for rat WAP promoter activity, is lacking. The relatively small size of this fragment allows its insertion into a murine leukemia virus-based retroviral vector in place of the viral promoter. Infection of a number of established human mammary and nonmammary cell lines with such a retroviral vector revealed that the WAP promoter was limited in its activity to mammary tumor cell lines. Expression in tumorigenic mammary cells was even more pronounced when these cells were introduced into the mammary fat pads of mice. This is the first demonstration that the WAP promoter is active in human mammary cells and mammary tumor cells in general, and suggests that the extended proximal WAP promoter may be useful for directing therapeutic gene expression to human mammary tumors.


Incident reports--their purpose and scope.
Accidents in the health care setting may be inevitable, but their frequency can be decreased with a dedicated focus on patient safety. Risk reduction naturally flows from a positive approach to risk containment and control that includes learning from past errors. Part One of this two-part series on incident reports talks about identifying and correcting errors, which results in decreased harm to patients and personnel, decreased facility risk liability and regulatory sanctions, and less negative publicity. Although it may be human nature to make mistakes, it also is human nature to create solutions, identify alternatives, and meet future challenges.


New mouthwash: an efficacious intervention for oral ulceration associated with Behçet's disease.
Topical interventions to treat oral ulcers in Behçet's disease (BD) are crucial to control disease activity and improve patients' quality of life. Our aim was to evaluate the effectiveness of a new BD mouthwash (BD MW) for oral ulceration. A retrospective cross-sectional study was carried out on 261 BD patients (141 women, mean (SD) age 39.9 (11.8) years, and 120 men, mean (SD) age 41.141(3.7) years). All were assessed using the oral ulcer severity score (OUSS), oral health quality of life (OHQoL), and the Behçet's disease current activity form (BDCAF). Patients were divided into three groups: one group used the BD MW, one group used a betamethasone mouthwash, and the other used no therapeutic mouthwash. Patients were assessed at three and six months. The OUSS in those using the BD MW was nine times lower than it was in those using betamethasone mouthwash (p=0.001), and 12 times lower than it was in the no mouthwash group (p=0.001). Compared with the baseline data, use of the BD MW during the first three months significantly reduced the OUSS, the BDCAF score, and intraoral scarring, and also improved OHQoL (p=0.001, 0.019, 0.012, and 0.001, respectively). Ongoing use of the BD MW after six months significantly improved the OUSS, OHQoL, and intraoral scars, and kept oral and systemic disease activity under control. A total of 20/31 patients reported high levels of satisfaction with its use, and a patients' satisfaction score showed a preference for it. This study confirms the efficacy of the BD MW in patients with recurrent oral ulceration (ROU). It is more efficacious than betamethasone mouthwash used alone.


Functional and mutational characterization of human MIA40 acting during import into the mitochondrial intermembrane space.
A first component involved in import into the mitochondrial intermembrane space, named Mia40, has been described recently in yeast. Here, we identified the human MIA40 as a novel and ubiquitously expressed component of human mitochondria. It belongs to a novel protein family whose members share six highly conserved cysteine residues constituting a -CXC-CX9C-CX9C- motif. Human MIA40 is significantly smaller than the fungal protein and lacks the N-terminal extension including a transmembrane region and mitochondrial targeting signal. It forms soluble complexes within the intermembrane space of human mitochondria. Depletion of MIA40 in human cells by RNA interference specifically affected steady-state levels of small and cysteine-containing intermembrane space proteins like DDP1 and TIM10A, suggesting that MIA40 acts along the import pathway into the intermembrane space. Studies on the in vivo redox state of human MIA40 demonstrated that it contains intramolecular disulfide bonds. Thiol-trapping assays revealed the co-existence of different oxidation states of human MIA40 within the cell. Furthermore, we show that the twin -CX9C- motif is specifically required for import and stability of MIA40 in mitochondria. Partial mutation of this motif affects stable accumulation of MIA40 in the intermembrane space, whereas mutation of all cysteine residues in this motif inhibits import in mitochondria. Taken together, we conclude that the biogenesis and function of MIA40 in the mitochondrial intermembrane space is dependent on redox processes involving conserved cysteine residues.


Spinal IL-33/ST2 Signaling Contributes to Neuropathic Pain via Neuronal CaMKII-CREB and Astroglial JAK2-STAT3 Cascades in Mice.
Emerging evidence indicates that nerve damage-initiated neuroinflammation and immune responses, which are evidenced by the up-regulation of proinflammatory cytokines, contribute to the development of neuropathic pain. This study investigated the role of spinal interleukin (IL)-33 and its receptor ST2 in spared nerve injury (SNI)-induced neuropathic pain. The von Frey test and acetone test were performed to evaluate neuropathic pain behaviors (n = 8 to 12), and Western blot (n = 4 to 6), immunohistochemistry, real-time polymerase chain reaction (n = 5), and Bio-Plex (n = 5) assays were performed to understand the molecular mechanisms. Intrathecal administration of ST2-neutralizing antibody or ST2 gene knockout (ST2) significantly attenuated the SNI-induced mechanical and cold allodynia. On the 7th day after SNI, the expression of spinal IL-33 and ST2 was increased by 255.8 ± 27.3% and 266.4 ± 83.5% (mean ± SD), respectively. Mechanistic studies showed that the increased expression of the spinal N-methyl-D-aspartate (NMDA) receptor subunit 1 after SNI was reduced by ST2 antibody administration or ST2. The induction of nociceptive behaviors in naive mice due to recombinant IL-33 was reversed by the noncompetitive NMDA antagonist MK-801. ST2 antibody administration or ST2 markedly inhibited the increased activation of the astroglial janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade and the neuronal calcium-calmodulin-dependent kinase II (CaMKII)-cyclic adenosine monophosphate response element-binding protein (CREB) cascade after SNI. Moreover, intrathecal pretreatment with the CaMKII inhibitor KN-93 or the JAK2-STAT3 cascade inhibitor AG490 attenuated recombinant IL-33-induced nociceptive behaviors and NMDA subunit 1 up-regulation in naive mice. Spinal IL-33/ST2 signaling contributes to neuropathic pain by activating the astroglial JAK2-STAT3 cascade and the neuronal CaMKII-CREB cascade.