Risk model-based management for second primary lung cancer among lung cancer survivors through a validated risk prediction model.
Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk-prediction model (called SPLC-RAT) was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. The predictive performance of SPLC-RAT was evaluated in a hospital-based cohort of lung cancer survivors. The authors analyzed data from 8448 ever-smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997-2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC-RAT and further explored the potential of improving SPLC detection through risk model-based surveillance using SPLC-RAT versus existing clinical surveillance guidelines. Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person-years. The application of SPLC-RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10-year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC-RAT development cohort), the observed SPLC incidence was significantly elevated in the high-risk versus low-risk subgroup (13.1% vs. 1.1%, p < 1 × 10-6 ). The risk-based surveillance through SPLC-RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow-ups needed to detect one SPLC (162 vs. 202). In a large, hospital-based cohort, the authors validated the predictive performance of SPLC-RAT in identifying high-risk survivors of SPLC and showed its potential to improve SPLC detection through risk-based surveillance. Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC). However, no evidence-based guidelines for SPLC surveillance are available for lung cancer survivors. Recently, an SPLC risk-prediction model was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. Using a large, real-world cohort of lung cancer survivors, we showed the high predictive accuracy and risk-stratification ability of the SPLC risk-prediction model. Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model-based surveillance strategies compared to the existing consensus-based clinical guidelines, including the National Comprehensive Cancer Network.


An analysis of lipoproteins, bile acids, and red cell membranes associated with target cells and spur cells in patients with liver disease.
Most patients with stable cirrhosis of the alcoholic have "target" red cells; however, a minority have "spur" cells and severe hemolytic anemia. These two syndromes were studied in 27 patients with target cells and 17 patients with spur cells, all of whom had advanced cirrhosis. The cholesterol and phospholipid content of red cell membranes effectively distinguished target cells from spur cells. Target cells alone were rich in lecithin, and both the cholesterol/phospholipid and cholesterol/lecithin mole ratios were greater in spur cells. The cholesterol/phospholipid mole ratio of both types of red cells correlated closely with the free cholesterol saturation of serum lipoproteins, as defined by the amount of free cholesterol relative to phospholipid and protein in these lipoproteins. Lecithin: cholesterol acyltransferase (LCAT) activity was decreased in most patients with target cells and spur cells; however, the relationship between this activity and the lipid abnormalities observed was weak. Serum bile acid levels also correlated poorly with serum and cell lipids. However, in patients with target cells the amount of cholic and deoxycholic acids in serum was approximately equal to the amount of chenodeoxycholic acid, whereas in patients with spur cells chenodeoxycholic acid (the precursor of lithocholic acid) predominated.


Comparative outcome of stapled trans-anal rectal resection and macrogol in the treatment of defecation disorders.
To prospectively assess the efficacy and safety of stapled trans-anal rectal resection (STARR) compared to standard conservative treatment, and whether preoperative symptoms and findings at defecography and anorectal manometry can predict the outcome of STARR. Thirty patients (Female, 28; age: 51 ± 9 years) with rectocele or rectal intussusception, a defecation disorder, and functional constipation were submitted for STARR. Thirty comparable patients (Female, 30; age 53 ± 13 years), who presented with symptoms of rectocele or rectal intussusception and were treated with macrogol, were assessed. Patients were interviewed with a standardized questionnaire at study enrollment and 38 ± 18 mo after the STARR procedure or during macrogol treatment. A responder was defined as an absence of the Rome III diagnostic criteria for functional constipation. Defecography and rectoanal manometry were performed before and after the STARR procedure in 16 and 12 patients, respectively. After STARR, 53% of patients were responders; during conservative treatment, 75% were responders. After STARR, 30% of the patients reported the use of laxatives, 17% had intermittent anal pain, 13% had anal leakage, 13% required digital facilitation, 6% experienced defecatory urgency, 6% experienced fecal incontinence, and 6% required re-intervention. During macrogol therapy, 23% of the patients complained of abdominal bloating and 13% of borborygmi, and 3% required digital facilitation. No preoperative symptom, defecographic, or manometric finding predicted the outcome of STARR. Post-operative defecography showed a statistically significant reduction (P < 0.05) of the rectal diameter and rectocele. The post-operative anorectal manometry showed that anal pressure and rectal sensitivity were not significantly modified, and that rectal compliance was reduced (P = 0.01). STARR is not better and is less safe than macrogol in the treatment of defecation disorders. It could be considered as an alternative therapy in patients unresponsive to macrogol.


Numerical taxonomy of coryneform bacteria isolated from pond-reared shrimp (Penaeus aztecus) and pond water.
Gram-positive, catalase-positive, nonsporeforming, pleomorphic rods isolated from pond-reared shrimp and pond water were compared with type cultures of the Corynebacteriaceae. Classification of the type cultures based on 66 cell and colony characters proved comparable to one based on 163 morphological, biochemical, and physiological characters. This similarity was not observed with pond isolates. With the aid of numerical analysis, pond isolates could be placed into six major groups based on certain biochemical and physiological tests. Coryneform bacteria isolated from shrimp and water exhibited little similarity to the type cultures. The pond isolates probably are members of the Corynebacteriaceae not previously studied in detail.


[Value of serum CA 19-9 determination in the diagnosis of pancreatic carcinoma].
In this communication, serum Ca19-9 was determined in a series of patients with benign and malignant GI diseases. It was found that CA19-9 was positive in 86.7% of 30 pancreatic cancer patients with an average level of 427.53 u/ml, the value was statistically different from that found in non-malignant control group. Serum CA19-9 determination, in this series, helped to make definite diagnosis of pancreatic cancer in 6 cases, in which B-mode ultrasonography failed to diagnose, and in another 3 cases in which CT scanning was unable to 'see' the tumors. The combination of CA19-9, B-mode ultrasonography, and CT made definite diagnosis in 100% of all 30 pancreatic cancer patients. The authors discussed the significance of CA19-9 determination in the diagnosis and differential diagnosis of pancreatic cancer.


Phase 2 trial of erlotinib with or without PF-3512676 (CPG 7909, a Toll-like receptor 9 agonist) in patients with advanced recurrent EGFR-positive non-small cell lung cancer.
This phase 2 study assessed PF-3512676 plus erlotinib in patients with epidermal growth factor receptor-positive advanced non-small cell lung cancer after prior chemotherapy failure. Patients were randomized 1:1 to PF-3512676 (0.20 mg/kg injected subcutaneously once weekly) plus erlotinib (150 mg daily) or erlotinib alone. The primary objective was to estimate progression-free survival (PFS). Patients received PF-3512676 plus erlotinib (n = 18) or erlotinib alone (n = 21). The study was halted because an unplanned interim analysis indicated that large improvement in PFS with addition of PF-3512676 would be unlikely. In the PF-3512676-plus-erlotinib and erlotinib-alone arms, median PFS was 1.6 and 1.7 mo (hazard ratio, 1.00; 95% confidence interval, 0.5-2.0; P = 0.9335), respectively. Salient grade ≥ 3 adverse events in PF-3512676-plus-erlotinib and erlotinib-alone arms were diarrhea (5/0), dyspnea (5/6), fatigue (4/1), other flu-like symptoms (2/0), anemia (2/1), and lymphocytopenia (based on laboratory values, 1/4). Adding PF-3512676 to erlotinib did not show potential for increased progression-free survival over erlotinib alone in patients with advanced recurrent epidermal growth factor receptor-positive non-small cell lung cancer.


[Pheochromocytoma of the broad ligament].
The authors report a rare case where a pheochromocytoma which was not in the adrenal gland occurred in the broad ligament. A review of the literature resulted in only three published cases being found. When the symptomatology suggests that there may be a pheochromocytoma in the body one has to research where it is sited and one has to think of such a possibility if a tumour in the broad ligament is found during an operation, so that the risks of operating on these tumours can be lessened.


A cage for the collection of excreta from individual mice in radioactive tracer studies.
A simple and inexpensive unit for the collection of excreta from individual mice was designed. The results of experiments in which counts of collected radioactive excreta were made closely approximated those previously obtained using a whole-body gamma counter.


Estimating an exchange-rate between care-related and health-related quality of life outcomes for economic evaluation: An application of the wellbeing valuation method.
Quality of life outcomes for family carers and patients may be measured in different ways within the same economic evaluation. We used the wellbeing valuation method to calculate "exchange rates" between care-related outcomes (the Carer Experience Scale and CarerQoL-7D) and health-related (the EQ-5D-5L) outcomes. Data on quality of life outcomes were collected through a postal quality of life survey in the UK. A random effects model was used to estimate carers' wellbeing as a function of their EQ-5D-5L, Carer Experience Scale (or CarerQoL-7D) and a set of control variables. When life satisfaction was used as the measure of wellbeing, a one-point gain in the Carer Experience Scale (0-100 scale) was equivalent (in wellbeing terms) to a 0.014 gain in EQ-5D-5L value; and a one point gain in the CarerQoL-7D (0-100 scale) was equivalent to a 0.033 gain in EQ-5D-5L. The exchange rate values were reduced when capability was used as the measure of wellbeing. The exchange rates estimated in this study offer a means to place carer and patient outcomes, measured via different quality of life instruments, on a common scale, although there are important issues to consider in operationalising the technique.


In Situ Observation of Coulomb Fission of Individual Plasmonic Nanoparticles.
Reshaping plasmonic nanoparticles with laser pulses has been extensively researched as a tool for tuning their properties. However, in the absence of direct observations of the processes involved, important mechanistic details have remained elusive. Here, we present an in situ electron microscopy study of one such process that involves Coulomb fission of plasmonic nanoparticles under femtosecond laser irradiation. We observe that gold nanoparticles encapsulated in a silica shell fission by emitting progeny droplets comprised of about 10-500 atoms, with ejection preferentially occurring along the laser polarization direction. Under continued irradiation, the emitted droplets coalesce into a second core within the silica shell, and the system evolves into a dual-core particle. Our findings are consistent with a mechanism in which electrons are preferentially emitted from the gold core along the laser polarization direction. The resulting anisotropic charge distribution in the silica shell then determines the direction in which progeny droplets are ejected. In addition to yielding insights into the mechanism of Coulomb fission in plasmonic nanoparticles, our experiments point toward a facile method for forming surfaces decorated with aligned dual-gold-core silica shell particles.


Patterns of looking behavior in full-term and low birth weight infants at 40 weeks post-conceptional age.
Given the usefulness of visual behavior as an assessment method in older infants, a simple method of visual behavioral evaluation applicable in clinical settings was utilized to gather descriptive data on 42 infants at term. Using an "infant control" method for determining the duration of stimulus presentation, a series of four patterned targets was presented to 25 healthy full-term (FT) and 17 low birth weight (LBW) infants at 40 weeks postconceptional age. Infants were examined in their nursery cribs, and each stimulus was presented until the infant reached a criterion of a 50% or greater decrement in looking time. LBW infants looked for longer time periods, without pause, than FT infants; LBW mean trial length was twice that of FTs. Although total looking time was longer for the LBW group, LBW infants took twice the length of time as FTs to reach the decrement criterion for the first target and thus viewed fewer targets than FT infants. Despite the longer looking of LBW infants, only 41%, as compared to 56% of the FT group, showed an increase in looking time when a new stimulus was presented. The quality of LBW infants' visual behavior was more often marked by long, continuous looking at the same pattern, in contrast to shorter, more discrete and rapidly decrementing looks by the FT newborn. While there was a large variability within groups, the differential patterns of visual behavior are considered likely to reflect variations in processing of information, possibly associated with differences in integrity or maturation of the visual system.


Catalyzing Interdisciplinary Research and Training: Initial Outcomes and Evolution of the Affinity Research Collaboratives Model.
Team science has been recognized as critical to solving increasingly complex biomedical problems and advancing discoveries in the prevention, diagnosis, and treatment of human disease. In 2009, the Evans Center for Interdisciplinary Biomedical Research (ECIBR) was established in the Department of Medicine at Boston University School of Medicine as a new organizational paradigm to promote interdisciplinary team science. The ECIBR is made up of affinity research collaboratives (ARCs), consisting of investigators from different departments and disciplines who come together to study biomedical problems that are relevant to human disease and not under interdisciplinary investigation at the university. Importantly, research areas are identified by investigators according to their shared interests. ARC proposals are evaluated by a peer review process, and collaboratives are funded annually for up to three years.Initial outcomes of the first 12 ARCs show the value of this model in fostering successful biomedical collaborations that lead to publications, extramural grants, research networking, and training. The most successful ARCs have been developed into more sustainable organizational entities, including centers, research cores, translational research projects, and training programs.To further expand team science at Boston University, the Interdisciplinary Biomedical Research Office was established in 2015 to more fully engage the entire university, not just the medical campus, in interdisciplinary research using the ARC mechanism. This approach to promoting team science may be useful to other academic organizations seeking to expand interdisciplinary research at their institutions.


Mapping of dihydropyridine binding residues in a less sensitive invertebrate L-type calcium channel (LCa v 1).
Invertebrate L-type calcium channel, LCa(v) 1, isolated from the pond snail Lymnaea stagnalis is nearly indistinguishable from mammalian Ca(v) 1.2 (α1C) calcium channel in biophysical characteristics observed in vitro. These L-type channels are likely constrained within a narrow range of biophysical parameters to perform similar functions in the snail and mammalian cardiovascular systems. What distinguishes snail and mammalian L-type channels is a difference in dihydropyridine sensitivity: 100 nM isradipine exhibits a significant block of mammalian Ca(v) 1.2 currents without effect on snail LCa(v)1 currents. The native snail channel serves as a valuable surrogate for validating key residue differences identified from previous experimental and molecular modeling work. As predicted, three residue changes in LCa(v)1 (N_3o18, F_3i10, and I_4i12) replaced with DHP-sensing residues in respective positions of Ca(v) 1.2, (Q_3o18, Y_3i10, and M_4i12) raises the potency of isradipine block of LCa(v)1 channels to that of mammalian Ca(v) 1.2. Interestingly, the single N_3o18_Q mutation in LCa(v) 1 channels lowers DHP sensitivity even further and the triple mutation bearing enhanced isradipine sensitivity, still retains a reduced potency of agonist, (S)-Bay K8644.


Comparative Study of the Mechanical Unfolding Pathways of α- and β-Peptides.
Using molecular simulations, we analyze the unfolding pathways of various peptides. We compare the mechanical unfolding of a β-alanine's octamer (β-HAla8) and an α-alanine's decamer (α-Ala10). Using force-probe molecular-dynamics simulations, to induce unfolding, we show that the 3(14)-helix formed by β-HAla8 is mechanically more stable than the α-helix formed by α-Ala10, although both structures are stabilized by six hydrogen bonds. Additionally, computations of the potential of mean force validate this result and show that also the thermal stability of the 3(14)-helix is higher. It is demonstrated that β-HAla8 unfolds in a two-step fashion with a stable intermediate. This is contrasted with the known single-step scenario of the unfolding of α-Ala10. Furthermore, we present a study of the chain-length dependence of the mechanical unfolding pathway of the 3(14)-helix. The calculation of the dynamic strength for oligomers with chain lengths ranging from 6 to 18 monomers shows that the unfolding pathway of helices with an integer and noninteger number of turns has m + 1 and m energy barriers, respectively, with m being the number of complete turns. The additional barrier for helices with an integer number of turns is shown to be related to the breaking of the N-terminus' hydrogen bond.


Estrogen induces expression of secretory leukocyte protease inhibitor in rat uterus.
In rodents, the steroid hormone estrogen (E) profoundly influences the early events in the uterus leading to embryo implantation. It is thought that E triggers the expression of a unique set of genes in the endometrium that in turn control implantation. To identify these E-induced genes, we employed a delayed implantation model system in which embryo attachment to rat endometrium is dependent upon E administration. Using a gene expression screen method, we isolated a number of cDNAs representing mRNAs whose expression is either turned on or turned off in response to an implantation-inducing dose of E. We identified one of these cDNAs as that encoding secretory leukocyte protease inhibitor (SLPI), an inhibitor of serine proteases. The expression of SLPI mRNA was induced in the uteri of ovariectomized rats in response to E, confirming the hormonal regulation of this molecule. Spatiotemporal analysis revealed a biphasic pattern of expression of SLPI mRNA during early pregnancy. A considerable amount of SLPI mRNA was detected in the uterine epithelium on Day 1 of pregnancy. The level of this mRNA, however, declined sharply on Days 2 and 3 of gestation. Interestingly, on Day 4 of gestation, there was a marked resurgence in SLPI mRNA expression in the uterine epithelium. This second burst of SLPI expression diminished by Day 6 of pregnancy. The transient induction of SLPI mRNA during Days 4 and 5 overlapped with the window of implantation in the rat. Although the precise function of SLPI in the uterus eludes us presently, its known effects as a serine protease inhibitor in other tissues and its hormone-induced expression in the rat uterus immediately preceding implantation lead us to propose that this gene plays an important role in controlling excessive proteolysis and inflammation during a critical phase of early pregnancy.


Perioperative management of neurosurgical patients with methicillin-resistant Staphylococcus aureus.
The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has posed a challenge in the treatment of neurosurgical patients. The authors investigated the impact of MRSA colonization and infection in the neurosurgical population at a community-based, tertiary care referral center. Hospitalized patients under the care of the Kaiser Permanente inpatient neurosurgery service were prospectively entered into a database. In Phase I of the study, 492 consecutive patients were followed. Per hospital policy, the 260 patients from this group who were admitted to the intensive care unit (ICU) underwent screening for MRSA based on nasal swab cultures and a review of their medical history for prior MRSA infections. These patients were designated as either MRSA positive (17 patients, 6.5% of screened patients) or MRSA negative (243 patients). The 232 patients admitted to non-ICU nursing units did not undergo MRSA screening and were designated as unscreened. In Phase II of the study, the authors reviewed 1005 neurosurgical admissions and completed a detailed chart review in 62 MRSA-positive patients (6.2%). Eleven patients received nonoperative treatment. Five patients presented with community-acquired neurosurgical infections, and the causative organism was MRSA in 3 cases. Forty-six patients underwent 55 procedures, and the authors reviewed their perioperative management. In Phase I of the study, the authors found that for the MRSA-positive, MRSA-negative, and unscreened groups, the rates of postoperative neurosurgical wound infections caused by all pathogens were 23.5, 4.1, and 1.3%, respectively. For MRSA wound infections, the rates were 23.5, 0.8, and 0%, respectively. In Phase II, patients with MRSA were noted to have the following clinical features: male sex in 63%, a malignancy in 39.1%, diabetes in 34.8%, prior MRSA infection in 21.7%, immunosuppressed state in 17.4%, and a traumatic injury in 15.2%. The rate of postoperative neurosurgical wound infection in patients who received MRSA-specific prophylactic antibiotic therapy (usually vancomycin) was 7.4% (27 procedures) compared with 32.1% (28 procedures) in patients who received the standard treatment (usually cefazolin) (p = 0.04). Wound care for ICU patients was standardized for postoperative Days 0-7 with chlorhexidine cleaning at bandage changes at 3-day intervals. Wound cultures from neurosurgical site infections in patients with prior MRSA colonization or infection grew MRSA in 7 of 11 patients. Neurosurgical patients identified with MRSA colonization or a prior history of MRSA infections benefit from specific perioperative care, including prophylactic antibiotics active against MRSA (such as vancomycin) and postoperative wound care with coverings and chlorhexidine antisepsis to reduce MRSA wound colonization.


Evidence of Egg Diversity in Squamate Evolution from Cretaceous Anguimorph Embryos.
Lizards are remarkable amongst amniotes, for they display a unique mosaic of reproduction modes ranging from egg-laying to live-bearing. Within this patchwork, geckoes are believed to represent the only group to ever have produced fully calcified rigid-shelled eggs, contrasting with the ubiquitous parchment shelled-eggs observed in other lineages. However, this hypothesis relies only on observations of modern taxa and fossilised gecko-like eggshells which have never been found in association with any embryonic or parental remains. We report here the first attested fossil eggs of lizards from the Early Cretaceous of Thailand, combining hard eggshells with exquisitely preserved embryos of anguimoph (e.g. Komodo dragons, mosasaurs). These fossils shed light on an apparently rare reproduction strategy of squamates, demonstrate that the evolution of rigid-shelled eggs are not an exclusive specialization of geckoes, and suggest a high plasticity in the reproductive organs mineralizing eggshells.


Activation of AMPK/mTORC1-Mediated Autophagy by Metformin Reverses Clk1 Deficiency-Sensitized Dopaminergic Neuronal Death.
The autophagy-lysosome pathway (ALP) plays a critical role in the pathology of Parkinson's disease (PD). Clk1 (coq7) is a mitochondrial hydroxylase that is essential for coenzyme Q (ubiquinone) biosynthesis. We have reported previously that Clk1 regulates microglia activation via modulating microglia metabolic reprogramming, which contributes to dopaminergic neuronal survival. This study explores the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrate that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in the substantia nigra pars compacta of Clk+/- mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects. These mechanistic studies indicate that Clk1 regulates the AMP-activated protein kinase (AMPK)/rapamycin complex 1 pathway, which in turn impairs the ALP and TFEB nuclear translocation. As a result, Clk1 deficiency promotes dopaminergic neuronal damage in vivo and in vitro, which ultimately contributes to sensitizing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal death and behavioral impairments in Clk1-deficient mice. Moreover, we found that activation of autophagy by the AMPK activator metformin increases dopaminergic neuronal survival in vitro and in the MPTP-induced PD model in Clk1 mutant mice. These results reveal that Clk1 plays a direct role in dopaminergic neuronal survival via regulating ALPs that may contribute to the pathologic development of PD. Modulation of Clk1 activity may represent a potential therapeutic target for PD.


Quantitative diffusion imaging and genotype-by-sex interactions in a rat model of Alexander disease.
The clinical diagnosis and classification of Alexander disease (AxD) relies in part on qualitative neuroimaging biomarkers; however, these biomarkers fail to distinguish and discriminate different subtypes of AxD, especially in the presence of overlap in clinical symptoms. To address this gap in knowledge, we applied neurite orientation dispersion and density imaging (NODDI) to an innovative CRISPR-Cas9 rat genetic model of AxD to gain quantitative insights into the neural substrates and brain microstructural changes seen in AxD and to potentially identify novel quantitative NODDI biomarkers of AxD. Multi-shell DWI of age- and sex-matched AxD and wild-type Sprague Dawley rats (n = 6 per sex per genotype) was performed and DTI and NODDI measures calculated. A 3 × 2 × 2 analysis of variance model was used to determine the effect of genotype, biological sex, and laterality on quantitative measures of DTI and NODDI across regions of interest implicated in AxD. There is a significant effect of genotype in the amygdala, hippocampus, neocortex, and thalamus in measures of both DTI and NODDI brain microstructure. A genotype by biological sex interaction was identified in DTI and NODDI measures in the corpus callosum, hippocampus, and neocortex. We present the first application of NODDI to the study of AxD using a rat genetic model of AxD. Our analysis identifies alterations in NODDI and DTI measures to large white matter tracts and subcortical gray nuclei. We further identified genotype by sex interactions, suggesting a possible role for biological sex in the neuropathogenesis of AxD.


Anthocyanin rich extract of Brassica oleracea L. alleviates experimentally induced myocardial infarction.
Cardioprotective potential of anthocyanin rich red cabbage extract (ARCE) was assessed in H2O2 treated rat neonatal cardiomyoblasts (H9c2 cells) and isoproterenol (ISO) induced rodent model of myocardial infarction. H2O2 treated H9c2 cells recorded cytotoxicity (48-50%) and apoptosis (57.3%), the same were reduced in presence of ARCE (7-10% & 12.3% respectively). Rats pretreated with ARCE for 30 days followed by ISO treatment recorded favourable heart: body weight ratio as compared to ISO treated group. Also, the mRNA levels of enzymatic antioxidants (sod and catalase) and apoptotic genes (bax and bcl-2) in ARCE+ISO treated group were similar to the control group suggesting that ARCE pretreatment prevents ISO induced depletion of enzymatic antioxidants and apoptosis. Histoarchitecture of ventricular tissue of ISO treated group was marked by infracted areas (10%) and derangement of myocardium whereas, ARCE+ISO treated group (4.5%) recorded results comparable to control (0%). ARCE+ISO treated group accounted for upregulation of caveolin-3 and SERCA2a expression as compared to the ISO treated group implying towards ARCE mediated reduction in membrane damage and calcium imbalance. Molecular docking scores and LigPlot analysis of cyanidin-3-glucoside (-8.7 Kcal/mol) and delphinidin-3-glucoside (-8.5 Kcal/mol) showed stable hydrophobic and electrostatic interactions with β1 adrenergic receptor. Overall this study elucidates the mechanism of ARCE mediated prevention of experimentally induced myocardial damage.


Understanding the Anomalous Diffusion of Water in Aqueous Electrolytes Using Machine Learned Potentials.
The diffusivity of water in aqueous cesium iodide solutions is larger than that in neat liquid water and vice versa for sodium chloride solutions. Such peculiar ion-specific behavior, called anomalous diffusion, is not reproduced in typical force field based molecular dynamics (MD) simulations due to inadequate treatment of ion-water interactions. Herein, this hurdle is tackled by using machine learned atomic potentials (MLPs) trained on data from density functional theory calculations. MLP based atomistic MD simulations of aqueous salt solutions reproduce experimentally determined thermodynamic, structural, dynamical, and transport properties, including their varied trends in water diffusivities across salt concentration. This enables an examination of their intermolecular structure to unravel the microscopic underpinnings of the differences in their transport properties. While both ions in CsI solutions contribute to the faster diffusion of water molecules, the competition between the heavy retardation by Na ions and the slight acceleration by Cl ions in NaCl solutions reduces their water diffusivity.


Engineered extracellular vesicles as brain therapeutics.
Extracellular vesicles (EVs) are communication channels between different cell types in the brain, between the brain and the periphery and vice-versa, playing a fundamental role in physiology and pathology. The evidence that EVs might be able to cross the blood-brain barrier (BBB) make them very promising candidates as nanocarriers to treat brain pathologies. EVs contain a cocktail of bioactive factors, yet their content and surface can be further engineered to enhance their biological activity, stability and targeting ability. Native and engineered EVs have been reported for the treatment of different brain pathologies, although issues related to their modest accumulation and limited local therapeutic effect in the brain still need to be addressed. In this review, we cover the therapeutic applications of native and bioengineered EVs for brain diseases. We also review recent data about the interaction between EVs and the BBB and discuss the challenges and opportunities in clinical translation of EVs as brain therapeutics.


Hypoxia alters MicroRNA expression in rat cortical pericytes.
Microvascular adaptation to metabolic stress is important in the maintenance of tissue homeostasis. Nowhere is this more important than in the central nervous system (CNS) where the cellular constituents of the neurovascularture including endothelial cells, pericytes and some astroglia must make fine-tuned autoregulatory modulations that maintain the delicate balance between oxygen availability and metabolic demand. miRNAs have been reported to play an important regulatory role in many cellular functions including cell differentiation, growth and proliferation, lineage determination, and metabolism. In this study, we investigated the possible role of miRNAs in the CNS capillary pericyte response to hypoxic stress. Micro-array analysis was used to examine the expression of 388 rat miRNAs in primary rat cortical pericytes with and without exposure to low oxygen (1%) after 24 or 48 hr. Pericytes subjected to hypoxia showed 27 miRNAs that were higher than control and 31 that were lower. Validation and quantification was performed by Real Time RT-PCR on pericytes subjected to 2 hr, 24 hr, or 48 hr of hypoxia. Hypoxia induced changes included physiological pathways governing the stress response, angiogenesis, migration and cell cycle regulation. miRNAs associated with HIF-1α (miR-322[1], miR-199a [2]), TGF-β1 (miR-140[3], miR-145[4], miR-376b-3p[5]) and VEGF (miR-126a[6], miR-297[7], miR-16[8], miR-17-5p[9]) were differentially regulated. Systematic and integrative analysis of possible gene targets analyzed by DAVID bioinformatics resource (http://david.abcc.ncifcrf.gov) and MetaSearch 2.0 (GeneGo) for some of these miRNAs was conducted to determine possible gene targets and pathways that may be affected by the post-transcriptional changes after hypoxic insult.


A Survey Regarding Preference in the Management of Bilateral Stone Disease and a Comparison of Clavien Complication Rates in Bilateral vs Unilateral Percutaneous Nephrolithotomy.
To discuss complications of simultaneous bilateral percutaneous nephrolithotomy (SB-PCNL) when compared with unilateral percutaneous nephrolithotomy and survey surgeon preference in bilateral stone disease management. A database of all participating percutaneous nephrolithotomy (PCNL) patients who underwent treatment at Indiana University Health Methodist Hospital within a 10-year period from 2006 to 2015 by a single surgeon (JL) was utilized. Perioperative data, as well as complications, defined according to the Clavien grading system, were recorded. A survey of members of the Endourological Society was performed regarding surgical management in the setting of bilateral stone disease. A total of 563 patients were identified over the study period with 129 undergoing SB-PCNL. Overall, SB-PCNL patients had a longer procedure (176.9 vs 115.6 minutes, P <.0001), were more likely to undergo a secondary procedure (73% vs 44, P <.001), and had a longer hospital stay (3.2 vs 2.3 days, P <.001). Notably, there were no differences in the number or the severity of complications between the 2 groups. A total of 153 endourologists completed the survey. Of these endourologists, 58 (38%) performed bilateral PCNL under anesthesia. The top reasons for electing not to perform bilateral PCNLs included the duration of bilateral procedures (53%), bilateral renal injury (48%), and rare performance of bilateral surgery (35%). Although the procedure length was longer in the SB-PCNL group, there were similar rates of complications and severity between unilateral PCNL and SB-PCNL. A majority of endourologists surveyed do not perform bilateral PCNL but would perform bilateral ureteroscopy with the duration of the procedure and concern for bilateral renal injury representing the most common reasons.


Purification and properties of a manganese-stimulated endonuclease from Bacillus subtilis.
An endonuclease stimulated by manganese or calcium ions was isolated from Bacillus subtilis. This enzyme attacked double- or single-stranded deoxyribonucleic acid from a variety of sources, including B. subtilis, and was purified from the material released into the medium during protoplast formation. The enzyme appeared as a single peak after glycerol gradient centrifugation and comprised approximately 30 to 35% of the protein in the most purified preparations, as estimated by gel electrophoresis. It had a molecular weight of about 46,000. The mode of action of the enzyme was endonucleolytic, and circular deoxyribonucleic acid was readily cleaved. The enzyme introduced a limited number of both double- and single-strand breaks into native deoxyribonucleic acid, generally yielding products of 1 X 10(6) daltons or more in size. The reasons for this limitation of cleavage were not clear. The activity of the enzyme was inhibited by low levels of Cu2+, Co2+, Hg2+, and Zn2+. It was also inhibited by high concentrations of NaCl. A role for this enzyme in bacterial transormation is suggested.


Use of Fish Oil Nanoencapsulated with Gum Arabic Carrier in Low Fat Probiotic Fermented Milk.
Fish oil consists of omega-3 fatty acids which play an important role in human health. Its susceptibility to oxidation causes considerable degradation during the processing and storage of food products. Accordingly, encapsulation of this ingredient through freeze drying was studied with the aim of protecting it against environmental conditions. Gum arabic (GA) was used as the wall material for fish oil nanoencapsulation where tween 80 was applied as the emulsifier. A water-in-oil (W/O) emulsion was prepared by sonication, containing 6% fish oil dispersed in aqueous solutions including 20% and 25% total wall material. The emulsion was sonicated at 24 kHz for 120 s. The emulsion was then freeze-dried and the nanocapsules were incorporated into probiotic fermented milk, with the effects of nanocapsules examined on the milk. The results showed that the nanoparticles encapsulated with 25% gum arabic and 4% emulsifier had the highest encapsulation efficiency (EE) (87.17%) and the lowest surface oil (31.66 mg/100 kg). Using nanoencapsulated fish oil in fermented milk significantly (p<0.05) increased the viability of Lactobacillus plantarum as well as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) contents. The fermented milk sample containing fish oil nanoencapsulated with 25% wall material and 4% emulsifier yielded the greatest probiotic bacterial count (8.41 Log CFU/mL) and the lowest peroxide value (0.57 mEq/kg). Moreover, this sample had the highest EPA and DHA contents. Utilizing this nanoencapsulated fish oil did not adversely affect fermented milk overall acceptance. Therefore, it can be used for fortification of low fat probiotic fermented milk.


Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note.
Recent preclinical studies have demonstrated that convection-enhanced delivery (CED) can be used to perfuse the brain and brainstem with therapeutic agents while simultaneously tracking their distribution using coinfusion of a surrogate magnetic resonance (MR) imaging tracer. The authors describe a technique for the successful clinical application of this drug delivery and monitoring paradigm to the brainstem. Two patients with progressive intrinsic brainstem lesions (one with Type 2 Gaucher disease and one with a diffuse pontine glioma) were treated with CED of putative therapeutic agents mixed with Gd-diethylenetriamene pentaacetic acid (DTPA). Both patients underwent frameless stereotactic placement of MR imaging-compatible outer guide-inner infusion cannulae. Using intraoperative MR imaging, accurate cannula placement was confirmed and real-time imaging during infusion clearly demonstrated progressive filling of the targeted region with the drug and Gd-DTPA infusate. Neither patient had clinical or imaging evidence of short- or long-term infusate-related toxicity. Using this technique, CED can be used to safely perfuse targeted regions of diseased brainstem with therapeutic agents. Coinfused imaging surrogate tracers can be used to monitor and control the distribution of therapeutic agents in vivo. Patients with a variety of intrinsic brainstem and other central nervous system disorders may benefit from a similar treatment paradigm.


Blood acquisition and processing by three Anopheles (Diptera: Culicidae) species with different innate susceptibilities to Plasmodium falciparum.
Anopheles freeborni Aitken, An. gambiae Giles, and An. albimanus Weidemann exhibit excellent, good, and poor susceptibility to Plasmodium falciparum Welch, respectively. To determine why they differ, 5 variables relating to blood-feeding behavior and 10 variables associated with bloodmeal processing were evaluated for each species. The 3 Anopheles species did not differ in their probing behavior, but An. gambiae took 1.7 times longer to complete engorgement than either An. freeborni or An. albimanus. No interspecific differences were seen in patterns of prediuresis, blood compaction time, midgut pH, bloodmeal clearance, ovarian development, and peritrophic matrix formation. In prediuretic fluid and in blood obtained from midguts soon after mosquito feeding, erythrocytes were agglutinated heavily in An. albimanus, agglutinated moderately in An. freeborni, and unagglutinated in An. gambiae. Erythrocyte hemolysis was greatest in An. gambiae. The significant differences in patterns of blood-feeding behavior and bloodmeal processing among the 3 Anopheles species did not adequately explain interspecific differences in susceptibility to P. falciparum. Therefore, the primary mosquito-related determinants of sporogonic development may operate after bloodmeal processing, and during or after the ookinete-to-oocyst developmental transition.


Pre-injury Comorbidities Are Associated With Functional Impairment and Post-concussive Symptoms at 3- and 6-Months After Mild Traumatic Brain Injury: A TRACK-TBI Study.
Introduction: Over 70% of traumatic brain injuries (TBI) are classified as mild (mTBI), which present heterogeneously. Associations between pre-injury comorbidities and outcomes are not well-understood, and understanding their status as risk factors may improve mTBI management and prognostication. Methods: mTBI subjects (GCS 13-15) from TRACK-TBI Pilot completing 3- and 6-month functional [Glasgow Outcome Scale-Extended (GOSE)] and post-concussive outcomes [Acute Concussion Evaluation (ACE) physical/cognitive/sleep/emotional subdomains] were extracted. Pre-injury comorbidities >10% incidence were included in regressions for functional disability (GOSE ≤ 6) and post-concussive symptoms by subdomain. Odds ratios (OR) and mean differences (B) were reported. Significance was assessed at p < 0.0083 (Bonferroni correction). Results: In 260 subjects sustaining blunt mTBI, mean age was 44.0-years and 70.4% were male. Baseline comorbidities >10% incidence included psychiatric-30.0%, cardiac (hypertension)-23.8%, cardiac (structural/valvular/ischemic)-20.4%, gastrointestinal-15.8%, pulmonary-15.0%, and headache/migraine-11.5%. At 3- and 6-months separately, 30.8% had GOSE ≤ 6. At 3-months, psychiatric (GOSE ≤ 6: OR = 2.75, 95% CI [1.44-5.27]; ACE-physical: B = 1.06 [0.38-1.73]; ACE-cognitive: B = 0.72 [0.26-1.17]; ACE-sleep: B = 0.46 [0.17-0.75]; ACE-emotional: B = 0.64 [0.25-1.03]), headache/migraine (GOSE ≤ 6: OR = 4.10 [1.67-10.07]; ACE-sleep: B = 0.57 [0.15-1.00]; ACE-emotional: B = 0.92 [0.35-1.49]), and gastrointestinal history (ACE-physical: B = 1.25 [0.41-2.10]) were multivariable predictors of worse outcomes. At 6-months, psychiatric (GOSE ≤ 6: OR = 2.57 [1.38-4.77]; ACE-physical: B = 1.38 [0.68-2.09]; ACE-cognitive: B = 0.74 [0.28-1.20]; ACE-sleep: B = 0.51 [0.20-0.83]; ACE-emotional: B = 0.93 [0.53-1.33]), and headache/migraine history (ACE-physical: B = 1.81 [0.79-2.84]) predicted worse outcomes. Conclusions: Pre-injury psychiatric and pre-injury headache/migraine symptoms are risk factors for worse functional and post-concussive outcomes at 3- and 6-months post-mTBI. mTBI patients presenting to acute care should be evaluated for psychiatric and headache/migraine history, with lower thresholds for providing TBI education/resources, surveillance, and follow-up/referrals. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01565551.


The effects of Tynnanthus fasciculatus (Bignoniaceae) infusion on testicular parenchyma of adult Wistar rats.
Traditional medicine provides strong guidance for scientific experiments involving plant products used by the Brazilian people. The species "cipó-cravo" (Tynnanthus fasciculatus) is a plant commonly used either to combat indigestion and stomach aches, or as a general stimulant and aphrodisiac. In this study, the effects of "cipó-cravo" infusion were investigated within the testicular parenchyma of adult Wistar rats. Rats were divided into 3 groups: a control (distilled water) and two treated groups, which received the plant infusion (100 and 200mg/animal/day). The 200mg dose promoted a significant increase of the testicular parenchyma weight and of the volume and total length of the seminiferous tubules, as well as in total daily sperm production and sperm production per gram of testis.


Calcium channel blockers for the treatment of coronary artery spasm: rationale, effects, and nursing responsibilities.
Coronary artery spasm is recognized as a cause of ischemic heart disease, producing a syndrome of the variant form of angina that occurs at rest. Spasm also may play a role in other types of rest angina (unstable angina) and exertional angina. Calcium is essential for the basic tonus of vascular smooth muscle. The accentuated contraction that occurs in coronary artery spasm is the result of an increase in intracellular calcium ions. Current therapy is aimed at blocking the slow calcium currents that are responsible for electrical activation and contraction of smooth muscle cells. A marked coronary vasodilatation is produced with calcium channel blockers, thus demonstrating effective therapy for coronary artery spasm. A similar effect is achieved by nitrates, and these agents will continue to have a role in the therapy of spasm. Calcium channel blockers produce beneficial effects on myocardial oxygen supply and demand and, therefore, are also useful in the prevention of classic exertional angina caused by fixed obstruction. Verapamil and diltiazem possess electrophysiologic effects and have, in addition, proved useful in the treatment of supraventricular dysrhythmias.


Postoccupancy evaluations in zoological settings.
A postoccupancy evaluation (POE) is a systematic assessment performed to examine the effectiveness of the built environment after occupation. Although POEs have been mainly used to examine the effectiveness of built environments for human usage, they can and should be adapted for use in zoological settings. Zoological exhibits have evolved from when hygiene concerns ruled design to current trends that involve elaborate exhibits that often cost millions of dollars. Thus, it is imperative to conduct evaluations to ensure that these exhibits function to meet the complex needs of all users. It is crucial to perform a comprehensive POE that focuses on all three user groups; animals, visitors, and staff. However, work in this field is limited. Animal research has tended to remain very primate-focused with differing opinions as to what constitutes optimal outcomes. Zoo visitor studies often have limited scope and differing methodologies. Additionally, research on zoo staff opinions and feedback is almost nonexistent. A new exhibit opening at a zoo has huge potential for improving the welfare of the animals it will house, enhancing the zoo visitor experience, and improving the workplace for zoo personnel. Building the best possible exhibits requires not only the analysis of how the built environment affects all three groups, but also dissemination of those findings to guide future design.


Mass spectral identification of the metabolites of alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)-benzylamine (MK-251), a novel antiarrhythmic agent, in various species.
The identification of a number of metabolites of the novel antiarrhythmic agent, alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)benzylamine (MK-251), is presented. The compound is extensively metabolized by dog, monkey, baboon and man. Similar metabolic profiles were obtained for all species. Isolation and purification were accomplished by solvent extraction and chromatographic (column, gas and thin-layer) procedures. Gas chromatography, derivatization, infrared, nuclear magnetic resonance and particularly combined gas chromatography low and high resolution mass spectrometry techniques were employed to characterize the metabolites. The major urinary and plasma metabolites were identified as 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]-2-propanol and its glucuronide conjugate. Other metabolites characterized were: the N-glucuronide of MK-251; 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]propene; 2-nitro-2-[4-)alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]propane; alpha,alpha-dimethyl-4(alpha,alpha,beta,beta-tetrafluorophenethyl)benzyl methyl ether; and 4-(alpha,alpha,beta,beta-tetrafluorophenethyl)acetophenone. The 0-methyl ether metabolite represents the first instance of in vivo alkylation of a tertiary alcohol. Tentative identification was made for the N-hydroxy analog of MK-251 and for the glycol analog of 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]-2-propanol. The observed pharmacological response appears to result mainly from MK-251 and not from the four metabolites.


Progressive erosion of genetic and epigenetic variation in callus-derived cocoa (Theobroma cacao) plants.
*Relatively little is known about the timing of genetic and epigenetic forms of somaclonal variation arising from callus growth. We surveyed for both types of change in cocoa (Theobroma cacao) plants regenerated from calli of various ages, and also between tissues from the source trees. *For genetic change, we used 15 single sequence repeat (SSR) markers from four source trees and from 233 regenerated plants. For epigenetic change, we used 386 methylation-sensitive amplified polymorphism (MSAP) markers on leaf and explant (staminode) DNA from two source trees and on leaf DNA from 114 regenerants. *Genetic variation within source trees was limited to one slippage mutation in one leaf. Regenerants were far more variable, with 35% exhibiting at least one mutation. Genetic variation initially accumulated with culture age but subsequently declined. MSAP (epigenetic) profiles diverged between leaf and staminode samples from source trees. Multivariate analysis revealed that leaves from regenerants occupied intermediate eigenspace between leaves and staminodes of source plants but became progressively more similar to source tree leaves with culture age. *Statistical analysis confirmed this rather counterintuitive finding that leaves of 'late regenerants' exhibited significantly less genetic and epigenetic divergence from source leaves than those exposed to short periods of callus growth.


Structural and Psycho-Social Limits to Climate Change Adaptation in the Great Barrier Reef Region.
Adaptation, as a strategy to respond to climate change, has limits: there are conditions under which adaptation strategies fail to alleviate impacts from climate change. Research has primarily focused on identifying absolute bio-physical limits. This paper contributes empirical insight to an emerging literature on the social limits to adaptation. Such limits arise from the ways in which societies perceive, experience and respond to climate change. Using qualitative data from multi-stakeholder workshops and key-informant interviews with representatives of the fisheries and tourism sectors of the Great Barrier Reef region, we identify psycho-social and structural limits associated with key adaptation strategies, and examine how these are perceived as more or less absolute across levels of organisation. We find that actors experience social limits to adaptation when: i) the effort of pursuing a strategy exceeds the benefits of desired adaptation outcomes; ii) the particular strategy does not address the actual source of vulnerability, and; iii) the benefits derived from adaptation are undermined by external factors. We also find that social limits are not necessarily more absolute at higher levels of organisation: respondents perceived considerable opportunities to address some psycho-social limits at the national-international interface, while they considered some social limits at the local and regional levels to be effectively absolute.


Relationship Between Sclerostin (SOST) Expression and Genetic Loci rs851056, rs1230399 Polymorphisms and Bone Mineral Density in Postmenopausal Women with Type 2 Diabetes in Xinjiang.
The Wnt signaling pathway plays a valuable role in bone metabolism. SOST is a major inhibitor of the Wnt signaling pathway. The expression of SOST and genetic polymorphism might be associated with bone mineral density in postmenopausal women with type 2 diabetes mellitus (T2DM). This study aims to explore whether SOST protein expression and genetic locus rs851056, rs1230399 polymorphism is associated with bone mineral density in postmenopausal women with T2DM in Xinjiang. A total of 136 Xinjiang postmenopausal women were divided into four groups: A (-/-), B (±), C (-/+), and D (+/+) by assessing their OGTT and bone mass. Genetic polymorphisms were determined using the mass ARRAY mass spectrometer. 1) Genotypes and allele frequencies at rs851056 were statistically significant differences in groups B and D patients compared to group A, respectively. 2) Individuals carrying the GG genotype had lower HDL, Ca, and ALP as compared to those carrying the GC/CC genotypes in group C. In contrast, individuals carrying the GG genotype had higher BMD (L1-4) as compared to those carrying the GC/CC genotypes in group D. 3) SOST protein expression levels were higher in groups C and D than in group A. 4). BMD (L1-4) was negatively correlated with SOST protein. 5) Multiple linear regression analysis for BMD-dependent variables showed that the decrease of BMI and TG were risk factors for BMD (L1-4), besides, the decrease of BMI, ALP, and extended years of menopause were all risk factors for BMD (femoral neck). SOST protein expression and genetic locus rs851056, rs1230399 polymorphism are associated with bone mineral density in postmenopausal women with type 2 diabetes mellitus in Xinjiang.


Double-antibody fluorescence immunoassay of tobramycin.
This heterogeneous assay for tobramycin involves fluorescein-labeled tobramycin, which competes with native unlabeled tobramycin for anti-tobramycin binding sites. Bound and free labeled antigen are separated by precipitation with a second antibody. Fluorescence intensity of the resuspended precipitate is inversely proportional to native tobramycin concentration. Background interference was consistently about 10% of the total fluorescence precipitated. Assay sensitivity was sufficient to detect nanogram quantities of tobramycin per assay tube. Correlation coefficients (r) were 0.96 and 0.98 for comparisons of this assay with a microbiological assay and a radioimmunoassay, respectively. Mean analytical recovery was 101% and the CV was less than 10% throughout the therapeutic range.


The advantages of oral cytopathology in the early diagnosis of HIV/AIDS: three case reports.
Oral lesions are common in human immunodeficiency virus (HIV)-infected patients, which may indicate impairment of the patient's general health status, and, in many cases, the oral lesions are the first sign of an HIV infection. Oral hairy leukoplakia (OHL) is a benign lesion of the oral mucosa related to Epstein-Barr virus (EBV) observed in HIV-positive individuals. The aim of this study was to report the contribution of oral cytopathology in the investigation of the HIV/AIDS status of patients as well as in the clinical and subclinical identification of OHL. Three patients were referred to the Oral Medicine Clinic in 2010. The patients were submitted to oral examination, and scrapes of the tongue were obtained. The Papanicolaou staining technique was used, and cytopathological analysis showed nuclear changes corresponding to cytopathic effects of EBV epithelial infection and candidiasis. The final diagnosis was OHL and candidiasis. Based on cytopathological diagnosis, an HIV serologic test was requested which revealed positive HIV serology. None of the patients was aware of their HIV serological status, and thus the cytopathology, by identifying OHL, contributed to the early diagnosis of HIV/AIDS. Cytopathology should be used as a routine procedure and it may be the method of choice for clinical and subclinical OHL diagnosis.


Three-color versus four-color multiparameter cell cycle analyses of primary acute myeloid leukemia samples.
Checkpoint alterations that impact cell cycle and apoptosis responses to therapeutic treatments may produce drug resistance in acute myeloid leukemia (AML). To study these, we have developed flow cytometry assays of checkpoint function that also allow quantitation of key molecular regulators of apoptosis and cell cycle. We have used three-color (3C) assays, with FITC-labeled anti-BCL-2 and PE-labeled anti-proliferating cell nuclear antigen (PCNA) antibodies, and the DNA dye 7-aminoactinomycin, to characterize primary leukemia cells identified in DNA x side light scatter (SSC) histograms. We showed that 3C assays are accurate and reproducible in analyses of leukemia cell lines and of primary AML and normal bone marrow samples (Banker et al.: Blood 89: 243-255, 1997; Banker et al.: Leukemia Res 22: 221-239, 1998; Banker et al.: Clin Cancer Res 4: 3051-3062, 1998). To further confirm the validity of our SSC leukemia cell gating and to address whether immunophenotypic AML subsets might have different biologic properties, we have now designed four-color (4C) flow assays to characterize checkpoint status in leukemic blasts specifically identified by surface immunostaining. In modeling this assay strategy, PE/Cy5-labeled anti-CD34 antibody was used to detect blasts, with FITC-labeled anti-BCL-2, PE-labeled anti-PCNA antibodies, and Hoechst 33342 (H33342) DNA dye. Four-color CD34-gated data was concordant with 3C, SSC-gated data for leukemia cell lines and for most primary AML samples with high and intermediate blast counts. BCL-2 and PCNA immunopositivity and sub-G1 apoptosis determinations were different in the CD34-gated versus SSC-gated blasts in particular samples with smaller CD34(+) subsets, suggesting that leukemia samples can contain blast subsets with different biologic properties. On the other hand, PCNA-gated cell-cycle distributions in untreated cells and G1 versus S phase cell-cycle arrests after cytosine arabinoside treatments were completely concordant in 4C and 3C assays. We conclude that both 3C and 4C assays can be used to characterize protein expression and cell-cycle drug response patterns in leukemia blasts, but that 4C assays may additionally allow discrimination of these properties in immunophenotypic leukemia subsets.


Lung cancer in women: analysis of the national Surveillance, Epidemiology, and End Results database.
In order to further characterize the effect of gender on the clinicopathologic features and survival of patients with lung cancer, and to determine gender-associated differences in temporal trends, we analyzed data that had been entered into a population-based cancer database. Data on demographics, stage at diagnosis, histology, initial therapy, and survival were obtained on all patients with primary bronchogenic carcinoma registered in the national Surveillance, Epidemiology, and End Results database from 1975 to 1999. Of the 228,572 eligible patients, 35.8% were female. The median age at diagnosis was 66 years for both men and women. However, women accounted for 40.9% of patients who were < 50 years of age and for 35.4% of older patients. The incidence of lung cancer in men peaked at 72.5 per 100,000 person-years in 1984 and then declined to 47 per 100,000 person-years by 1999. In women, the incidence continued to rise to a peak of 33.1 per 100,000 person-years in 1991 before reaching a plateau at 30.2 to 32.3 per 100,000 person-years from 1992 to 1999. These changes have resulted in a marked narrowing of the male/female incidence ratio from 3.56 in 1975 to 1.56 in 1999. As initial treatment, women with local disease underwent surgery more frequently than did men. Stage-specific survival rates were better for women at all stages of disease (p < 0.0001). In a multivariate analysis, male gender was an independent negative prognostic factor (p < 0.0001). The incidence rate of lung cancer in women in the United States has reached a plateau. However, women are relatively overrepresented among younger patients, raising the question of gender-specific differences in the susceptibility to lung carcinogens. At each stage of the disease, the relative survival of women is better than that of men, with the largest difference noted in patients with local disease.


Long-term effects of maternal smoking on quality of life. Results from the Copenhagen Perinatal Birth Cohort 1959-61.
The Copenhagen Perinatal Birth Cohort 1959-61 is a prospective longitudinal perinatal study that included all deliveries (over 20 weeks gestation, birthweight over 250 g) that took place at the University Hospital (Rigshospitalet) in Copenhagen, Denmark during the period of September 21, 1959 to December 21, 1961 and used in this follow-up study to investigate the connection between maternal smoking during pregnancy and the quality of life of the child 31 to 33 years later. The latest follow-up study from the cohort was performed in 1993 and 7,222 of the surviving children were identified (now aged between 31 and 33 years) and contacted with a nonanonymous questionnaire on several aspects of quality of life issues. There were 4,626 usable responses (f = 2,489, m = 2,131) corresponding to a response rate of 64.1%. The children whose mothers were nonsmokers or smoked less than three cigarettes a day had a quality of life that was 2.7% better than those children whose mothers had smoked over ten cigarettes per day. At first glance these figures seem small; however, when compared with other early life factors we see that mothers smoking more than ten cigarettes per day is one of the most important early predictors in our study for the quality of life (QOL) of the child as an adult. As most people in our study have a QOL rating between 55% and 85%, 2.7% is about 10% of normal variation. It seems that exposure to tobacco smoke during pregnancy has a small but significant effect on the quality of life in later adult life. However, the underlying causal factor for this reduction in quality of life remains unclear. Nevertheless, pregnant mothers should be made aware of the potential long-term effects smoking can have on their children.


Transillumination and optical coherence tomography for the detection and diagnosis of enamel caries.
Caries is one of the most prevalent and preventable conditions worldwide. If identified early enough then non-invasive techniques can be applied, and therefore this review focusses on early caries involving the enamel surface of the tooth. The cornerstone of caries detection and diagnosis is a visual and tactile dental examination, although alternative approaches are available. These include illumination-based devices that could potentially support the dental examination. There are three categories of illumination devices that exploit various methods of application and interpretation, each primarily defined by different wavelengths, optical coherence tomography (OCT), near-infrared (NIR), and fibre-optic technology, which incorporates more recently developed digital fibre optics (FOTI/DIFOTI). To estimate the diagnostic test accuracy of different illumination tests for the detection and diagnosis of enamel caries in children or adults. We also planned to explore the following potential sources of heterogeneity: in vitro or in vivo studies with different reference standards; tooth surface (occlusal, proximal, smooth surface, or adjacent to a restoration); single or multiple sites of assessment on a tooth surface; and the prevalence of caries into dentine. Cochrane Oral Health's Information Specialist undertook a search of the following databases: MEDLINE Ovid (1946 to 15 February 2019); Embase Ovid (1980 to 15 February 2019); US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov, to 15 February 2019); and the World Health Organization International Clinical Trials Registry Platform (to 15 February 2019). We studied reference lists as well as published systematic review articles. We included diagnostic accuracy study designs that compared the use of illumination-based devices with a reference standard (histology, enhanced visual examination with or without radiographs, or operative excavation). These included prospective studies that evaluated the diagnostic accuracy of a single index test and studies that directly compared two or more index tests. Both in vitro and in vivo studies of primary and permanent teeth were eligible for inclusion. We excluded studies that explicitly recruited participants with caries into dentine or frank cavitation. We also excluded studies that artificially created carious lesions and those that used an index test during the excavation of dental caries to ascertain the optimum depth of excavation. Two review authors extracted data independently and in duplicate using a standardised data extraction form and quality assessment based on QUADAS-2 specific to the clinical context. Estimates of diagnostic accuracy were determined using the bivariate hierarchical method to produce summary points of sensitivity and specificity with 95% confidence regions. The comparative accuracy of different illumination devices was conducted based on indirect and direct comparisons between methods. Potential sources of heterogeneity were pre-specified and explored visually and more formally through meta-regression. We included 24 datasets from 23 studies that evaluated 16,702 tooth surfaces. NIR was evaluated in 6 datasets (673 tooth surfaces), OCT in 10 datasets (1171 tooth surfaces), and FOTI/DIFOTI in 8 datasets (14,858 tooth surfaces). The participant selection domain had the largest number of studies judged at high risk of bias (16 studies). Conversely, for the index test, reference standard, and flow and timing domains the majority of studies were judged to be at low risk of bias (16, 12, and 16 studies respectively). Concerns regarding the applicability of the evidence were judged as high or unclear for all domains. Notably, 14 studies were judged to be of high concern for participant selection, due to selective participant recruitment, a lack of independent examiners, and the use of an in vitro study design. The summary estimate across all the included illumination devices was sensitivity 0.75 (95% confidence interval (CI) 0.62 to 0.85) and specificity 0.87 (95% CI 0.82 to 0.92), with a diagnostic odds ratio of 21.52 (95% CI 10.89 to 42.48). In a cohort of 1000 tooth surfaces with a prevalence of enamel caries of 57%, this would result in 142 tooth surfaces being classified as disease free when enamel caries was truly present (false negatives), and 56 tooth surfaces being classified as diseased in the absence of enamel caries (false positives). A formal comparison of the accuracy according to device type indicated a difference in sensitivity and/or specificity (Chi2(4) = 34.17, P < 0.01). Further analysis indicated a difference in the sensitivity of the different devices (Chi2(2) = 31.24, P < 0.01) with a higher sensitivity of 0.94 (95% CI 0.88 to 0.97) for OCT compared to NIR 0.58 (95% CI 0.46 to 0.68) and FOTI/DIFOTI 0.47 (95% CI 0.35 to 0.59), but no meaningful difference in specificity (Chi2(2) = 3.47, P = 0.18). In light of these results, we planned to formally assess potential sources of heterogeneity according to device type, but due to the limited number of studies for each device type we were unable to do so. For interpretation, we presented the coupled forest plots for each device type according to the potential source of heterogeneity. We rated the certainty of the evidence as low and downgraded two levels in total due to avoidable and unavoidable study limitations in the design and conduct of studies, indirectness arising from the in vitro studies, and imprecision of the estimates. Of the devices evaluated, OCT appears to show the most potential, with superior sensitivity to NIR and fibre-optic devices. Its benefit lies as an add-on tool to support the conventional oral examination to confirm borderline cases in cases of clinical uncertainty. OCT is not currently available to the general dental practitioner, and so further research and development are necessary. FOTI and NIR are more readily available and easy to use; however, they show limitations in their ability to detect enamel caries but may be considered successful in the identification of sound teeth. Future studies should strive to avoid research waste by ensuring that recruitment is conducted in such a way as to minimise selection bias and that studies are clearly and comprehensively reported. In terms of applicability, any future studies should be undertaken in a clinical setting that is reflective of the complexities encountered in caries assessment within the oral cavity.


Alterations in activities of calmodulin and heat-stable calmodulin-binding protein in rat testis.
Effects of postnatal development, surgical cryptorchidism, and hypophysectomy on the activity of calmodulin and of a 32,000-molecular weight (32) calmodulin-binding protein (Ono et al., J. Biol. Chem. 259: 9011-9016, 1984) were examined in rat testis. In adult rats, approximately 95% of their activities distributed in seminiferous tubule preparation, and most of them were in the 105,000-g supernatant. Both activities were low early in the development, but the calmodulin activity increased between 25 and 45 days of age, and the 32 K calmodulin-binding protein activity increased between 35 and 45 days of age. In contrast, surgical cryptorchidism caused a rapid decline in their activities in the abdominal testis, whereas their activities in a scrotal testis did not decline. Hypophysectomy similarly resulted in a gradual decline in their activities. Replacement of follicle-stimulating hormone or testosterone for 7 days from 30 days after hypophysectomy did not quantitatively restore either the testes weight or the activities of the proteins. The results indicate a primary distribution of both proteins in mature germ cells.


Using risk adjustment approaches in child welfare performance measurement: Applications and insights from health and mental health settings.
Federal policymaking in the last decade has dramatically expanded performance measurement within child welfare systems, and states are currently being fiscally penalized for poor performance on defined outcomes. However, in contrast to performance measurement in health settings, current policy holds child welfare systems solely responsible for meeting outcomes, largely without taking into account the effects of factors at the level of the child, and his or her social ecology, that might undermine the performance of child welfare agencies. Appropriate measurement of performance is predicated upon the ability to disentangle individual, as opposed to organizational, determinants of outcomes, which is the goal of risk adjustment methodologies. This review briefly conceptualizes and examines risk adjustment approaches in health and child welfare, suggests approaches to expanding its use to appropriately measure the performance of child welfare agencies, and highlights research gaps that diminish the appropriate use of risk adjustment approaches - and which consequently suggest the need for caution - in policymaking around performance measurement of child welfare agencies.


Risks associated with the microbiological quality of bodies of fresh and marine water used for recreational purposes: summary estimates based on published epidemiological studies.
The current European standards for microbiological quality of bathing water (i.e., all running or still fresh waters or parts thereof and/or sea water [with the exception of water intended for therapeutic purposes and water used in swimming pools]) were issued in 1976 and are currently undergoing revision. In this article, the authors propose parameters for select microorganism indicators to assist in the establishment of public-health-based objectives for fresh and marine water quality. A type-II meta-analysis of the results of 18 published epidemiological studies was implemented in an attempt to characterize the relationship(s) between concentrations of bacterial indicators and rates of acute gastrointestinal diseases among bathers who had used fresh or marine water for recreational purposes. The authors fit multiple linear-regression models, which allowed for random effects across studies, to derive dose-response curves. Several confounders and effect modifiers were controlled for in the analyses. Risks were then estimated for a hypothetical individual who would bathe 20 times/yr in water that contained a given concentration of microorganisms. For fresh-water-associated highly credible gastrointestinal illnesses, a level of 10 fecal coliforms/100 ml water yielded an attributable risk of 0.2 cases/1,000 person-years; a risk of 2 cases/1,000 person-years was found for fecal streptococci. The corresponding yearly attributable risks were 1 and 13 cases/1,000 person-years, respectively, for 100 bacteria/100 ml fresh water. Risks associated with fecal coliforms were found to be lower in marine water than in fresh water. Irrespective of the type of water examined, total coliforms were related only weakly with acute digestive morbidity. Developers of future bathing-water standards should state the level of risk deemed acceptable for public health. The authors of this study maintain that levels of fecal coliforms and fecal streptococci should be used as criteria for infectious risk management associated with bodies of marine and fresh water used for recreational purposes.


A452, an HDAC6-selective inhibitor, synergistically enhances the anticancer activity of chemotherapeutic agents in colorectal cancer cells.
Although histone deacetylase inhibitors (HDACi) alone could be clinically useful, these are most recently used in combination with other anticancer agents in clinical trials for cancer treatment. Recently, we reported the anticancer activity of an HDAC6-selective inhibitor A452 toward various cancer cell types. This study aims to present a potent synergistic antiproliferative effect of A452/anticancer agent treatment in colorectal cancer cells (CRC) cells, independently of the p53 status. A452 in combination with irinotecan, or SAHA is more potent than either drug alone in the apoptotic pathway as evidenced by activated caspase-3 and PARP, increased Bak and pp38, decreased Bcl-xL, pERK, and pAKT, and induced apoptotic cells. Furthermore, A452 enhances DNA damage induced by anticancer agents as indicated by the increased accumulation of γH2AX and the activation of the checkpoint kinase Chk2. The silencing of HDAC6 enhances the cell growth inhibition and cell death caused by anticancer agents. In addition, A452 induces the synergistic suppression of cell migration and invasion. This study suggests a mechanism by which HDAC6-selective inhibition can enhance the efficacy of specific anticancer agents in CRC cells.


A kainate receptor-selective RNA aptamer.
Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are two major, closely related receptor subtypes in the glutamate ion channel family. Excessive activities of these receptors have been implicated in a number of central nervous system diseases. Designing potent and selective antagonists of these receptors, especially of kainate receptors, is useful for developing potential treatment strategies for these neurological diseases. Here, we report on two RNA aptamers designed to individually inhibit kainate and AMPA receptors. To improve the biostability of these aptamers, we also chemically modified these aptamers by substituting their 2'-OH group with 2'-fluorine. These 2'-fluoro aptamers, FB9s-b and FB9s-r, were markedly resistant to RNase-catalyzed degradation, with a half-life of ∼5 days in rat cerebrospinal fluid or serum-containing medium. Furthermore, FB9s-r blocked AMPA receptor activity. Aptamer FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency. This inhibitory profile makes FB9s-b a powerful template for developing tool molecules and drug candidates for treatment of neurological diseases involving excessive activities of the GluK1 and GluK2 subunits.


Chlorine isotope effects from isotope ratio mass spectrometry suggest intramolecular C-Cl bond competition in trichloroethene (TCE) reductive dehalogenation.
Chlorinated ethenes are prevalent groundwater contaminants. To better constrain (bio)chemical reaction mechanisms of reductive dechlorination, the position-specificity of reductive trichloroethene (TCE) dehalogenation was investigated. Selective biotransformation reactions (i) of tetrachloroethene (PCE) to TCE in cultures of Desulfitobacterium sp. strain Viet1; and (ii) of TCE to cis-1,2-dichloroethene (cis-DCE) in cultures of Geobacter lovleyi strain SZ were investigated. Compound-average carbon isotope effects were -19.0‰ ± 0.9‰ (PCE) and -12.2‰ ± 1.0‰ (TCE) (95% confidence intervals). Using instrumental advances in chlorine isotope analysis by continuous flow isotope ratio mass spectrometry, compound-average chorine isotope effects were measured for PCE (-5.0‰ ± 0.1‰) and TCE (-3.6‰ ± 0.2‰). In addition, position-specific kinetic chlorine isotope effects were determined from fits of reactant and product isotope ratios. In PCE biodegradation, primary chlorine isotope effects were substantially larger (by -16.3‰ ± 1.4‰ (standard error)) than secondary. In TCE biodegradation, in contrast, the product cis-DCE reflected an average isotope effect of -2.4‰ ± 0.3‰ and the product chloride an isotope effect of -6.5‰ ± 2.5‰, in the original positions of TCE from which the products were formed (95% confidence intervals). A greater difference would be expected for a position-specific reaction (chloride would exclusively reflect a primary isotope effect). These results therefore suggest that both vicinal chlorine substituents of TCE were reactive (intramolecular competition). This finding puts new constraints on mechanistic scenarios and favours either nucleophilic addition by Co(I) or single electron transfer as reductive dehalogenation mechanisms.


Aberrant regulation of the metabolism of the insulin receptor in Swarm rat chondrosarcoma chondrocytes.
Treatment of Swarm rat chondrosarcoma chondrocytes for 3 days in media containing either non-recombinant pig or recombinant human insulin (1 micrograms/ml) increased the rate of proteoglycan synthesis approximately 6-fold compared with cells cultured in the absence of insulin. The concentrations of human and pig insulin that stimulated the cells to double their rate of proteoglycan synthesis were approximately 1 ng/ml and approximately 2 ng/ml respectively. Because physiological concentrations of insulin do not influence proteoglycan synthesis in non-transformed chondrocytes, the findings indicated a possible abnormality in the insulin-dependent regulation of the insulin receptor in these tumour cells. Like most cells, chondrosarcoma chondrocytes down-regulated their insulin receptors when incubated with insulin for 30 min. However, the number of plasma-membrane and intracellular insulin receptors did not decrease when the chondrocytes were exposed to insulin chronically for 4 days. Chondrocytes were cultured in media containing 2H-, 13C- and 15N-labelled amino acids, and the heavy-isotope density-shift method was used to investigate both the rate of degradation and the rate of synthesis of the insulin receptor. Although the rate of synthesis of the receptor was slightly faster in the insulin-treated cultures, as assessed by a slightly faster rate of appearance of the 'heavy' receptor, the rate of degradation of the receptor was slower in the insulin-treated cultures. The half-lives for the 'light' receptors were approx. 18 h and 10 h for chondrocytes cultured in insulin-containing and insulin-free media respectively. These studies in vitro indicate that the apparent up-regulation of insulin receptors that occurs in this transformed cell upon long-term exposure to insulin is primarily the result of a decreased rate of receptor degradation.


Transfusion-related cytomegalovirus infection following noncardiac surgery.
Clinically evident cytomegalovirus (CMV) infections developed in five patients after noncardiac surgery. Each of them had received several blood transfusions and had evidence of primary CMV infection. These five cases were identified in a single eight-month period, suggesting that this syndrome must be occurring with greater frequency than is commonly appreciated. Three of five patients had undergone splenectomy, and review of the literature for documented cases of posttransfusion CMV mononucleosis following non-cardiac-bypass surgery disclosed an additional nine patients, five of whom had had splenectomies. This striking association suggests the possibility that the spleen plays a role in controlling the incidence or clinical manifestations of posttransfusion CMV infections. Alternatively, this association may only reflect the frequent requirement for many blood transfusions in this type of surgery.


Analysis of the beta' subunit of DNA-dependent RNA polymerase does not support the hypothesis inferred from 16S rRNA analysis that Oenococcus oeni (formerly Leuconostoc oenos) is a tachytelic (fast-evolving) bacterium.
rRNA sequencing has shown that leuconostocs comprise three distinct phylogenetic lineages which have been designated separate genera (viz., the genera Leuconostoc sensu stricto, Oenococcus, and Weissella). In addition, the 16S rRNA line formed by Oenococcus oeni (formerly Leuconostoc oenos) is exceptionally long; this fact, together with variations in the compositions of conserved positions in the 16S rRNA, has led to the hypothesis (D. Yang and C. R. Woese, Syst. Appl. Microbiol. 12:145-149, 1989) that this organism is a fast-evolving bacterium. Previous evidence that the leuconostocs should be divided into three genera and that O. oeni is an example of tachytelic evolution has come solely from rRNA analyses. In this study we seqenced the rpoC gene encoding the beta' subunit of DNA-dependent RNA polymerase of leuconostocs and performed a comparative phylogenetic analysis. The subdivision of the leuconostocs into three distinct lineages was confirmed by the rpoC gene data, but no evidence that indicated that O. oeni is evolving at an extraordinary rate was found. If O. oeni is truly tachytelic, then fast-evolving phenomena would be expected to occur throughout the whole genome, including this independent molecular chronometer.


LE-UDA: Label-Efficient Unsupervised Domain Adaptation for Medical Image Segmentation.
While deep learning methods hitherto have achieved considerable success in medical image segmentation, they are still hampered by two limitations: (i) reliance on large-scale well-labeled datasets, which are difficult to curate due to the expert-driven and time-consuming nature of pixel-level annotations in clinical practices, and (ii) failure to generalize from one domain to another, especially when the target domain is a different modality with severe domain shifts. Recent unsupervised domain adaptation (UDA) techniques leverage abundant labeled source data together with unlabeled target data to reduce the domain gap, but these methods degrade significantly with limited source annotations. In this study, we address this underexplored UDA problem, investigating a challenging but valuable realistic scenario, where the source domain not only exhibits domain shift w.r.t. the target domain but also suffers from label scarcity. In this regard, we propose a novel and generic framework called "Label-Efficient Unsupervised Domain Adaptation" (LE-UDA). In LE-UDA, we construct self-ensembling consistency for knowledge transfer between both domains, as well as a self-ensembling adversarial learning module to achieve better feature alignment for UDA. To assess the effectiveness of our method, we conduct extensive experiments on two different tasks for cross-modality segmentation between MRI and CT images. Experimental results demonstrate that the proposed LE-UDA can efficiently leverage limited source labels to improve cross-domain segmentation performance, outperforming state-of-the-art UDA approaches in the literature.


The association between emotional well-being and the incidence of stroke in older adults.
Individuals with high levels of depressive symptoms have an increased risk of many illnesses, including stroke. Measures of depressive symptoms include questions about the presence of negative affect, such as sadness, as well as the absence of positive affect, such as happiness and optimism. We assessed whether positive or negative affect, or both, predicted risk of stroke. Data were from a 6-year prospective cohort study of a population-based sample of 2478 older whites and blacks from five counties in North Carolina who reported no history of stroke at the baseline interview. Baseline, in-person interviews were conducted to gather information on sociodemographic, psychosocial, and health-related characteristics of subjects. Thereafter interviews were conducted annually for 6 years. Increasing scores on the modified version of the Center for Epidemiological Studies Depression Scale (CES-D) were significantly associated with stroke incidence for the overall sample (relative risk [RR] = 1.04 for each one-point increase, 95% confidence interval [CI] = 1.01-1.09) over the 6-year follow-up period after adjusting for sociodemographic characteristics, blood pressure, body mass index, smoking status, and selected chronic diseases. Positive affect score demonstrated a strong inverse association with stroke incidence (RR = 0.74, 95% CI = 0.62-0.88). Increasing scores on the modified CES-D are related to an increased risk of stroke, whereas high levels of positive affect seem to protect against stroke in older adults.


Regulation of glucocorticoid receptors during adaptive liver growth.
Mirex, an organochlorine pesticide, is a potent inducer of liver hyperplasia and hypertrophy in intact (INT) rats. In contrast, mirex elicits predominantly hyperplastic liver growth in adrenalectomized (ADX) rats and hypertrophic liver growth in thyroidectomized (THX) rats. Supplements of glucocorticoids restore liver hypertrophy and inhibit DNA synthesis in ADX mirex-dosed rats. Because responsiveness to glucocorticoids is in part dependent on the number and affinity of glucocorticoid receptors (GR) we have measured hepatic GR levels and dexamethasone inducibility of tyrosine aminotransferase (TAT) in mirex-dosed INT, ADX, and THX rats. Specific [3H]dexamethasone binding sites decreased to 48, 49, and 59% of control values in mirex-dosed INT, ADX, and THX rats, respectively, with no changes in the apparent equilibrium dissociation constant at 48 h postdose. The significant depletion of hepatic cytosolic GR in all experimental groups dosed with mirex failed to impair both uninduced and dexamethasone-induced TAT levels in these groups. It appears that the decrease in steroid binding is neither a result of an interaction between mirex and hepatic GR nor a simple "dilution" of receptors due to the accompanying liver hypertrophy. Taken collectively, these data suggest that despite the ligand-independent downregulation of hepatic GR, responsiveness of hepatocytes from mixed-dosed rats to glucocorticoids is not altered. Therefore, glucocorticoid-mediated liver hypertrophy in mirex-dosed rats probably involves either 1) modulation of steps subsequent to ligand binding and activation translocation of hepatic GR, 2) glucocorticoid effects at extrahepatic sites that release factors that are the actual effectors of parenchymal cell enlargement, or 3) an unconventional receptor-mediated mechanism.


Determinants of maternal health services utilization in urban settings of the Democratic Republic of Congo--a case study of Lubumbashi City.
The use of maternal health services, known as an indirect indicator of perinatal death, is still unknown in Lubumbashi. The present study was therefore undertaken in order to determine the factors that influence the use of mother and child healthcare services in Lubumbashi, Democratic Republic of the Congo. This was transversal study of women residing in Lubumbashi who had delivered between January and December 2009. In total, 1762 women were sampled from households using indicator cluster surveys in all health zones. Antenatal consultations (ANC), delivery assisted by qualified healthcare personnel (and delivery in a healthcare facility) as well as postnatal consultations (PNC) were dependent variables of study. The factors determining non-use of maternal healthcare services were researched via logistic regression with a 5% materiality threshold. The use of maternal healthcare services was variable; 92.6% of women had attended ANC at least once, 93.8% of women had delivered at a healthcare facility, 97.2% had delivered in the presence of qualified healthcare personnel, while the rate of caesarean section was 4.5%. Only 34.6% postnatal women had attended PNC by 42 days after delivery. During these ANC visits, only 60.6% received at least one dose of vaccine, while 38.1% received Mebendazole, 35.6% iron, 32.7% at least one dose of SulfadoxinePyrimethamine, 29.2% folic acid, 15.5% screening for HIV and 12.8% an insecticide treated net.In comparison to women that had had two or three deliveries before, primiparous and grand multiparous women were twice as likely not to use ANC during their pregnancy. Women who had unplanned pregnancies were also more likely not to use ANC or PNC than those who had planned pregnancies alone or with their partner. The women who had not used ANC were also more likely not to use PNC. The women who had had a trouble-free delivery were more likely not to use PNC than those who had complications when delivering. In Lubumbashi, a significant proportion of women continue not to make use of healthcare services during pregnancy, as well as during and after childbirth. Women giving birth for the first time, those who have already given birth many times, and women with an unwanted pregnancy, made less use of ANC. Moreover, women who had not gone for ANC rarely came back for postnatal consultations, even if they had given birth at a healthcare facility. Similarly, those who gave birth without complications, less frequently made use of postnatal consultations. As with ANCs, women with unwanted pregnancies rarely went for postnatal visits.In addition to measures aimed at reinforcing women's autonomy, efforts are also needed to reinforce and improve the information given to women of childbearing age, as well as communication between the healthcare system and the community, and participation from the community, since this will contribute to raising awareness of safe motherhood and the use of such services, including family planning.


Clinical outcomes in patients co-infected with COVID-19 and Staphylococcus aureus: a scoping review.
Endemic to the hospital environment, Staphylococcus aureus (S. aureus) is a leading bacterial pathogen that causes deadly infections such as bacteremia and endocarditis. In past viral pandemics, it has been the principal cause of secondary bacterial infections, significantly increasing patient mortality rates. Our world now combats the rapid spread of COVID-19, leading to a pandemic with a death toll greatly surpassing those of many past pandemics. However, the impact of co-infection with S. aureus remains unclear. Therefore, we aimed to perform a high-quality scoping review of the literature to synthesize the existing evidence on the clinical outcomes of COVID-19 and S. aureus co-infection. A scoping review of the literature was conducted in PubMed, Scopus, Ovid MEDLINE, CINAHL, ScienceDirect, medRxiv, and the WHO COVID-19 database using a combination of terms. Articles that were in English, included patients infected with both COVID-19 and S. aureus, and provided a description of clinical outcomes for patients were eligible. From these articles, the following data were extracted: type of staphylococcal species, onset of co-infection, patient sex, age, symptoms, hospital interventions, and clinical outcomes. Quality assessments of final studies were also conducted using the Joanna Briggs Institute's critical appraisal tools. Searches generated a total of 1922 publications, and 28 articles were eligible for the final analysis. Of the 115 co-infected patients, there were a total of 71 deaths (61.7%) and 41 discharges (35.7%), with 62 patients (53.9%) requiring ICU admission. Patients were infected with methicillin-sensitive and methicillin-resistant strains of S. aureus, with the majority (76.5%) acquiring co-infection with S. aureus following hospital admission for COVID-19. Aside from antibiotics, the most commonly reported hospital interventions were intubation with mechanical ventilation (74.8 %), central venous catheter (19.1 %), and corticosteroids (13.0 %). Given the mortality rates reported thus far for patients co-infected with S. aureus and COVID-19, COVID-19 vaccination and outpatient treatment may be key initiatives for reducing hospital admission and S. aureus co-infection risk. Physician vigilance is recommended during COVID-19 interventions that may increase the risk of bacterial co-infection with pathogens, such as S. aureus, as the medical community's understanding of these infection processes continues to evolve.


Approximating Quasiparticle and Excitation Energies from Ground State Generalized Kohn-Sham Calculations.
Quasiparticle energies and fundamental band gaps in particular are critical properties of molecules and materials. It was rigorously established that the generalized Kohn-Sham HOMO and LUMO orbital energies are the chemical potentials of electron removal and addition and thus good approximations to band edges and fundamental gaps from a density functional approximation (DFA) with minimal delocalization error. For other quasiparticle energies, their connection to the generalized Kohn-Sham orbital energies has not been established but remains highly interesting. We provide the comparison of experimental quasiparticle energies for many finite systems with calculations from the GW Green function and localized orbitals scaling correction (LOSC), a recently developed correction to semilocal DFAs, which has minimal delocalization error. Extensive results with over 40 systems clearly show that LOSC orbital energies achieve slightly better accuracy than the GW calculations with little dependence on the semilocal DFA, supporting the use of LOSC DFA orbital energies to predict quasiparticle energies. This also leads to the calculations of excitation energies of the N-electron systems from the ground state DFA calculations of the ( N - 1)-electron systems. Results show good performance with accuracy similar to TDDFT and the delta SCF approach for valence excitations with commonly used DFAs with or without LOSC. For Rydberg states, good accuracy was obtained only with the use of LOSC DFA. This work highlights the pathway to quasiparticle and excitation energies from ground density functional calculations.


Seven novel variants of the staphylococcal chromosomal cassette mec in methicillin-resistant Staphylococcus aureus isolates from Ireland.
Methicillin-resistant Staphylococcus aureus (MRSA) isolates recovered in Irish hospitals between 1971 and 2002 were characterized using multilocus sequence typing (MLST) (n = 130) and SCCmec typing (n = 172). Where atypical SCCmec typing results were obtained, PCR amplification of entire SCCmec elements, analysis of amplimer mobility, and nucleotide sequencing were undertaken. MLST revealed that 129/130 isolates had the same genotypes as internationally spread MRSA clones, including ST239, ST247, ST250, ST5, ST22, ST36, and ST8. A novel genotype, ST496, was identified in one isolate. Half of the isolates (86/172) had SCCmec type I, IA, II, III, or IV. The remaining 86 isolates harbored novel SCCmec variants in three distinct genetic backgrounds: (i) 74/86 had genotype ST8 and either one of five novel SCCmec II (IIA, IIB, IIC, IID, and IIE) or one of two novel SCCmec IV (IVE and IVF) variants; (ii) 3/86 had genotype ST239 and a novel SCCmec III variant; (iii) 9/86 had a novel SCCmec I variant associated with ST250. SCCmec IVE and IVF were similar to SCCmec IVc and IVb, respectively, but differed in the region downstream of mecA. The five SCCmec II variants were similar to SCCmec IVb in the region upstream of the ccr complex but otherwise were similar to SCCmec II, except for the following regions: SCCmec IIA and IID had a novel mec complex, A.4 (Delta mecI-IS1182-Delta mecI-mecR1-mecA-IS431mec); SCCmec IIC and IIE had a novel mec complex, A.3 (IS1182-Delta mecI-mecR1-mecA-IS431mec); SCCmec IID and IIE lacked pUB110; SCCmec IIC and IIE lacked a region of DNA between Tn554 and the mec complex; and SCCmec IIB lacked Tn554. This study has demonstrated a hitherto-undescribed degree of diversity within SCCmec.