Complex Control of Striatal Neurotransmission by Nicotinic Acetylcholine Receptors via Excitatory Inputs onto Medium Spiny Neurons.
The prevalence of nicotine dependence is higher than that for any other substance abuse disorder; still, the underlying mechanisms are not fully established. To this end, we studied acute effects by nicotine on neurotransmission in the dorsolateral striatum, a key brain region with respect to the formation of habits. Electrophysiological recordings in acutely isolated brain slices from rodent showed that nicotine (10 nm to 10 μm) produced an LTD of evoked field potentials. Current-clamp recordings revealed no significant effect by nicotine on membrane voltage or action potential frequency, indicating that the effect by nicotine is primarily synaptic. Nicotine did not modulate sIPSCs, or the connectivity between fast-spiking interneurons and medium spiny neurons, as assessed by whole-cell recordings combined with optogenetics. However, the frequency of sEPSCs was significantly depressed by nicotine. The effect by nicotine was mimicked by agonists targeting α7- or α4-containing nAChRs and blocked in slices pretreated with a mixture of antagonists targeting these receptor subtypes. Nicotine-induced LTD was furthermore inhibited by dopamine D2 receptor antagonist and occluded by D2 receptor agonist. In addition, modulation of cholinergic neurotransmission suppressed the responding to nicotine, which might reflect upon the postulated role for nAChRs as a presynaptic filter to differentially govern dopamine release depending on neuronal activity. Nicotine-induced suppression of excitatory inputs onto medium spiny neurons may promote nicotine-induced locomotor stimulation and putatively initiate neuroadaptations that could contribute to the transition toward compulsive drug taking.SIGNIFICANCE STATEMENT To decrease smoking, prevalence factors that may contribute to the development of nicotine addiction need to be identified. The data presented here show that nicotine suppresses striatal neurotransmission by selectively reducing the frequency of excitatory inputs to medium spiny neurons (MSNs) while rendering excitability, inhibitory neurotransmission, and fast-spiking interneuron-MSN connectivity unaltered. In addition, we show that the effect displayed by nicotine outlasts the presence of the drug, which could be fundamental for the addictive properties of nicotine. Considering the inhibitory tone displayed by MSNs on dopaminergic cell bodies and local terminals, nicotine-induced long-lasting depression of striatal output could play a role in behavioral transformations associated with nicotine use, and putatively elicit neuroadaptations underlying compulsive drug-seeking habits.


Ty3, a yeast retrotransposon associated with tRNA genes, has homology to animal retroviruses.
Ty3, a retrotransposon of Saccharomyces cerevisiae, is found within 20 base pairs (bp) of the 5' ends of different tRNA genes. Determination of the complete nucleotide sequence of one Ty3 retrotransposon (Ty3-2) shows that the element is composed of an internal domain 4,748 bp long flanked by long terminal repeats of the 340-bp sigma element. Three open reading frames (ORFs) longer than 100 codons are present in the sense strand. The first ORF, TYA3, encodes a protein with a motif found in the nucleic acid-binding protein of retroviruses. The second ORF, TYB3, has homology to retroviral pol genes. The deduced amino acid sequence of the reverse transcriptase domain shows the greatest similarity to Drosophila retrotransposon 17.6, with 43% identical residues. The inferred order of functional domains within TYB3--protease, reverse transcriptase, and endonuclease--resembles the order in Drosophila element 17.6 and in animal retroviruses but is different from that found in yeast elements Ty1 and Ty2. A second Ty3 element (Ty3-1) from a standard laboratory strain was overexpressed and shown to transpose.


[Problems in the early differentiation of mammalian gonads (embryonic histogenesis and mechanisms of regulation)].
The results obtained for the last decades on the problem of early differentiation of mammalian gonads are elucidated. The data on the role of different tissue sources in origin of somatic elements in sex gonads are critically estimated. New data on participation of meiosis-regulating substances (that are produced by the mesonephros and its derivatives) in processes initiating and inhibiting meiosis are presented. The matters on the character of interrelations between the histostructural organization of embryonic gonads and their steroidsynthetic activity are considered. The modern notions on histogenesis of hormonally active stromal elements of the gonads are reported. The role of the data discussed for further investigation of pathogenesis of development of sex anomalies, of disorders in human reproductive function is regarded, as well as that for revealing histogenesis of gonadal tumours.


CYP2J3 gene delivery reduces insulin resistance via upregulation of eNOS in fructose-treated rats.
Accumulating evidence suggests that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs) which play important roles in various pathophysiological processes. Interestingly, CYP-derived eicosanoids are vasodilatory, at least in part through their ability to activate eNOS and subsequent NO release. This study investigated the roles of eNOS in CYP2J3 gene delivery reducing blood pressure and improving insulin resistance in fructose-treated rats. CYP2J3 overexpression in vivo increased EET generation, reduced blood pressure and reversed insulin resistance as determined by insulin resistance index (HOMA-IR). Furthermore, administration of eNOS inhibitor L-NMMA significantly and partially abolished the beneficial effects of CYP2J3 gene delivery on hypertension and insulin resistance induced by fructose intake, and possible mechanism is associated with increased ET-1, ETA-receptor mRNA expression and reduced sensitivity of insulin to peripheral tissues and organs characterized by reduced activity of IRS-1/PI3K/AKT and AMPK signalling pathways. These data provide direct evidence that CYP2J3-derived EETs may alleviate insulin resistance at least in part through upregulated eNOS expression.


A general theory of coexistence and extinction for stochastic ecological communities.
We analyze a general theory for coexistence and extinction of ecological communities that are influenced by stochastic temporal environmental fluctuations. The results apply to discrete time (stochastic difference equations), continuous time (stochastic differential equations), compact and non-compact state spaces and degenerate or non-degenerate noise. In addition, we can also include in the dynamics auxiliary variables that model environmental fluctuations, population structure, eco-environmental feedbacks or other internal or external factors. We are able to significantly generalize the recent discrete time results by Benaim and Schreiber (J Math Biol 79:393-431, 2019) to non-compact state spaces, and we provide stronger persistence and extinction results. The continuous time results by Hening and Nguyen (Ann Appl Probab 28(3):1893-1942, 2018a) are strengthened to include degenerate noise and auxiliary variables. Using the general theory, we work out several examples. In discrete time, we classify the dynamics when there are one or two species, and look at the Ricker model, Log-normally distributed offspring models, lottery models, discrete Lotka-Volterra models as well as models of perennial and annual organisms. For the continuous time setting we explore models with a resource variable, stochastic replicator models, and three dimensional Lotka-Volterra models.


Long-term domiciliary oxygen therapy in cor pulmonale complicating chronic bronchitis and emphysema.
Ten patients with cor pulmonale complicating severe chronic bronchitis and emphysema have been treated with 2 litres/min of oxygen for prolonged periods in the day, at home, over 12 to 62 months. Two patients died after 12 and 36 months of treatment. Pulmonary arterial pressure was reduced in seven patients, and red cell mass in eight, when the oxygen was given for over 15 hours in the day. Hospital inpatient treatment was greatly reduced following the start of long-term oxygen treatment in all patients. This treatment is expensive, and a controlled trial is necessary to establish its definitive place and cost-effectiveness, but the results of such a current Medical Research Council trial will not be available for a further two years.


Immunopathogenesis of acute central nervous system disease produced by lymphocytic choriomeningitis virus. II. Adoptive immunization of virus carriers.
Lymphocytic choriomeningitis (LCM) virus carriers were established by intracerebral inoculation of adult BALB/c mice followed by a single dose of cyclophosphamide (CY) (150 mg/kg) 3 days after infection, and by intracerebral injection within 24 hr of birth. These carriers were then adoptively immunized with spleen cells or serum from immune or normal BALB/c donors. Transfer of immune spleen cells into drug-induced carriers consistently resulted in acutely fatal choriomeningitis, histologically strikingly similar to classical LCM. Normal spleen cells or immune serum failed to produce either central nervous system (CNS) pathology or illness with any regularity. In addition, focal necrosis of the cerebellum was seen after adoptive immunization of drug-induced carriers but only when mice received cells at least 3 wk after inoculation, which is probably explained by the gradual spread of infection from membranes to the neural parenchyma during the first month after establishment of the carrier state in adult mice. Immune spleen cells, when transferred to neonatal carriers, led to a decrease in virus titers in blood and brains and to development of antibody without acute CNS disease. It appears that the production of fatal choriomeningitis after LCM infection is determined in part by the distribution of viral antigen, and this is markedly different in neonatal and drug-induced carriers at the time of cell transfer. Another factor of potential importance is the much higher level of circulating viral antigen in the plasma of neonatal than in that of drug-induced LCM carriers. Classical LCM disease can only be transferred by immune lymphoid cells and not by antiserum. Furthermore, little or no complement-fixing (CF) antibody was found in the plasma of mice dying of acute choroiditis. These observations strongly suggest that acute choroiditis is dependent upon the cell-mediated immune response.


Immune complex deposition in the development of acute synovitis in the rabbit knee joint: quantitative, kinetic and morphological aspects.
The pathology of acute synovitis induced by immune complexes was investigated in this study. The reversed passive Arthus method of lesion induction was utilized, in conjunction with radiolabeled cell and protein markers, to quantitate inflammatory parameters and ascertain their kinetics in the synovial tissues of the rabbit. The rates of increased vessel permeability, polymorphonuclear leukocyte infiltration and platelet deposition were studied using 125-I-albumin, 51-CR-PMN-leukocytes and 111-In-platelets, respectively. Increase in vessel permeability over time was found to directly correlate with increased leukocyte infiltration (r = 9.08; P less than 0.01). Similar correlations between vascular permeability and platelet accumulation, and leukocyte infiltration and platelet accumulation, were not observed. The histological evaluation of synovial lesions corroborated the kinetic findings.


Pharmacovigilance Knowledge among Patients at a Teaching Hospital in Lalitpur District, Nepal.
Consumer's knowledge and perception towards adverse drug reactions (ADR) can play an important role in ensuring a healthy lifestyle and proper use of medicines. This study aimed to assess the knowledge and perception towards pharma covigilance in general and consumer pharmacovigilance in particular among out patients in a teaching hospital of Nepal. A descriptive cross-sectional study using qualitative and quantitative methods was carried out from 1(st) May to 3 June 2013. Every fifth patient visiting the outpatient pharmacy was interviewed using a semi-structured questionnaire. Gender, age, educational qualification, profession and ethnicity were noted. Twenty-three patients were interviewed. There were 10 males and 13 females. The age of the respondents ranged from 11 to 50 years with a mean age of 27.8 (SD = 5.61) years. Seven (30.43%) respondents were students studying in different levels. Thirteen (56.52%) participants were from the Newar community. Majority of the patients (86.95%) knew ADRs may be caused by the medicines they consume and 18 (78.26%) were of the opinion that ADRs should be reported to doctors and other health care professionals including pharmacists. Knowledge and perception were low in certain areas. There is a need for educational interventions for improving the awareness of patients and general public for ensuring medicine safety and promoting rational use of medicines.


Impact of Endolymphatic Hydrops and Semicircular Canal Dysfunction on the Incomplete Recovery of Acute Low-Frequency Sensorineural Hearing Loss.
The reasons for short-term, incomplete recovery of some acute low-frequency sensorineural hearing loss (ALFHL) are unclear. We investigated the impact of endolymphatic hydrops and semicircular canal dysfunction on the incomplete recovery of ALFHL. The impact of electrocochleography (EcochG), caloric test, video head impulse test (vHIT), cervical vestibular-evoked myogenic potential (cVEMP), and ocular vestibular-evoked myogenic potential (oVEMP) results on the incomplete recovery of 86 patients with ALFHL was analyzed. The correlation between a high abnormal rate of vestibular-evoked myogenic potential (VEMP) and aural fullness, dizziness, and level of hearing loss was also examined. Abnormal oVEMP with an odds ratio (OR) of 6.071 (P = .002) and EcochG with an OR of 5.919 (P = .005) were independent risk factors for incomplete recovery in ALFHL, but abnormal cVEMP, caloric test, and vHIT were not independent risk factors for ALFHL. There was no correlation between a high abnormal rate of VEMP and aural fullness, dizziness, or level of hearing loss in ALFHL. Abnormal oVEMP and EcochG values rather than caloric test and vHIT were risk factors for incomplete recovery of ALFHL, which may be related to the difficulty of successfully treating utricular and cochlear hydrops. High abnormal rate of VEMP was not correlated with hearing loss level, aural fullness, or dizziness in ALFHL. Abnormal oVEMP and EcochG values can indicate poor short-term prognosis of ALFHL.


Advances in Single-Cell Sequencing Technology and Its Application in Poultry Science.
Single-cell sequencing (SCS) uses a single cell as the research material and involves three dimensions: genes, phenotypes and cell biological mechanisms. This type of research can locate target cells, analyze the dynamic changes in the target cells and the relationships between the cells, and pinpoint the molecular mechanism of cell formation. Currently, a common problem faced by animal husbandry scientists is how to apply existing science and technology to promote the production of high-quality livestock and poultry products and to breed livestock for disease resistance; this is also a bottleneck for the sustainable development of animal husbandry. In recent years, although SCS technology has been successfully applied in the fields of medicine and bioscience, its application in poultry science has been rarely reported. With the sustainable development of science and technology and the poultry industry, SCS technology has great potential in the application of poultry science (or animal husbandry). Therefore, it is necessary to review the innovation of SCS technology and its application in poultry science. This article summarizes the current main technical methods of SCS and its application in poultry, which can provide potential references for its future applications in precision breeding, disease prevention and control, immunity, and cell identification.


Serosurvey for antibodies against Brucella abortus and Leptospira interrogans in pampas deer from Brazil.
A survey for antibodies against Brucella abortus, and Leptospira interrogans was conducted on 17 pampas deer (Ozotocerus bezoarticus) from Pantanal Matogrossense (State of Mato Grosso do Sul, Brazil) and on 24 pampas deer from Parque Nacional de Emas (State of Goiás, Brazil). Antibodies against B. abortus were detected by plate agglutination, rose Bengal, and complement fixation tests; antibodies against Leptospira interrogans were detected by the microscopic agglutination test. All sera were negative for B. abortus antibodies and all deer sera from Parque Nacional de Emas were negative for L. interrogans antibodies. Four (24%) of 17 sera from Pantanal Matogrossense were positive for L. interrogans serovar (n = 2) hardjo, wolffi (n = 1) and mini (n = 1). While these diseases do not appear to be of major importance to the health status of Pampas deer, it appears that deer are reservoir for leptospirosis in one of the study areas.


The Hycel-M multichannel analyzer--a model for evaluation.
We evaluated the Hycel-M Multichannel Analyzer on behalf of the British Department of Health and Social Security. The purpose of the evaluation was to determine the precision of the instrument over a prolonged period of time, to compare its results with those of well-tried laboratory procedures, and to determine how the instrument would perform under the rigors of routine analysis. In addition, experiments were designed and carried out to test specifically certain new features of the instrument. Some new approaches to the analysis of the data generated have been examined and are discussed. The findings are presented as a demonstration of an evaluation procedure.


The conserved aspartate ring of MCU mediates MICU1 binding and regulation in the mitochondrial calcium uniporter complex.
The mitochondrial calcium uniporter is a Ca2+ channel that regulates intracellular Ca2+ signaling, oxidative phosphorylation, and apoptosis. It contains the pore-forming MCU protein, which possesses a DIME sequence thought to form a Ca2+ selectivity filter, and also regulatory EMRE, MICU1, and MICU2 subunits. To properly carry out physiological functions, the uniporter must stay closed in resting conditions, becoming open only when stimulated by intracellular Ca2+ signals. This Ca2+-dependent activation, known to be mediated by MICU subunits, is not well understood. Here, we demonstrate that the DIME-aspartate mediates a Ca2+-modulated electrostatic interaction with MICU1, forming an MICU1 contact interface with a nearby Ser residue at the cytoplasmic entrance of the MCU pore. A mutagenesis screen of MICU1 identifies two highly-conserved Arg residues that might contact the DIME-Asp. Perturbing MCU-MICU1 interactions elicits unregulated, constitutive Ca2+ flux into mitochondria. These results indicate that MICU1 confers Ca2+-dependent gating of the uniporter by blocking/unblocking MCU.


Glutathione Consumptive Dual-Sensitive Lipid-Composite Nanoparticles Induce Immunogenic Cell Death for Enhanced Breast Tumor Therapy.
Although chemotherapy remains the standard therapy for tumor treatment, serious side effects can occur because of nontargeted distribution and damage to healthy tissues. Hollow mesoporous silica nanoparticles (HMSNs) modified with lipids offer potential as delivery systems to improve therapeutic outcomes and reduce adverse effects. Herein, we synthesized HMSNs with integrated disulfide bonds (HMSN) for loading with the chemotherapeutic agent oxaliplatin (OXP) which were then covered with the synthesized hypoxia-sensitive lipid (Lip) on the surface to prepare the dual-sensitive lipid-composite nanoparticles (HMSN-OXP-Lip). The empty lipid-composite nanoparticles (HMSN-Lip) would consume glutathione (GSH) in cells because of the reduction of disulfide bonds in HMSN and would also inhibit GSH production because of NADPH depletion driven by Lip cleavage. These actions contribute to increased levels of ROS that induce the immunogenic cell death (ICD) effect. Simultaneously, HMSN-Lip would disintegrate in the presence of high concentrations of GSH. The lipid in HMSN-OXP-Lip could evade payload leakage during blood circulation and accelerate the release of the OXP in the tumor region in the hypoxic microenvironment, which could significantly induce the ICD effect to activate an immune response for an enhanced therapeutic effect. The tumor inhibitory rate of HMSN-OXP-Lip was almost twice that of free OXP, and no apparent side effects were observed. This design provides a dual-sensitive and efficient strategy for tumor therapy by using lipid-composite nanoparticles that can undergo sensitive drug release and biodegradation.


A new metabolic pathway of morphine: in vivo and in vitro formation of morphinone and morphine-glutathione adduct in guinea pig.
The biliary excretion of morphine and its metabolites by guinea pigs after s.c. injection of morphine (25 mg/kg) was determined by high-performance liquid chromatography procedures. The amounts of morphinone (MO), morphinone-glutathione adduct (MO-GSH), morphine and morphine-3-glucuronide excreted over a 4-hr period were 1.27, 9.35, 1.13 and 7.54% of the administeral dose, respectively. In addition, trace amounts of morphine-GSH adduct and morphinone-cysteine adduct, derived from MO-GSH, were detected. Although MO-GSH formation from MO proceeded nonenzymatically with a relatively high rate, GSH S-transferases participated in the reaction, especially at lower GSH concentrations. Pretreatment of the animals with diethyl maleate and lithocholic acid-3-sulfate decreased the total biliary excretion of MO. On the other hand, pretreatment with naloxone increased the excretion of total MO. In vitro experiments using liver cytosolic preparations showed that lithocholic acid-3-sulfate inhibited the enzymatic formation of MO from morphine and of MO-GSH from MO. The effects of naloxone on MO formation in vitro were more complex. A reaction was stimulated at low and suppressed at higher concentrations. The results indicated that MO-GSH formation from morphine is inhibited by lithocholic acid-3-sulfate through actions on both morphine 6-dehydrogenase and GSH S-transferases. Low levels of naloxone were found to stimulate the morphine 6-dehydrogenase-mediated dehydrogenation of morphine to MO.


[The perception of permanent, continuous, in service education for nurses in a school hospital].
This study is aimed at discussing the conception of permanent, continuous, in service education among nurses at a school hospital. It is a research of qualitative nature, for which the data was gathered using the technique of focal group in six sessions recorded in audio and video. Nine nurses of a school hospital took part in it. For the analysis of the data was used the technique of collective subject speech, which consists of the organization and computation of the qualitative data of oral nature recorded, from which resulted a single speech. The research showed that the nurses differentiated the terms permanent education, continuous education and in service education, building their own concepts, highlighting the importance of differentiation in order to define the kind of approach to be taken to address the educative need presented.


Preclinical investigation of Pegylated arginase 1 as a treatment for retina and brain injury.
Arginase 1 (A1) is the enzyme that hydrolyzes the amino acid, L-arginine, to ornithine and urea. We have previously shown that A1 deletion worsens retinal ischemic injury, suggesting a protective role of A1. In this translational study, we aimed to study the utility of systemic pegylated A1 (PEG-A1, recombinant human arginase linked to polyethylene glycol) treatment in mouse models of acute retinal and brain injury. Cohorts of WT mice were subjected to retinal ischemia-reperfusion (IR) injury, traumatic optic neuropathy (TON) or brain cerebral ischemia via middle cerebral artery occlusion (MCAO) and treated with intraperitoneal injections of PEG-A1 or vehicle (PEG only). Drug penetration into retina and brain tissues was measured by western blotting and immunolabeling for PEG. Neuroprotection was measured in a blinded fashion by quantitation of NeuN (neuronal marker) immunolabeling of retina flat-mounts and brain infarct area using triphenyl tetrazolium chloride (TTC) staining. Furthermore, ex vivo retina explants and in vitro retina neuron cultures were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (R) and treated with PEG-A1. PEG-A1 given systemically did not cross the intact blood-retina/brain barriers in sham controls but reached the retina and brain after injury. PEG-A1 provided neuroprotection after retinal IR injury, TON and cerebral ischemia. PEG-A1 treatment was also neuroprotective in retina explants subjected to OGD/R but did not improve survival in retinal neuronal cultures exposed to OGD/R. In summary, systemic PEG-A1 administration is neuroprotective and provides an excellent route to deliver the drug to the retina and the brain after acute injury.


An updated knowledge of Black seed (Nigella sativa Linn.): Review of phytochemical constituents and pharmacological properties.
N. sativa (N. sativa) has been used since ancient times, when a scientific concept about the use of medicinal plants for the treatment of human illnesses and alleviation of their sufferings was yet to be developed. It has a strong religious significance as it is mentioned in the religious books of Islam and Christianity. In addition to its historical and religious significance, it is also mentioned in ancient medicine. It is widely used in traditional systems of medicine for a number of diseases including asthma, fever, bronchitis, cough, chest congestion, dizziness, paralysis, chronic headache, back pain and inflammation. The importance of this plant led the scientific community to carry out extensive phytochemical and biological investigations on N. sativa. Pharmacological studies on N. sativa have confirmed its antidiabetic, antitussive, anticancer, antioxidant, hepatoprotective, neuro-protective, gastroprotective, immunomodulator, analgesic, antimicrobial, anti-inflammatory, spasmolytic, and bronchodilator activity. The present review is an effort to explore the reported chemical composition and pharmacological activity of this plant. It will help as a reference for scientists, researchers, and other health professionals who are working with this plant and who need up to date knowledge about it.


Low dose of hydrochlorothiazide, in combination with angiotensin receptor blocker, reduces blood pressure effectively without adverse effect on glucose and lipid profiles.
Previous studies have shown highly effective lowering of blood pressure with thiazide diuretics in combination with angiotensin receptor blockers. However, thiazide diuretics may cause the development of diabetes and abnormal lipid metabolism. Little is known as to whether dysmetabolic potential of thiazide diuretics could be neutralized when adding angiotensin receptor blockers. This study consisted of 26 patients with essential hypertension. Patients were randomized to 24 weeks of treatment with either candesartan, 12 mg monotherapy (n = 13, group A), or hydrochlorothiazide (HCTZ), 6.25 mg in combination with candesartan, 8 mg (n = 13, group B). Before and after treatment, we assessed glucose and lipid profiles including adiponectin, resistin, and active glucagon-like peptide-1 (GLP-1) levels. At baseline, there were no differences in age, body mass index, systolic blood pressure (SBP), and diastolic blood pressure (DBP), as well as plasma levels of hemoglobin A1c, insulin, low-density lipoprotein cholesterol, triglycerides, adiponectin, resistin, and active GLP-1 between the two groups. There were significant reductions in SBP (from 152 ± 10 mmHg at baseline to 134 ± 12 mmHg after treatment) and DBP (from 84 ± 5 mmHg at baseline to 71 ± 8 mmHg after treatment) in group A. There were also significant reductions in SBP (from 148 ± 10 at baseline to 128 ± 7 mmHg after treatment) and DBP (from 90 ± 9 at baseline to 74 ± 12 mmHg after treatment) in group B. There were no differences in reduction of SBP or DBP after 24 weeks of treatment between the two groups. There were no changes of the glucose and lipid profiles, including adiponectin, resistin, insulin, and active GLP-1 levels after 24 weeks of treatment in both groups. A low dose of HCTZ in combination with candesartan reduces blood pressure effectively without adverse effects on the glucose and lipid profiles. Therefore, the combination of thiazide diuretics and angiotensin receptor blockers could assist patients in achieving long-term control of blood pressure with good tolerability.


Development of a structured interview schedule to assess stage of psychological recovery from enduring mental illness.
Abstract Objective. To develop a brief interview-based assessment tool, feasible for routine use in mental health service settings to measure an individual's stage of psychological recovery from an enduring mental illness. Method. Key indicators for each stage of psychological recovery were formulated according to the stages of psychological conceptual framework and an analysis of transcribed data wherein 17 consumer participants described their illness and recovery experiences. Upon development of the measure, Short Interview to assess Stages of Recovery (SIST-R), the instrument was evaluated by practitioners and consumers to examine its feasibility for use in mental health service settings. A pilot test with 18 mental health consumer participants compared results obtained by the SIST-R with those from an existing self-report stages of psychological recovery measure (STORI), a measure of psychological distress (K-10), and a measure of recovery (RAS). Results. Concordance between the SIST-R and the STORI was substantial (Somers' D = 0.61, P = 0.004). The mean scores from other recovery measures correspond with what could be theoretically expected across individual stages of recovery. Conclusion. This study contributes towards the strengthening of a recovery-oriented approach within clinical/mental health service settings with the development of an assessment tool that demonstrates potential clinical utility. There is a need to validate further the preliminary findings of this study.


Female genital tract giant cell arteritis associated with occult temporal arteritis.
Giant cell arteritis (GCA) of the female genital tract has been described as an incidental finding, but associated temporal arteritis (TA) has been rarely reported. We describe a case of female genital tract GCA associated with occult giant cell TA, which in the absence of cranial symptoms was confirmed by a random temporal artery biopsy. The patient remains asymptomatic at 12 month followup after treatment with prednisolone and azathioprine.


Risk factors for bronchiolitis hospitalization in infants: A French nationwide retrospective cohort study over four consecutive seasons (2009-2013).
Large studies are needed to update risk factors of bronchiolitis hospitalization. We performed a nationwide analysis of hospitalization rates for bronchiolitis over four consecutive bronchiolitis seasons to identify underlying medical disorders at risk of bronchiolitis hospitalization and assess their frequency. Data were retrieved from the French National Hospital Discharge database. Of all infants discharged alive from maternity wards from January 2008 to December 2013 in France (N = 3,884,791), we identified four consecutive cohorts at risk of bronchiolitis during the seasons of 2009-2010 to 2012-2013. The main outcome was bronchiolitis hospitalization during a season. Individual risk factors were collected. Among infants, 6.0% were preterm and 2.0% had ≥1 chronic condition including 0.2% bronchopulmonary dysplasia (BPD) and 0.2% hemodynamically significant congenital heart disease (HS-CHD). Bronchiolitis hospitalization rates varied between seasons (min: 1.26% in 2010-2011; max: 1.48% in 2012-2013; p<0.001). Except omphalocele, the following conditions were associated with an increased risk for bronchiolitis hospitalization: solid organ (9.052; 95% CI, 4.664-17.567) and stem cell transplants (6.012; 95% CI, 3.441-10.503), muscular dystrophy (4.002; 95% CI, 3.1095-5.152), cardiomyopathy (3.407; 95% CI, 2.613-4.442), HS-CHD (3.404; 95% CI, 3.153-3.675), congenital lung disease and/or bronchial abnormalities, Down syndrome, congenital tracheoesophageal fistula, diaphragmatic hernia, pulmonary hypertension, chromosomal abnormalities other than Down syndrome, hemodynamically non-significant CHD, congenital abnormalities of nervous system, cystic fibrosis, cleft palate, cardiovascular disease occurring during perinatal period, and BPD. Besides prematurity, BPD, and HS-CHD, eighteen underlying conditions were associated with a significant increased risk for bronchiolitis hospitalization in a nationwide population.


Glycemia-lowering effect of cobalt chloride in the diabetic rat: role of decreased gluconeogenesis.
Results of previous studies indicated that treatment of diabetic rats (induced by streptozotocin) with cobalt chloride (CoCl2) resulted in a significant decrement in serum glucose concentration. The present study was designed to determine the potential role of enhanced glucose uptake vs. decreased glucose production in the above response. The rate of systemic appearance of glucose, measured under fasting conditions using [3-3H]glucose tracer, was reduced from 35.5 +/- 2.5 to 17.5 +/- 1.8 micromol . kg-1 . min-1 in diabetic rats treated with 2 mM CoCl2 added to the drinking water for 10-14 days (P < 0.01). Tissue accumulation of intravenously administered 2-deoxy-[14C]glucose was significantly reduced in kidney and eye of diabetic rats treated with CoCl2, whereas the uptake remained unchanged in several other tissues including cerebrum, red and white skeletal muscle, heart, and liver. The relative content of phosphoenolpyruvate carboxykinase (PEPCK) mRNA was increased 3.1-fold in livers of diabetic compared with normal rats (P < 0.001), and treatment of diabetic rats with CoCl2 decreased hepatic PEPCK mRNA levels to normal. The content of PEPCK mRNA in the liver was decreased by 33% in CoCl2-treated normal rats (P < 0.05). Treatment with CoCl2 resulted in no change in cAMP levels in the livers of either diabetic or normal rats. These results suggest that the glycemia-lowering effect of CoCl2 is mediated by reductions in the rate of systemic appearance of glucose and hepatic gluconeogenesis.


Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle.
In heritable pulmonary arterial hypertension with germline mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, right ventricle (RV) dysfunction is associated with RV lipotoxicity; however, the underlying mechanism for lipid accumulation is not known. We hypothesized that lipid accumulation in cardiomyocytes with BMPR2 mutation occurs owing to alterations in lipid transport and impaired fatty acid oxidation (FAO), which is exacerbated by a high-lipid (Western) diet (WD). We used a transgenic mouse model of pulmonary arterial hypertension with mutant BMPR2 and generated a cardiomyocyte cell line with BMPR2 mutation. Electron microscopy and metabolomic analysis were performed on mouse RVs. By metabolomics analysis, we found an increase in long-chain fatty acids in BMPR2 mutant mouse RVs compared with controls, which correlated with cardiac index. BMPR2-mutant cardiomyocytes had increased lipid compared with controls. Direct measurement of FAO in the WD-fed BMPR2-mutant RV showed impaired palmitate-linked oxygen consumption, and metabolomics analysis showed reduced indices of FAO. Using both mutant BMPR2 mouse RVs and cardiomyocytes, we found an increase in the uptake of (14)C-palmitate and fatty acid transporter CD36 that was further exacerbated by WD. Taken together, our data suggest that impaired FAO and increased expression of the lipid transporter CD36 are key mechanisms underlying lipid deposition in the BMPR2-mutant RV, which are exacerbated in the presence of dietary lipids. These findings suggest important features leading to RV lipotoxicity in pulmonary arterial hypertension and may point to novel areas of therapeutic intervention.


Direct Visualization of Arsenic Binding on Green Rust Sulfate.
"Green rust" (GR), a redox-active Fe(II)-Fe(III) layered double hydroxide, is a potential environmentally relevant mineral substrate for arsenic (As) sequestration in reduced, subsurface environments. GR phases have high As uptake capacities at circum-neutral pH conditions, but the exact interaction mechanism between the GR phases and As species is still poorly understood. Here, we documented the bonding and interaction mechanisms between GR sulfate and As species [As(III) and As(V)] under anoxic and circum-neutral pH conditions through scanning transmission electron microscopy (STEM) coupled with energy-dispersive X-ray (EDX) spectroscopy and combined it with synchrotron-based X-ray total scattering, pair distribution function (PDF) analysis, and As K-edge X-ray absorption spectroscopy (XAS). Our highly spatially resolved STEM-EDX data revealed that the preferred adsorption sites of both As(III) and As(V) are at GR crystal edges. Combining this data with differential PDF and XAS allowed us to conclude that As adsorption occurs primarily as bidentate binuclear (2C) inner-sphere surface complexes. In the As(III)-reacted GR sulfate, no secondary Fe-As phases were observed. However, authigenic parasymplesite (ferrous arsenate nanophase), exhibiting a threadlike morphology, formed in the As(V)-reacted GR sulfate and acts as an additional immobilization pathway for As(V) (∼87% of immobilized As). We demonstrate that only by combining high-resolution STEM imaging and EDX mapping with the bulk (differential) PDF and extended X-ray absorption fine structure (EXAFS) data can one truly determine the de facto As binding nature on GR surfaces. More importantly, these new insights into As-GR interaction mechanisms highlight the impact of GR phases on As sequestration in anoxic subsurface environments.


Policy and procedure development: a novel approach.
This article outlines the process used by a multi-site acute academic health science centre to revise and manage its nursing policies and procedures. It describes how the organization progressed from a paper-based opinion-driven environment to an electronic evidence-based practice. The process was initiated on "Policy Day," a one-day collaborative workshop attended by the stakeholders. Policy Day also provided the mechanism for specialty areas, such as head and neck surgery, to share expertise with nursing and the interprofessional healthcare community.


Video processing to locate the tooltip position in surgical eye-hand coordination tasks.
Trajectories of surgical instruments in laparoscopic surgery contain rich information about surgeons' performance. In a simulation environment, instrument trajectories can be taken by motion sensors attached to the instruments. This method is not accepted by surgeons working in the operating room due to safety concerns. In this study, a novel approach of acquiring instrument trajectories from surgical videos is reported. A total of 12 surgical videos were obtained for this study. The videos were captured during simulated laparoscopic procedures where subjects were required to pick up and transport an object over 3 different targets using a laparoscopic grasper. An algorithm was developed to allow the computer to identify the tip of the grasper on each frame of video, and then compute the trajectories of grasper movement. The newly developed algorithm successfully identified tool trajectories from all 12 surgical videos. To validate the accuracy of this algorithm, the location of the tooltip in these videos were also manually labeled. The rate of accurate matching between these 2 methods was 98.4% of all video frames. Identifying tool movement from surgical videos creates an effective way to track instrument trajectories. This builds up the foundation for assessing psychomotor performance of surgeons in the operating room without jeopardizing patient safety.


Changes in mucosal IgG4+- and IL-10+-cell frequencies in adults with eosinophilic esophagitis on a two-food elimination diet.
Eosinophilic esophagitis (EoE) is increasingly diagnosed in patients with dysphagia. Type-2 immunity can induce EoE histopathology via non-IgE-dependent mechanisms, possibly involving IgG4 and IL-10. To elucidate the contribution of this response to EoE pathogenesis, we examined its association with clinical and histologic endpoints in adult EoE patients given a two-food elimination diet. IgG4- and IL-10-expressing cells were counted in esophageal biopsies and serum food-specific IgG4 measured at baseline and follow-up. Variables were correlated with histologic measures of disease activity. Patients exhibited significant reduction in esophageal eosinophilia and overall histology. A significant decrease in IL-10+-cell frequencies correlated with histologic changes. In contrast, a decline in serum and esophageal IgG4, while substantial, did not correlate with IL-10+-cell frequencies or histologic parameters. These results suggest a critical role of IL-10 in EoE pathogenesis. Conversely, IgG4 expression, while reflecting exposure to food antigens, is not obviously related to EoE histopathology or IL-10 expression.


Robotic inferior vena cava surgery.
Inferior vena cava (IVC) surgery is uncommon and has traditionally been performed through open surgical approaches. Renal cell carcinoma with IVC extension generally requires vena cavotomy and reconstruction. Open removal of malpositioned IVC filters (IVCF) is occasionally required after endovascular retrieval attempts have failed. As our experience with robotic surgery has advanced, we have applied this technology to surgery of the IVC. We reviewed our institution's experience with robotic surgical procedures involving the IVC to determine its safety and efficacy. All patients undergoing robotic surgery that included cavotomy and repair from 2011 to 2014 were retrospectively reviewed. Data were obtained detailing preoperative demographics, operative details, and postoperative morbidity and mortality. Ten patients (6 men) underwent robotic vena caval procedures at our institution. Seven patients underwent robotic nephrectomy with removal of IVC tumor thrombus and retroperitoneal lymph node dissection. Three patients underwent robotic explantation of an IVCF after multiple endovascular attempts at removal had failed. The patients with renal cell carcinoma were a mean age of was 65.4 years (range, 55-74 years). Six patients had right-sided malignancy. All patients had T3b lesions at time of diagnosis. Mean tumor length extension into the IVC was 5 cm (range, 1-8 cm). All patients underwent robotic radical nephrectomy, with caval tumor thrombus removal and retroperitoneal lymph node dissection. The average operative time for patients undergoing surgery for renal cell carcinoma was 273 minutes (range, 137-382 minutes). Average intraoperative blood loss was 428 mL (range, 150-1200 mL). The patients with IVCF removal were a mean age of 33 years (range, 24-41 years). Average time from IVCF placement until robotic removal was 35.5 months (range, 4.3-57.3 months). Before robotic IVCF removal, a minimum of two endovascular retrievals were attempted. Average operative time for patients undergoing IVCF removal was 163 minutes (range, 131-202 minutes). Intraoperative blood loss averaged 250 mL (range, 150-350 mL). All procedures were completed robotically. The mean length of stay for all patients was 3.5 days (range, 1-8 days). All patients resumed ambulation on postoperative day 1. Nine patients resumed a regular diet on postoperative day 2. One patient with a renal tumor sustained a colon injury during initial adhesiolysis, before robotic radical nephrectomy, which was recognized at the initial operation and repaired robotically. Robotic radical nephrectomy and caval tumor removal were then completed. No blood transfusions were required intraoperatively, but three patients required blood transfusions postoperatively. Although robotic IVC surgery is uncommon, our initial limited experience demonstrates it is safe and efficacious.


Sexual behaviour of lesbians and bisexual women.
To provide data about the sexual histories of a large sample of lesbians and bisexual women, to inform those who provide health care or carry out research with women who may be sexually active with other women. Cross sectional survey. 803 lesbians and bisexual women attending, as new patients, lesbian sexual health clinics, and 415 lesbians and bisexual women from a community sample. Self reported sexual history and sexual practice with both male and female partners. 98% of the whole sample gave a history of sexual activity with women, 83% within the past year, with a median of one female partner in that year. 85% of the sample reported sexual activity with men; for most (70%) this was 4 or more years ago. First sexual experience tended to be with a man (median 18 years old), with first sexual experience with a woman a few years later (median 21 years). Oral sex, vaginal penetration with fingers, and mutual masturbation were the most commonly reported sexual practices between women. Vaginal penetration with penis or fingers and mutual masturbation were the most commonly reported sexual activities with men. These data from the largest UK survey of sexual behaviour between women to date demonstrate that lesbians and bisexual women may have varied sexual histories with both male and female partners. A non-judgmental manner and careful sexual history taking without making assumptions should help clinicians to avoid misunderstandings, and to offer appropriate sexual health advice to lesbians and bisexual women.


Anti-oxidant effects of coenzyme Q10 on experimental viral myocarditis in mice.
We studied the effects of coenzyme Q10 (CoQ10) on mice with acute myocarditis inoculated with the encephalomyocarditis (EMC) virus with the analysis of indices of effects of oxidative injury and DNA damage in the myocardium. The mice were treated as follows: CoQ10 group (n = 118); CoQ10 1.0 mg (0.1 mL) x 2/d (0.1 mg/g/d), control group (n = 128); sham-liquid 0.1 mL x 2/d. The mice were injected intraperitoneally 1 day before and daily for 12 days after EMC virus inoculation. The expression of thioredoxin, a marker of oxidative stress overload, as well as 8-hydroxy-2'-deoxyguanosine, an established marker of DNA damage, in the myocardium was investigated. The survival rate was significantly higher (P < 0.01) in the CoQ10 group (46.8%, 29/62) than in the control group (14.3%, 10/70). There were significant increases of CoQ9 and CoQ10 in the heart, which are the biologically active forms of CoQ in mice, and significant decrease of serum creatine kinase (CK)-MB in the CoQ10 group as compared with the control group. Histologic examination showed that the severity of myocarditis was less severe (P < 0.01) in the CoQ10 group than in the control group. In addition, the up-regulation of myocardial thioredoxin with DNA damage, which was induced by the inflammatory stimuli by the virus, was suppressed by the CoQ10 treatment, which may reflect the anti-oxidant effects of CoQ10 treatment. Thus, pretreatment with CoQ10 may reduce the severity of viral myocarditis in mice associated with decreasing oxidative stress in the condition.


Differences in effects of oncogenes on resistance of gamma rays, ultraviolet light, and heat shock.
The effects of viral or activated cellular oncogenes on sensitivity to gamma rays, ultraviolet light, and heat shock were examined in SHOK (Syrian hamster Osaka-Kanazawa) cells and their transfectants. Resistance to gamma rays was conferred by the introduction of v-mos or c-cot genes, which coded serine/threonine kinase. Cells transfected with v-mos and c-cot genes increased their resistance to ultraviolet light and heat shock compared to their parent cells (SHOK cells). Of the activated ras genes, the N-ras gene developed a SHOK cell phenotype resistant to gamma rays and ultraviolet light. The Ha-ras gene produced SHOK cells resistant to ultraviolet light and heat shock, while introduction of the Ki-ras gene did not affect sensitivity. The v-erbB gene was found to be involved in the development of resistance to heat shock. Transfection with neo, c-myc, and v-fgr genes had little or no effect on cell survival. The karyotypes of SHOK cells and oncogene-containing cells were compared. No alterations were seen after the introduction of a foreign gene. Using cell cycle analysis, we found no apparent difference between SHOK cells and their transfectants. These results suggest that activation of serine/threonine kinase may be involved in common processes occurring after gamma-ray, ultraviolet-light, and heat-shock treatment, and that each oncogene may have a different effect on the development of a resistant phenotype.


Lymphoreticular disease in Kenya. Pathological pattern of the superficial lymphadenopathies.
In this paper, an attempt has been made to document accurately the pattern of lymphoreticular disease in Kenya. 1918 abnormal lymph node biopsies, seen over four years, were reviewed and classified according to their pathology: 853 tuberculymphomas. The pathological features, plus age, sex and tribal distribution of each group are discussed in detail. Where there is deviation from the known or established patterns, and where feasible an explanation has been offered. A possible immunological defect is preponderance of the bad prognostic histological types of Hodgkin's disease. The role of malaria in primary lymphoreticular neoplasia has been considered.


PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX.
Maintenance of chromatin homeostasis involves proper delivery of histone variants to the genome. The interplay between different chaperones regulating the supply of histone variants to distinct chromatin domains remains largely undeciphered. We report a role of promyelocytic leukemia (PML) protein in the routing of histone variant H3.3 to chromatin and in the organization of megabase-size heterochromatic PML-associated domains that we call PADs. Loss of PML alters the heterochromatic state of PADs by shifting the histone H3 methylation balance from K9me3 to K27me3. Loss of PML impairs deposition of H3.3 by ATRX and DAXX in PADs but preserves the H3.3 loading function of HIRA in these regions. Our results unveil an unappreciated role of PML in the large-scale organization of chromatin and demonstrate a PML-dependent role of ATRX/DAXX in the deposition of H3.3 in PADs. Our data suggest that H3.3 loading by HIRA and ATRX-dependent H3K27 trimethylation constitute mechanisms ensuring maintenance of heterochromatin when the integrity of these domains is compromised.


Therapy of severe aplastic anemia with anti-human thymocyte globulin and androgens: the effect of HLA-haploidentical marrow infusion.
Fifty-four patients with severe aplastic anemia were treated with horse anti-human thymocyte globulin (ATG) and androgens. Thirty of these patients also received an infusion of HLA-haploidentical marrow cells. Only those patients having evidence of hematologic recovery within 3 mo after ATG therapy were considered responders to the immunosuppressive regimen. Of 53 patients evaluable for response, 21 had complete or partial responses and 7 had minimal improvement by defined criteria. The remaining patients did not respond or died. Factors correlated with response to therapy included a short duration of aplasia and a high admission granulocyte count. Thirty-six patients (66.7%) are surviving between 18 and 43 mo, and 18 have died. Deaths were due to hemorrhage and/or infection. Short duration of aplasia and high granulocyte counts also correlated with survival, as did younger age. Four patients with complete or partial responses had a recurrence of severe aplasia 6-17 mo after their first course of ATG. Three of these patients were retreated with ATG (and oxymetholone in two cases). All three had second responses to therapy, but two of the three have had second relapses. The fourth patient responded to oxymetholone alone, but died after a second relapse. Mismatched marrow infusion had no effect on the incidence of response or survival.


A methodology to study the morphologic changes in lesions during in vitro angioplasty using MRI and image processing.
The assessment of morphologic changes in atherosclerotic lesions during interventional procedures such as transluminal balloon angioplasty is an issue of highest clinical importance. We propose a methodology that allows realistic 3D morphomechanical modeling of the vessel, the plaque and the lumen at different stages of in vitro angioplasty. We elaborate on a novel device designed to guide angioplasty under controlled experimental conditions. The device allows to reproduce in vivo conditions as good as possible, i.e. axial in situ pre-stretch, 100mmHg intraluminal pressure, 37 degrees C Tyrode solution, balloon inflation without external constraints using a high-pressure syringe and contrast medium. With a standard 1.5T MR-system we accomplish multi-spectral images at different stages of the angioplasty experiment. After MR image acquisition the specimen is used for histopathological analysis and biomechanical tests. A segmentation process is used to generate NURBS-based 3D geometric models of the individual vessel and plaque components at different balloon pressures. Tissue components are segmented automatically using generalized gradient vector flow active contours. We investigated 10 human femoral arteries. The effects of balloon compression on the individual artery components is particularly described for two obstructed arteries with an intact collagenous cap, a pronounced lipid pool and with calcification. In both arteries we observe a significant increase in lumen area after angioplasty. Dissection between intima and media and reduction of the lipid pool are primary mechanisms of dilatation. This methodology provides a basis for studying plaque biomechanics under supra-physiological loading conditions. It has the potential to improve and validate finite element models of atherosclerotic plaques which may allow a better prediction of angioplasty procedures.


Active Transport of Manganese in Isolated Membranes of Escherichia coli.
Accumulation of manganese was measured in subcellular membrane vesicles isolated from Escherichia coli. Accumulation of (54)Mn by vesicles in 0.5 m sucrose is stimulated by glucose and d-lactate and is inhibited by metabolic poisons such as dinitrophenol, m-chlorophenyl carbonylcyanide hydrazone, valinomycin, and nigericin. Manganese uptake by vesicles requires 10 mm calcium, which is not required for uptake of manganese by intact cells. The calcium requirement is specific and cannot be replaced by magnesium, sodium, or potassium. Strontium can replace calcium but is somewhat less effective than calcium. The uptake of manganese is via a manganese-specific system which shows saturation kinetics with manganese with a K(m) of 8 x 10(-6)m and a V(max) of 4 nmoles per min per g (wet weight) at 25 C. Magnesium and calcium do not compete for uptake. The accumulated manganese can be released from the vesicles by lipid active agents such as toluene, and can be exchanged for external manganese.


Flow-mediated regulation of G-protein expression in cocultured vascular smooth muscle and endothelial cells.
G-proteins have been implicated in the transduction of a number of flow-induced responses. We determined whether flow can modulate vascular endothelial or smooth muscle cell G-protein signaling. By use of a perfused transcapillary coculture system that permits the chronic exposure of cultured endothelial cells (ECs) and smooth muscle cells (SMCs) to physiological shear stresses, cocultures were exposed to stepwise increases in flow up to (1) 2 mL/min (low flow: 0.5 dyne/cm2), or (2) 44 mL/min (high flow: 15 dyne/cm2) and maintained for 72 hours before SMCs and ECs were harvested separately. Using Western blot analysis, EC Gi alpha3 expression was significantly increased (41+/-2.9%) by high-flow conditions compared with low-flow. The changes in G-protein expression were associated with a significant increase in endothelial nitric oxide synthase (eNOS) activity, elevated prostacyclin levels in the perfusing media, increased pertussis toxin-catalyzed ADP ribosylation of Gi alpha substrates, and enhanced agonist-stimulated GTPase activity in cocultured ECs. In contrast, high flow induced a significant decrease in Gi alpha1-2 expression (57 5%) in SMCs cocultured with ECs, an effect that was endothelium dependent, inhibited by indomethacin, and correlated with a decrease in pertussis toxin-catalyzed ADP ribosylation of Gi alpha substrates, reduced agonist-stimulated GTPase activity, and enhanced basal and G-protein-stimulated adenylyl cyclase activity. These data demonstrate that flow mediates selective changes in EC and SMC G-protein expression concomitant with changes in G-protein functionality and cellular signaling capacity. Moreover, flow-induced changes in SMC G-protein signaling capacity are endothelium dependent and require a cyclooxygenase product. G-protein modulation may thus represent an important mechanism whereby hemodynamic forces regulate vessel wall function.


Cardiac pheochromocytomas detected by Tc-99m-hydrazinonicotinyl-Tyr3-octreotide (HYNIC-TOC) scintigraphy.
Primary pheochromocytomas of the heart are extremely rare tumors and difficult to diagnose. Iodine labeled metaiodobenzylguanidine (MIBG) is the first choice of the nuclear medicine modality in the evaluation of adrenal pheochromocytoma. However, the sensitivity of MIBG in the diagnosis of extraadrenal pheochromocytoma is less optimal. In this preliminary report, the efficacy of octreotide scintigraphy using Tc-99m labeled hydrazinonicotinyl-Tyr3-octreotide (HYNIC-TOC) in the evaluation of primary cardiac pheochromocytoma was assessed.


SHANK3 haploinsufficiency: a "common" but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders.
Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with Phelan-McDermid syndrome, caused by either deletion of 22q13.33 or SHANK3 mutations, using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. This study and prior studies demonstrate that this syndrome appears to be one of the more penetrant causes of ASD. In this companion review, we show that in samples ascertained for ASD, SHANK3 haploinsufficiency is one of the more prevalent monogenic causes of ASD, explaining at least 0.5% of cases. We note that SHANK3 haploinsufficiency remains underdiagnosed in ASD and developmental delay, although with the increasingly widespread use of chromosomal microarray analysis and targeted sequencing of SHANK3, the number of cases is bound to rise.


Sexual side effects and prostate cancer treatment decisions: patient information needs and preferences.
Prostate cancer treatment decision making requires complex trade-offs among treatment outcomes, and sexual function is a central consideration for most men. Although sexual function is included in prostate cancer decision models, survival and fear of recurrence and cancer progression weigh more heavily in these decisions for many men than concerns about treatment impact on sexuality. In this article, we discuss the importance of sexuality in men's treatment decisions for prostate cancer. We focus on men's preferences for maintaining sexual function and their needs for information about the risk of sexual side effects with prostate cancer treatment. Our review suggests that among men diagnosed with prostate cancer sexual function is less important to men than concerns about survival, but is more highly valued than other side effects and treatment characteristics. However, there is evidence that concerns about sexuality are not in proportion with the associated risk for sexual problems with prostate cancer treatment and men acknowledge unmet needs for information about sexuality in making prostate cancer treatment decisions.


Adherence to diet, physical activity and body weight recommendations and breast cancer incidence in the Black Women's Health Study.
Adherence to cancer prevention recommendations has been associated with lower incidence of breast cancer in previous studies, but evidence in African American women is limited. This project evaluated the association between adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and breast cancer incidence among African American women. The Black Women's Health Study (analytic cohort = 49,103) is an ongoing prospective cohort study of African American women, ages 21-69 years at baseline (1995). Adherence scores for seven WCRF/AICR recommendations (adherent = 1, partial adherence = 0.5, non-adherence = 0) were calculated using questionnaire data and summed for overall (maximum = 7) and diet only (maximum = 5) scores. Associations between baseline and time-varying adherence scores and breast cancer incidence (N = 1,827 incident cases through 2011) were evaluated using proportional hazards regression. In this cohort, 8.5% adhered >4 recommendations. Adherence at baseline was not associated with breast cancer incidence. Higher overall time-varying adherence (per 0.5 point increase) was associated with lower breast cancer incidence (HR: 0.90, 95% CI: 0.84-0.96). Adherence to physical activity, sugar beverage and red and processed meat recommendations were also associated with reduced risk. Adherence to the WCRF/AICR recommendations was low and may be associated with lower breast cancer incidence in African American women.


Autoimmune Hemolytic Anemia in a 24-Year-Old Patient With COVID-19 Complicated by Secondary Cryptococcemia and Acute Necrotizing Encephalitis: A Case Report and Review of Literature.
Since the initial reported outbreak of coronavirus disease 2019 (COVID-19), many unique case reports have been published in the medical literature. Here we report a complicated clinical course of a young patient with COVID-19 who presented initially with recurrent autoimmune hemolytic anemia (AIHA). He subsequently developed bilateral pulmonary emboli, and ultimately succumbed to encephalitis and cryptococcemia in the context of being treated with high dose immunosuppression for the AIHA. Combining immunosuppression with active COVID-19 infection presents some truly challenging diagnostic and management scenarios which this case summarizes and highlights very well. Based on this case, we propose some strategies on how to approach these difficult decisions while also recognizing the significant gaps that exist in such an evolving topic. Lastly, this case also represents a potentially novel presentation of secondary fungal infection of the central nervous system (CNS) related to COVID-19.


On the Quantum Chemical Nature of Lead(II) "Lone Pair".
We study the quantum chemical nature of the Lead(II) valence basins, sometimes called the lead "lone pair". Using various chemical interpretation tools, such as molecular orbital analysis, natural bond orbitals (NBO), natural population analysis (NPA) and electron localization function (ELF) topological analysis, we study a variety of Lead(II) complexes. A careful analysis of the results shows that the optimal structures of the lead complexes are only governed by the 6s and 6p subshells, whereas no involvement of the 5d orbitals is found. Similarly, we do not find any significant contribution of the 6d. Therefore, the Pb(II) complexation with its ligand can be explained through the interaction of the 6s2 electrons and the accepting 6p orbitals. We detail the potential structural and dynamical consequences of such electronic structure organization of the Pb (II) valence domain.


On the evolution of genetic incompatibility systems. V. Origin of sporophytic self-incompatibility in response to overdominance in viability.
Conditions for the origin of partial sporophytic self-incompatibility (SSI) are obtained from two quantitative models, which differ with respect to the determination of offspring viability. Offspring viability depends solely on the source (self or nonself) of the fertilizing pollen in the first model, which describes changes only at a primitive S-locus itself. Two loci evolve in the second model: overdominant viability selection maintains an arbitrary number of alleles at one locus, with SSI under the control of a separate locus. In both cases, the origin of SSI requires that the relative change in the numbers of offspring derived by the two reproductive modes compensate for the twofold cost of outcrossing. In the first model studied, the viability of inbred offspring fully determines the relative change in the numbers of inbred and outbred offspring produced. In the second model, the relative change in offspring numbers depends in addition on associations between the S-locus and the viability locus. Because these two-locus associations are comparable in magnitude to the differences between the viabilities of inbred and outbred offspring, SSI can arise under less restrictive conditions than expected from the one-locus model. Greater allelic multiplicity at the viability locus facilitates the origin of SSI by reducing the relative viability of inbred offspring. Tight linkage between the S-locus and the viability locus and high rates of receipt of self-pollen promote the generation and maintenance of associations between the S-locus and the viability locus. In populations in which more than two viability alleles are maintained, the active S-allele can invade even in the absence of linkage with the viability locus. The present study establishes that incompatibility systems can arise in response to identity disequilibrium between a modifier of incompatibility and a locus subject to overdominant viability selection; in particular, compensation for the twofold cost of outcrossing does not require preexisting gametic level disequilibria.


Motor and somatosensory evoked potential findings in HTLV-I associated myelopathy.
The central motor and sensory conduction times were measured using the motor and somatosensory evoked potentials in 21 patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) to evaluate the functions of the corticospinal tract and posterior column. The control subjects were closely matched for gender, age and height with the patients in the central sensory conduction time (CSCT) and central motor conduction time (CMCT) studies. An abnormal upper limb (UL) CMCT was present in six of 34 limbs (17.6%) while the lower limb (LL) CMCT was abnormal in 31 of 42 limbs (73.8%). No patients had an abnormal UL CSCT while the LL CSCT was abnormal in 10 of 32 limbs (31.3%). The frequency of abnormal LL CMCT was significantly higher than that for an abnormal LL CSCT. The duration of the disease and the disability score did not significantly influence the evoked potential findings. These results indicate that major lesions of the spinal cord in HAM/TSP patients tend to be localized more in the descending corticospinal pathways than in the ascending posterior columns at the thoracic spinal cord level. This finding also closely agrees with the clinico-pathological findings of HAM/TSP.


Responses of Mycobacterium sp. LB501T to the low bioavailability of solid anthracene.
Several recent reports have indicated that some bacteria may have adapted to the low bioavailability of hydrophobic environmental chemicals and that generalizations about the bioavailability of compounds such as polycyclic aromatic hydrocarbons (PAHs) may be inappropriate. Experimental evidence and theoretical considerations show that the utilization of PAHs requires bioavailability-enhancing mechanisms of the bacteria such as: (1) high-affinity uptake systems, (2) adhesion to the solid substrate, and (3) biosurfactant excretion. We examined possible specific physiological responses of anthracene-degrading Mycobacterium sp. LB501T to poorly water-soluble anthracene in batch cultures, using solid anthracene as a sole carbon source. Mycobacterium sp. LB501T exhibited a high specific affinity for anthracene (a(o)A=32,500 l g(-1) protein h(-1)) and grew as a confluent biofilm on solid anthracene present as sole carbon source. No biofilm formation on anthracene was observed when excess glucose was provided as an additional substrate. This difference could be attributed to a modification of the cell surface of the bacterium. Anthracene-grown cells were significantly more hydrophobic and more negatively charged than glucose-grown cells. In adhesion experiments, anthracene-grown cells adhered 1.5- to 8.0-fold better to hydrophobic Teflon and up to 70-fold better to anthracene surfaces than glucose-grown cells. However, no production of biosurfactants was observed. Our results thus indicate that attachment and biofilm formation may be a specific response of Mycobacterium sp. LB501T to optimize substrate bioavailability.


The Effect of Stiff Foot Plate Length on Walking Gait Mechanics.
Exoskeletons are increasingly being used to treat gait pathologies. Many of these exoskeletons use a foot plate to actuate the foot, altering the effective stiffness of the foot. Stiffness of the biological foot and ankle plays an important role in the energy modulating function of the leg, so it is important to examine how a foot plate in and of itself impacts gait. Therefore, this study quantified how foot plates themselves alter the walking gait of 16 healthy young adults. The effect of the foot plate length was also examined through the use of two foot plates, one that ended at the metatarsals and one that extended past the toes, about 20% longer. Gait parameters examined included walking speed, step frequency, joint angles for the hip, knee, ankle, forefoot, and toe, ground reaction forces (GRF), and foot-ankle power. The most significant changes were caused by the full plate, which caused an average 13% decrease in the ankle range of motion (ROM) and a 23% decrease in forward GRF at push off. The shorter plate also decreased ankle ROM to a lesser degree. This indicates that the presence of a foot plate impacted foot and ankle kinematics. However, the presence of the tested foot plate had no effect on walking speed or hip or knee kinematics. This indicates that subjects were mostly able to compensate both kinematically and energetically via their foot and ankle for the increased foot stiffness due to the tested foot plate.


Physical analysis of phr gene transcription in Escherichia coli K-12.
The phr gene of Escherichia coli K-12 encodes the light-dependent, DNA repair enzyme photolyase, which removes UV light-induced pyrimidine dimers from cellular DNA. From Southern hybridization analysis of several strains containing successively extended phr deletions, we have determined the direction of transcription of the phr gene on the E. coli K-12 chromosome. Northern (RNA) hybridization analysis suggests that the phr gene is cotranscribed with a previously identified gene of unknown function (orf169) into two messages of different lengths. S1 nuclease mapping analysis indicates that the two transcripts share a single termination site but initiate at two different sites. Finally, we have determined that the presence of orf169 is not necessary for phr gene activity in vivo.


Search for Higgs Boson Decay to a Charm Quark-Antiquark Pair in Proton-Proton Collisions at sqrt[s]=13 TeV.
A search for the standard model Higgs boson decaying to a charm quark-antiquark pair, H→cc[over ¯], produced in association with a leptonically decaying V (W or Z) boson is presented. The search is performed with proton-proton collisions at sqrt[s]=13 TeV collected by the CMS experiment, corresponding to an integrated luminosity of 138 fb^{-1}. Novel charm jet identification and analysis methods using machine learning techniques are employed. The analysis is validated by searching for Z→cc[over ¯] in VZ events, leading to its first observation at a hadron collider with a significance of 5.7 standard deviations. The observed (expected) upper limit on σ(VH)B(H→cc[over ¯]) is 0.94 (0.50_{-0.15}^{+0.22})pb at 95% confidence level (C.L.), corresponding to 14 (7.6_{-2.3}^{+3.4}) times the standard model prediction. For the Higgs-charm Yukawa coupling modifier, κ_{c}, the observed (expected) 95% C.L. interval is 1.1<|κ_{c}|<5.5 (|κ_{c}|<3.4), the most stringent constraint to date.


Evaluating Correlations Between Premium Cigar Smoking and Mental Health and Substance Use Dependence Conditions Among U.S. Adults, 2010-2019.
Improved understanding of health conditions associated with premium cigar smoking can inform efforts to reduce cigar use. This paper extends findings commissioned for the National Academies of Science, Engineering, and Medicine report on premium cigars. We pooled 2010-2019 National Survey on Drug Use and Health data to evaluate cross-sectional associations between premium cigar smoking and mental health and substance use conditions among U.S. adults. A series of logistic regression models adjusted for age, sex, race and ethnicity, cigarette smoking, and alcohol consumption compared odds of each condition associated with past-month premium cigar smoking relative to past-month nonpremium cigar smoking, never tobacco use, and current established cigarette smoking. Premium cigar smoking was associated with lower adjusted odds of past month serious psychological distress, past year major depressive episode, and cannabis and illicit drug dependence relative to nonpremium cigar and cigarette smoking; however, higher odds of alcohol and cannabis dependence were observed relative to never tobacco use, and lower odds of alcohol dependence were observed relative to current cigarette smoking but not current nonpremium cigar smoking. We observed considerable variation in both magnitude and direction of associations between premium cigar smoking and mental health and substance use indicators depending on the condition and reference group to which premium cigar smoking was compared. Premium cigar smoking frequently cooccurs with cigarette smoking and alcohol consumption, thus potential health correlates must be considered in appropriate context. We observed considerable variation in direction and magnitude of association depending on the health condition and reference population, as well as potential for reverse causality and residual confounding in this cross-sectional analysis. As the tobacco landscape continues to evolve, rigorous scientific studies that incorporate clear differentiation of cigar type, measures of cumulative use, and temporal data collection are necessary to fully evaluate the health effects of premium cigar smoking and effectively inform Food and Drug Administration regulation.


Chronic fatigue syndrome: evaluation and treatment.
Severe fatigue is a common complaint among patients. Often, the fatigue is transient or can be attributed to a definable organic illness. Some patients present with persistent and disabling fatigue, but show no abnormalities on physical examination or screening laboratory tests. In these cases, the diagnosis of chronic fatigue syndrome (CFS) should be considered. CFS is characterized by debilitating fatigue with associated myalgias, tender lymph nodes, arthralgias, chills, feverish feelings, and postexertional malaise. Diagnosis of CFS is primarily by exclusion with no definitive laboratory test or physical findings. Medical research continues to examine the many possible etiologic agents for CFS (infectious, immunologic, neurologic, and psychiatric), but the answer remains elusive. It is known that CFS is a heterogeneous disorder possibly involving an interaction of biologic systems. Similarities with fibromyalgia exist and concomitant illnesses include irritable bowel syndrome, depression, and headaches. Therefore, treatment of CFS may be variable and should be tailored to each patient. Therapy should include exercise, diet, good sleep hygiene, antidepressants, and other medications, depending on the patient's presentation.


The Characteristic Curvature (Cc) of Ionic Surfactants Assessed via Small-Angle X-ray Scattering.
The characteristic curvature (Cc), within the hydrophilic-lipophilic difference + net (Hn) - average (Ha) curvature (HLD-NAC) framework, is the dimensionless net curvature, -Hn·L (L is the surfactant's tail length parameter), that a surfactant acquires at the characteristic condition (T = 25 °C, no added cosurfactants, oil with an equivalent alkane carbon number (EACN) of zero and for ionic surfactants, a total salinity (S) of 1 g NaCl/100 mL). A recent article demonstrated the validity of the Cc concept, where Hn was assessed via oil and water solubilization radii. Here, we assess Hn from the characteristic length (ξ) obtained from the analysis of SAXS profiles of microemulsions produced at semicharacteristic conditions (characteristic condition but varying S). The predicted relationship, -L·Hn,semicharacteristic = Ccbi + bi·ln(S), was confirmed with the five ionic surfactants explored. The SAXS-assessed Cc (Cc = Ccbi/bi) values are consistent with those obtained from solubilization studies and phase inversion scans. The Cc-SAXS method provides a way to assess the hydrophobicity of ionic surfactants directly, avoiding the bias that could be introduced by cosurfactants in phase inversion studies and minimizing the impact of potential uncertainties in the surfactant volume to area ratio (vs/as) required to calculate the solubilization radii in the solubilization method.


A novel mechanoeffector role of fibroblast S100A4 in myofibroblast transdifferentiation and fibrosis.
Fibroblast to myofibroblast transdifferentiation mediates numerous fibrotic disorders, such as idiopathic pulmonary fibrosis (IPF). We have previously demonstrated that non-muscle myosin II (NMII) is activated in response to fibrotic lung extracellular matrix, thereby mediating myofibroblast transdifferentiation. NMII-A is known to interact with the calcium-binding protein S100A4, but the mechanism by which S100A4 regulates fibrotic disorders is unclear. In this study, we show that fibroblast S100A4 is a calcium-dependent, mechanoeffector protein that is uniquely sensitive to pathophysiologic-range lung stiffness (8 - 25 kPa), and thereby mediates myofibroblast transdifferentiation. Re-expression of endogenous fibroblast S100A4 rescues the myofibroblastic phenotype in S100A4 KO fibroblasts. Analysis of NMII-A/actin dynamics reveals that S100A4 mediates unraveling and redistribution of peripheral actomyosin to a central location, resulting in a contractile myofibroblast. Furthermore, S100A4 loss protects against murine in vivo pulmonary fibrosis, and S100A4 expression is dysregulated in IPF. Our data reveal a novel mechanosensor/effector role for endogenous fibroblast S100A4 in inducing cytoskeletal redistribution in fibrotic disorders such as IPF.


A 50-year-old woman addicted to heroin: review of treatment of heroin addiction.
Heroin addiction is a complicated medical and psychiatric issue, with well-established as well as newer modes of treatment. The case of Ms W, a 50-year-old woman with a long history of opiate addiction who has been treated successfully with methadone for 9 years and who now would like to consider newer alternatives, illustrates the complex issues of heroin addiction. The treatment of heroin addiction as a chronic disease is reviewed, including social, medical, and cultural issues and pharmacologic treatment with methadone and the more experimental medication options of buprenorphine and naltrexone.


Exercise frequency and maternal mental health: Parallel process modelling across the perinatal period in an Australian pregnancy cohort.
Since the potential mental health benefits of exercise during pregnancy remain unclear, this study examined longitudinally the bidirectional relationship between exercise and maternal mental health symptoms during the perinatal period, and included adjustment for both depression and antidepressant treatment. Data were collected across pregnancy (first and third trimesters) and the postpartum (six and 12 months) for 258 women drawn from an Australian pregnancy cohort, the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS). The women were assessed for depression using the EPDS, anxiety using the STAI and a clinical diagnostic interview (SCID-IV), and self-reported use of antidepressants. Exercise was measured using self-reported weekly frequency of 30-min bouts of moderate to vigorous exercise, and data were analyzed using parallel process growth curve modelling. On average, women's weekly exercise frequency declined during pregnancy, returning to first trimester levels by 12 months postpartum. Women with depression and taking antidepressants reported lower first trimester exercise compared to control women. However, where non-medicated depressed women remained lower and continued to decline to 12 months, women taking antidepressants reported increasing levels of exercise during the perinatal period. Notably, a steeper decline in exercise frequency during the perinatal period was associated with a faster rate of increase in depressive and anxiety symptoms. This study is the first to examine the longitudinal interaction between exercise and mental health symptoms across the perinatal period. These preliminary findings demonstrate potential benefits for depressive and anxious symptoms when maintaining levels of early-pregnancy exercise throughout pregnancy and the postpartum.


Methods for Developing Patient-Reported Outcome-Based Performance Measures (PRO-PMs).
To recommend methods for assessing quality of care via patient-reported outcome-based performance measures (PRO-PMs) of symptoms, functional status, and quality of life. A Technical Expert Panel was assembled by the American Medical Association-convened Physician Consortium for Performance Improvement. An environmental scan and structured literature review were conducted to identify quality programs that integrate PRO-PMs. Key methodological considerations in the design, implementation, and analysis of these PRO-PM data were systematically identified. Recommended methods for addressing each identified consideration were developed on the basis of published patient-reported outcome (PRO) standards and refined through public comment. Literature review focused on programs using PROs to assess performance and on PRO guidance documents. Thirteen PRO programs and 10 guidance documents were identified. Nine best practices were developed, including the following: provide a rationale for measuring the outcome and for using a PRO-PM; describe the context of use; select a measure that is meaningful to patients with adequate psychometric properties; provide evidence of the measure's sensitivity to differences in care; address missing data and risk adjustment; and provide a framework for implementation, interpretation, dissemination, and continuous refinement. Methods for integrating PROs into performance measurement are available.


Widespread disruption in brain activation patterns to a working memory task during cocaine abstinence.
Cocaine abstinence is associated with impaired performance in cognitive functions including attention, vigilance and executive function. Here we test the hypothesis that cognitive dysfunction during cocaine abstinence reflects in part impairment of cortical and subcortical regions modulated by dopamine. We used functional magnetic resonance imaging (fMRI) to study brain activation to a verbal working memory task in cocaine abusers (n=16) and healthy controls (n=16). Compared to controls, cocaine abusers showed: (1) hypoactivation in the mesencephalon, where dopamine neurons are located, as well as the thalamus, a brain region involved in arousal; (2) larger deactivation in dopamine projection regions (putamen, anterior cingulate, parahippocampal gyrus, and amygdala); and (3) hyperactivation in cortical regions involved with attention (prefrontal and parietal cortices), which probably reflects increased attention and control processes as compensatory mechanisms. Furthermore, the working memory load activation was lower in the prefrontal and parietal cortices in cocaine abusers when compared with controls, which might reflect limited network capacity. These abnormalities were accentuated in the cocaine abusers with positive urines for cocaine at time of study (as compared to cocaine abusers with negative urines) suggesting that the deficits may reflect in part early cocaine abstinence. These findings provide evidence of impaired function of regions involved with executive control, attention and vigilance in cocaine abusers. This widespread neurofunctional disruption is likely to underlie the cognitive deficits during early cocaine abstinence and to reflect involvement of dopamine as well as other neurotransmitters.


Regional differences in the ontogeny of the serotonergic projection to the cerebral cortex.
We used light and electron microscope immunocytochemistry to compare the development of the pattern of innervation and synaptic organization of the serotonin (5-HT) afferent system in sensory (visual and somatosensory) and motor areas of the rat cerebral cortex. Serotonin-labeled fibers were present in all cortical areas at birth appearing as two tangential streams, one above and one below the cortical plate. These fibers gradually arborized sending branches into all cortical layers in an "inside-out" sequence that broadly paralleled the gradient of neurogenesis and differentiation in the cortex. A striking feature at the early stages of postnatal development of the visual and somatosensory cortex was the transient presence of a dense accumulation of 5-HT fibers in layer IV. In agreement with earlier reports, transient aggregations of serotonergic axons characterized sensory but not motor areas of the cortex. The innervation pattern characteristic of the adult cortex was attained by the end of the 3rd postnatal week. Electron microscopic analysis of the developing visual cortex showed that 5-HT-containing axonal varicosities formed synaptic contacts, predominantly of the asymmetrical variety, throughout postnatal life. The proportion of varicosities forming synapses increased gradually from birth to reach a peak at the end of the 2nd week, then declined markedly in the subsequent week before rising again at later stages. It appears that the formation of exuberant synapses by 5-HT axons coincides with the period of maturation of the neuronal circuitry of this cortical area. When quantitative analysis was restricted only to layer IV, the proportion of varicosities forming synapses reached a peak at the end of the 1st week of life, when transient innervation was most prominent in this layer. These results suggest that the effects of this dense band of serotonergic axons may be mediated through axodendritic synapses. The types of postsynaptic elements involved in the formation of synapses varied according to age, suggesting progressive morphological differentiation of cortical target neurons or, alternatively, a continuous process of removal and establishment of new connections by 5-HT axons in the visual cortex. In contrast, analysis in the motor cortex revealed a continuous increase in the proportion of 5-HT varicosities engaged in synaptic contacts from birth to the late sages of development. The results presented here provide anatomical evidence for a differential role of 5-HT in the maturation of the cerebral cortex.


Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats.
Nonalcoholic fatty liver disease (NAFLD) can develop into end-stage disease that includes cryptogenic cirrhosis and hepatocellular carcinoma. Bacterial endotoxin, for example lipopolysaccharide (LPS), plays an important role in the pathogenesis of NAFLD. The aim of this study was to assess the role of LPS in the development of NAFLD. Twenty-one male Zucker (fa/fa) rats were divided into three groups: rats fed for twelve weeks on a diet rich in disaccharide (D12 group), rats similarly managed but treated with LPS (LPS group), and those on the same diet for 24 weeks (D24 group). Histological examination demonstrated that this protocol induced hepatic steatosis in the LPS and D24 groups. Significant, marked accumulation of lipid droplets was observed in the LPS group, compared with the D24 group. Rats from the LPS group showed a decrease in plasma adiponectin levels, an increase in plasma leptin levels, and greater expression of FAS and SREBP-1c mRNA in the liver, compared with rats from the D24 group. These finding coincided with histological findings. We therefore suggest that LPS may accelerate the progression of hepatic steatosis.


Coupling of ecosystem-scale plant water storage and leaf phenology observed by satellite.
Plant water storage is fundamental to the functioning of terrestrial ecosystems by participating in plant metabolism, nutrient and sugar transport, and maintenance of the integrity of the hydraulic system of the plant. However, a global view of the size and dynamics of the water pools stored in plant tissues is still lacking. Here, we report global patterns of seasonal variations in ecosystem-scale plant water storage and their relationship with leaf phenology, based on space-borne measurements of L-band vegetation optical depth. We find that seasonal variations in plant water storage are highly synchronous with leaf phenology for the boreal and temperate forests, but asynchronous for the tropical woodlands, where the seasonal development of plant water storage lags behind leaf area by up to 180 days. Contrasting patterns of the time lag between plant water storage and terrestrial groundwater storage are also evident in these ecosystems. A comparison of the water cycle components in seasonally dry tropical woodlands highlights the buffering effect of plant water storage on the seasonal dynamics of water supply and demand. Our results offer insights into ecosystem-scale plant water relations globally and provide a basis for an improved parameterization of eco-hydrological and Earth system models.


Emergency department use after outpatient thyroidectomy across three states.
Although outpatient thyroidectomy has become common, few large-scale studies have examined post-thyroidectomy emergency department use, readmission, and encounters not resulting in readmission, known as "treat-and-release" encounters. We evaluated post-outpatient thyroidectomy emergency department use and readmission and characterized associated factors. Using the Healthcare Cost and Utilization Project databases, we identified adult outpatient (same-day or <24-hour discharge) thyroidectomies performed in Florida, Maryland, and New York from 2016 to 2017. We identified the procedures linked with emergency department treat-and-release encounters and readmissions within 30 days postoperatively and the factors associated with post-thyroidectomy emergency department use and readmission. Of the 17,046 patients who underwent outpatient thyroidectomy at 374 facilities, 7.5% had emergency department treat-and-release encounters and 2.3% readmissions. The most common reasons for emergency department treat-and-release encounters (9.9%) and readmissions (22.2%) were hypocalcemia-related diagnoses. Greater odds of treat-and-release were associated with identifying as non-Hispanic Black (adjusted odds ratio: 1.5, 95% confidence interval: 1.3-1.8) or Hispanic race/ethnicity (adjusted odds ratio: 1.4, 95% CI: 1.1-1.6), having Medicaid insurance (adjusted odds ratio: 2.7, 95% CI: 2.3-3.2), and living in non-metropolitan areas (adjusted odds ratio: 1.6, 95% CI: 1.1-2.2). We observed no associations between these factors and the odds of readmission. Emergency department use after outpatient thyroidectomy is common. Racial, ethnic, socioeconomic, and geographic disparities are associated with treat-and-release encounters but not readmissions. Standardization of perioperative care pathways, focusing on identifying and addressing specific issues in vulnerable populations, could improve care, reduce disparities, and improve patient experience by avoiding unnecessary emergency department visits after outpatient thyroidectomy.


Nutrients for cognitive development in school-aged children.
This review considers the research to date on the role of nutrition in cognitive development in children, with a particular emphasis on the relatively neglected post-infancy period. Undernutrition and deficiencies of iodine, iron, and folate are all important for the development of the brain and the emergent cognitive functions, and there is some evidence to suggest that zinc, vitamin B12, and omega-3 polyunsaturated fatty acids may also be important. Considerations for future research include a focus on the interactions between micronutrients and macronutrients that might be influential in the optimization of cognitive development; investigation of the impact of nutritional factors in children after infancy, with particular emphasis on effects on the developing executive functions; and selection of populations that might benefit from nutritional interventions, for example, children with nutrient deficiencies or those suffering from attention deficit-hyperactivity disorder and dyslexia.


Detection of malingering on the Luria-Nebraska Neuropsychological Battery: an initial and cross-validation.
A formula for detecting faked LNNB profiles was validated on 68 experimental malingerers and adequately motivated patients matched on education, age, and severity of profile. The formula was then cross-validated on 51 malingerers and 202 patients. The formula yielded a cross-validated 23% false negative rate and a 9% false positive rate, for an overall hit rate of 88%. If normal and profoundly impaired profiles are eliminated from the cross-validation analysis, the false negative rate is 17% and the false positive rate 7%, for an overall hit rate of 91%.


Dynamic changes in the osmotic water permeability of protoplast plasma membrane.
The osmotic water permeability coefficient (P(f)) of plasma membrane of maize (Zea mays) Black Mexican Sweet protoplasts changed dynamically during a hypoosmotic challenge, as revealed using a model-based computational approach. The best-fitting model had three free parameters: initial P(f), P(f) rate-of-change (slope(P(f))), and a delay, which were hypothesized to reflect changes in the number and/or activity of aquaporins in the plasma membrane. Remarkably, the swelling response was delayed 2 to 11 s after start of the noninstantaneous (but accounted for) bath flush. The P(f) during the delay was < or =1 microm s(-1). During the swelling period following the delay, P(f) changed dynamically: within the first 15 s P(f) either (1) increased gradually to approximately 8 microm s(-1) (in the majority population of low-initial-P(f) cells) or (2) increased abruptly to 10 to 20 microm s(-1) and then decreased gradually to 3 to 6 microm s(-1) (in the minority population of high-initial-P(f) cells). We affirmed the validity of our computational approach by the ability to reproduce previously reported initial P(f) values (including the absence of delay) in control experiments on Xenopus oocytes expressing the maize aquaporin ZmPIP2;5. Although mercury did not affect the P(f) in swelling Black Mexican Sweet cells, phloretin, another aquaporin inhibitor, inhibited swelling in a predicted manner, prolonging the delay and slowing P(f) increase, thereby confirming the hypothesis that P(f) dynamics, delay included, reflected the varying activity of aquaporins.


Direct exposure at the air-liquid interface: evaluation of an in vitro approach for simulating inhalation of airborne substances.
In toxicology, the strategies for testing the hazardous potential of substances are changing as a result of the ongoing progress in the development of in vitro methods and the demand of the authorities to reduce animal testing. Even in the complex field of inhalation toxicology with its high requirements on the technical implementation and cell culture models, the preconditions for using such methods are fulfilled. We here introduce a sophisticated technique that enables the stable and reproducible exposure of cultivated cells to airborne substances at the air-liquid interface by means of the CULTEX(®) Radial Flow System (RFS) module. The feasibility and suitability of the experimental setup is demonstrated by dose-response investigations of mainstream cigarette smoke and particulate matter of four substances in different lung epithelial cell lines. A dose-dependent cytotoxcity of the test substances was verified by applying different exposure times. The high reproducibility of the results indicate the reliability of the presented method and recommend the integration of such in vitro approaches in the field of inhalation toxicology by advancing their regulatory validation.