Goal- and signal-directed incentive: conditioned approach, seeking, and consumption established with unsweetened alcohol in rats.
Many theories of addictive behavior propose that cues signaling drug administration influence the likelihood of drug-taking and drug-seeking behavior. We investigated the behavioral impact of cues associated with unsweetened ethanol and their interaction with responding maintained by ethanol self-administration. Our goal was to establish the influence of such cues on ethanol seeking. The experiment used a matching contingency and saccharin-fading procedure to establish equal levels of responding to two spatially distinct levers using unsweetened 10% ethanol solution. After ethanol self-administration was established, a brief cue light located alternately over each lever location was either paired or unpaired (control) with the opportunity to consume the same ethanol solution. Finally, self-administration was re-established, and the effect of the cue was measured in a transfer design. The reaction to lights paired with the opportunity to ingest unsweetened ethanol had three main effects: (1) induction of operant behavior reinforced by ethanol, (2) stimulation of ethanol-seeking behavior (drinker entries), and (3) cue-directed approach and contact behavior (i.e. autoshaping or sign-tracking). Cue-directed behavior to the light interacted with choice behavior in a manner predicted by the location of the cue light, enhancing responding only when the approach response did not interfere with the operant response. These findings replicate and extend the effects of Pavlovian conditioning on ethanol-seeking and support-conditioned incentive theories of addictive behavior. Signals for ethanol influence spatial choice behavior and may be relevant to attentional bias shown to alcohol-associated stimuli in humans.


Modification of a Validated Risk Stratification Tool to Characterize Geriatric Hip Fracture Outcomes and Optimize Care in a Post-COVID-19 World.
(1) To demonstrate how a risk assessment tool modified to account for the COVID-19 virus during the current global pandemic is able to provide risk assessment for low-energy geriatric hip fracture patients. (2) To provide a treatment algorithm for care of COVID-19 positive/suspected hip fractures patients that accounts for their increased risk of morbidity and mortality. One academic medical center including 4 Level 1 trauma centers, 1 university-based tertiary care referral hospital, and 1 orthopaedic specialty hospital. One thousand two hundred seventy-eight patients treated for hip fractures between October 2014 and April 2020, including 136 patients treated during the COVID-19 pandemic between February 1, 2020 and April 15, 2020. The Score for Trauma Triage in the Geriatric and Middle-Aged ORIGINAL (STTGMAORIGINAL) score was modified by adding COVID-19 virus as a risk factor for mortality to create the STTGMACOVID score. Patients were stratified into quartiles to demonstrate differences in risk distribution between the scores. Inpatient and 30-day mortality, major, and minor complications. Both STTGMA score and COVID-19 positive/suspected status are independent predictors of inpatient mortality, confirming their use in risk assessment models for geriatric hip fracture patients. Compared with STTGMAORIGINAL, where COVID-19 patients are haphazardly distributed among the risk groups and COVID-19 inpatient and 30 days mortalities comprise 50% deaths in the minimal-risk and low-risk cohorts, the STTGMACOVID tool is able to triage 100% of COVID-19 patients and 100% of COVID-19 inpatient and 30 days mortalities into the highest risk quartile, where it was demonstrated that these patients have a 55% rate of pneumonia, a 35% rate of acute respiratory distress syndrome, a 22% rate of inpatient mortality, and a 35% rate of 30 days mortality. COVID-19 patients who are symptomatic on presentation to the emergency department and undergo surgical fixation have a 30% inpatient mortality rate compared with 12.5% for patients who are initially asymptomatic but later develop symptoms. The STTGMA tool can be modified for specific disease processes, in this case to account for the COVID-19 virus and provide a robust risk stratification tool that accounts for a heretofore unknown risk factor. COVID-19 positive/suspected status portends a poor outcome in this susceptible trauma population and should be included in risk assessment models. These patients should be considered a high risk for perioperative morbidity and mortality. Patients with COVID-19 symptoms on presentation should have surgery deferred until symptoms improve or resolve and should be reassessed for surgical treatment versus definitive nonoperative treatment with palliative care and/or hospice care. Prognostic Level III. See Instructions for Authors for a complete description of Levels of Evidence.


A study to look at the effects of a hydrolat spray on hot flushes in women being treated for breast cancer.
Women undergoing treatment for breast cancer may experience hot flushes, which greatly impact on quality of life. The use of water sprays or moist wipes to lower skin temperature is often recommended. A peppermint and neroli hydrolat spray was compared to a plain water spray to assess which was preferred, in a single-blind randomised control crossover trial. Only 18 of the 44 patients (41%) preferred the hydrolat spray to a plain water spray, which was less than the 80% required to offer this spray as a standard suggestion for hot flush management. However a small number of those choosing it found it extremely helpful. Both sprays appeared to lessen hot flush annoyance. Previous chemotherapy appeared to be a factor influencing the choice of spray.


HtrA2/Omi is involved in 6-OHDA-induced endoplasmic reticulum stress in SH-SY5Y cells.
Endoplasmic reticulum (ER) stress has been shown to be associated with the pathogenesis of neurodegenerative disorders including Parkinson's disease (PD). HtrA2/Omi, from its participation in protein quality control, is involved in ER stress. However, little is known about the relationship between HtrA2/Omi and ER stress in PD. Here, we explored the association of HtrA2/Omi and ER stress in a cell model of PD and found that the expression level of HtrA2/Omi decreased with ER stress induction in 6-OHDA-treated SH-SY5Y cells. Furthermore, silencing endogenous expression of HtrA2/Omi with siRNA resulted in aggregated ER stress and cell death. Taken together, our results show that HtrA2/Omi may exert a protective function in 6-OHDA-induced cell death by regulating ER stress-related proteins. This research offers some clues as why mutations in HtrA2/Omi lead to higher susceptibility in some PD patients.


Decoupling hydrogen and oxygen evolution during electrolytic water splitting using an electron-coupled-proton buffer.
Hydrogen is essential to several key industrial processes and could play a major role as an energy carrier in a future 'hydrogen economy'. Although the majority of the world's hydrogen supply currently comes from the reformation of fossil fuels, its generation from water using renewables-generated power could provide a hydrogen source without increasing atmospheric CO₂ levels. Conventional water electrolysis produces H₂ and O₂ simultaneously, such that these gases must be generated in separate spaces to prevent their mixing. Herein, using the polyoxometalate H₃PMo₁₂O₄₀, we introduce the concept of the electron-coupled-proton buffer (ECPB), whereby O₂ and H₂ can be produced at separate times during water electrolysis. This could have advantages in preventing gas mixing in the headspaces of high-pressure electrolysis cells, with implications for safety and electrolyser degradation. Furthermore, we demonstrate that temporally separated O₂ and H₂ production allows greater flexibility regarding the membranes and electrodes that can be used in water-splitting cells.


Recombinant Hep G2 cells that express alcohol dehydrogenase and cytochrome P450 2E1 as a model of ethanol-elicited cytotoxicity.
HepG2 cells were transfected with recombinant plasmids, one carrying the murine alcohol dehydrogenase (ADH) gene and the other containing the gene encoding human cytochrome P450 2E1 (CYP2E1). One of recombinant clones called VL-17A exhibited ADH and CYP2E1 specific activities comparable to those in isolated rat hepatocytes. VL-17A cells oxidized ethanol and generated acetaldehyde, the levels of which depended upon the initial ethanol concentration. Compared with unexposed VL-17A cells, ethanol exposure increased the cellular redox (lactate:pyruvate ratio) and caused cell toxicity, indicated by increased leakage of lactate dehydrogenase into the medium,. Exposure of VL-17A cells to 100mM ethanol significantly elevated caspase 3 activity, an indicator of apoptosis, but this ethanol concentration did not affect caspase 3 activity in parental HepG2 cells. Because ethanol consumption causes a decline in hepatic protein catabolism, we examined the influence of ethanol exposure on proteasome activity in HepG2, VL-17A, E-47 (CYP2E1(+)) and VA-13 (ADH(+)) cells. Exposure to 100mM ethanol caused a 25% decline in the chymotrypsin-like activity of the proteasome in VL-17A cells, but the enzyme was unaffected in the other cell types. This inhibitory effect on the proteasome was blocked when ethanol metabolism was blocked by 4-methyl pyrazole. We conclude that recombinant VL-17A cells, which express both ADH and CYP2E1 exhibit hepatocyte-like characteristics in response to ethanol. Furthermore, the metabolism of ethanol by these cells via ADH and CYP2E1 is sufficient to bring about an inhibition of proteasome activity that may lead to apoptotic cell death.


Altered Gut Microbiota and Host Metabolite Profiles in Women With Human Immunodeficiency Virus.
Alterations in gut microbiota (GMB) and host metabolites have been noted in individuals with HIV. However, it remains unclear whether alterations in GMB and related functional groups contribute to disrupted host metabolite profiles in these individuals. This study included 185 women (128 with longstanding HIV infection, 88% under antiretroviral therapy; and 57 women without HIV from the same geographic location with comparable characteristics). Stool samples were analyzed by 16S rRNA V4 region sequencing, and GMB function was inferred by PICRUSt. Plasma metabolomic profiling was performed using liquid chromatography-tandem mass spectrometry, and 133 metabolites (amino acids, biogenic amines, acylcarnitines, and lipids) were analyzed. Four predominant bacterial genera were identified as associated with HIV infection, with higher abundances of Ruminococcus and Oscillospira and lower abundances of Bifidobacterium and Collinsella in women with HIV than in those without. Women with HIV showed a distinct plasma metabolite profile, which featured elevated glycerophospholipid levels compared with those without HIV. Functional analyses also indicated that GMB lipid metabolism was enriched in women with HIV. Ruminococcus and Oscillospira were among the top bacterial genera contributing to the GMB glycerophospholipid metabolism pathway and showed positive correlations with host plasma glycerophospholipid levels. One bacterial functional capacity in the acetate and propionate biosynthesis pathway was identified to be mainly contributed by Bifidobacterium; this functional capacity was lower in women with HIV than in women without HIV. Our integrative analyses identified altered GMB with related functional capacities that might be associated with disrupted plasma metabolite profiles in women with HIV.


Neurotherapeutic and antioxidant response of D-ribose-L-Cysteine nutritional dietary supplements on Alzheimer-type hippocampal neurodegeneration induced by cuprizone in adult male wistar rat model.
Cuprizone is a neurotoxicant causing neurodegeneration through enzymes inhibition and oxidative stress. D-Ribose-L-Cysteine (DRLC) is a powerful antioxidant with neuroprotective properties. This study explored the antioxidant response of DRLC against cuprizone-induced behavioral alterations, biochemical imbalance and hippocampal neuronal damage in adult wistar rats. Thirty two (32) adult male wistar rats (150-200g) were divided into four groups (n = 8). Group A received normal saline only as placebo; Group B received 0.5% cuprizone diet only; Group C received a combination of 0.5% cuprizone diet and 100 mg/kg bw of DRLC and Group D received 100 mg/kg bw of DRLC only. The administration was done through oral gavage once daily for 45 days. After the last treatment, neurobehavioral tests (Morris Water Maze and Y maze) was conducted; animals sacrificed and brain harvested for histological analysis and biochemical estimations of levels of antioxidants, oxidative stress markers, neurotransmitters and enzyme activitties. The results showed significant memory decline, hippocampal alterations, decrease levels of antioxidant markers, enzyme and neurotransmitters activities with concomitant increase in norepinephrine and oxidative stress markers in cuprizone induced rats relative to normal but was attenuated with DRLC administration. Cuprizone causes cognitive impairment and neurodegeneration through oxidative stress; however, administration of DRLC ameliorated neuropathological alteration induced by cuprizone.


Effect of exposure routes on the relationships of lethal toxicity to rats from oral, intravenous, intraperitoneal and intramuscular routes.
The lethal toxicity values (log 1/LD(50)) of 527 aliphatic and aromatic compounds in oral, intravenous, intramuscular and intraperitoneal routes were used to investigate the relationships of log 1/LD(50) from different exposure routes. Regression analysis shows that the log 1/LD(50) values are well correlated between intravenous and intraperitoneal or intramuscular injections. However, the correlations between oral and intravenous or intraperitoneal routes are relatively poor. Comparison of the average residuals indicates that intravenous injection is the most sensitive exposure route and oral administration is the least sensitive exposure route. This is attributed to the difference in kinetic process of toxicity testing. The toxic effect of a chemical can be similar or significantly different between exposure routes, depending on the absorption rates of chemicals into blood. Inclusion of hydrophobic parameter and fractions of ionic forms can improve the correlations between intravenous and intraperitoneal or oral routes, but not between intraperitoneal and oral routes. This is due to the differences of absorption rate in different exposure environments from different routes. Several factors, such as experimental uncertainty, metabolism and toxic kinetics, can affect the correlations between intravenous and intraperitoneal or oral routes.


Total antioxidant capacity, hydrogen peroxide, malondialdehyde and total nitric oxide concentrations in patients with severe persistent allergic asthma: its relation to omalizumab treatment.
Asthma is a chronic inflammatory disease and omalizumab is indicated for moderate-to-severe persistent asthma. The results of many studies have shown that oxidative stress is involved in asthma pathogenesis. However, there is no data available to evaluate the alterations in total antioxidant capacity, hydrogen peroxide, malondialdehyde, and total nitric oxide concentrations. The objective was to determine whether treatment with omalizumab in severe allergic asthma influences systemic levels of oxidative stress markers. The first group of 14 patients included 6 male and 8 female subjects with severe persistent asthma, having a mean age of 42.4 years. The second group included 14 newly diagnosed allergic asthma patients with a mean age of 43.8 years. All patients were followed in the Immunology and Allergy Clinic of the Antalya Education and Training Hospital and were evaluated by clinical status. A third group of 14 age-sex matched healthy controls were also included. Serum samples were collected and stored at -70 degrees C until use for the determination of total antioxidant capacity, hydrogen peroxide, malondialdehyde, and total nitric oxide concentrations. Serum IgE levels, ANA (antinuclear antibody), RF (rheumatoid factor), hepatitis markers, C3, C4, and eosinophil levels were evaluated in all patients. All assays were carried out in duplicate. The mean IgE levels were as follow: Group I: 459.785 IU/mL; Group II: 124.8 IU/mL, and Group III: 39.88 IU/mL. Total antioxidant capacity levels of Group IB, group II, and group III were lower than the IA group. Total antioxidant capacity levels of groups II and III were higher than in group IB. Hydrogen peroxide concentrations in group IB were lower than in group IA, while concentrations in group II were higher than in group IB. The malondialdehyde concentration of group IB was lower than in all other groups. The malondialdehyde concentration of group III was higher than all other groups. The malondialdehyde concentration of group II was lower than in group III. The total nitric oxide level of group IB was lower than all other groups. The total nitric oxide level of group III was higher than all other groups, while that of group II was higher than for both groups IA/IB. To monitor the omalizumab treatment efficacy in severe allergic asthma patients, total antioxidant capacity, hydrogen peroxide, malondialdehyde, and total nitric oxide concentrations might be new markers.


PROMIS Global-10 performs poorly relative to legacy shoulder instruments in patients undergoing total shoulder arthroplasty for glenohumeral arthritis.
The PROMIS Global-10 is a 10-item questionnaire that assesses general health-related quality of life. There is a paucity of research on the utility of the PROMIS Global-10 in the evaluation of orthopedic conditions. The aim of this study is to compare PROMIS Global-10 and legacy shoulder-specific patient-reported outcome measures (PROMs) in patients undergoing total shoulder arthroplasty (TSA) for shoulder arthritis. This retrospective cohort study included patients who underwent TSA for shoulder arthritis and completed preoperative and 1-year postoperative surveys. Primary outcome measures were the physical (PROMIS-P) and mental (PROMIS-M) components of PROMIS Global-10. The legacy PROMs included the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score, the Single Assessment Numeric Evaluation (SANE), and the Shoulder Activity Scale (SAS). Analyses included postoperative changes for each outcome, correlations between measures and a responsiveness assessment. A total of 170 patients met inclusion criteria. Average age and body mass index were 67.7 ± 7.8 years and 28.0 ± 4.9, respectively. All legacy PROMs and PROMIS-P were significantly higher at 1-year follow-up compared with the preoperative level (P < .0001), whereas PROMIS-M did not change (P = .06). Preoperatively, both PROMIS components were either poorly correlated with all legacy PROMs (r < .04, P < .05) or not correlated at all (P > .05). Postoperatively, PROMIS-M was poorly correlated with all legacy PROMs (r < .04, P < .01), whereas PROMIS-P had fair correlation with ASES (r = .5, P < .0001) and poor correlation with SANE and SAS (r < .04, P < .01). A floor effect was observed for SANE, and SANE and ASES had a ceiling effect. The effect sizes for SANE and ASES were high (d = 2.01 and 2.39 respectively), whereas the effect size for SAS was moderate (d = 0.65), and the effect sizes for the PROMIS measures were small (d < .5). ASES was the most responsive measure and PROMIS-M was the least responsive. PROMIS Global-10 had limited correlation with legacy PROMs and was less responsive at 1-year follow-up in patients following TSA. The Global-10 appears to have limited utility in the evaluation of patients with shoulder arthritis both preoperatively and after TSA.


Concurrent task performance enhances low-level visuomotor learning.
Visuomotor association learning involves learning to make a motor response to an arbitrary visual stimulus. This learning is essential for visual search and discrimination performance and is reliant upon a well-defined neural circuit in the brain that includes the prefrontal cortex and the hippocampal formation. In the present study, we investigated the possible role of attentional processes during such learning using dual-task interference. A motor, verbal, or perceptual concurrent task was performed during the learning/training block of a simple visual discrimination task. Contrary to expectation, the dual-task groups showed improved learning and learning-dependent performance compared with untrained control and non-dual-task trained groups. A second experiment revealed that this effect did not appear to be due to increased arousal level; the inclusion of alerting tones during learning did not result in facilitation. These findings suggest that the engagement of attention, but not arousal, during the acquisition of a visuomotor association can facilitate this learning and its expression.


Absence from work and emotional stress in women undergoing IVF or ICSI: an analysis of IVF-related absence from work in women and the contribution of general and emotional factors.
To assess productivity losses due to absence from work during in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment and to describe the pattern of IVF-related absence from work. Additionally, the influence of general and psychological variables on IVF-related absence from work was analyzed. Prospective cohort study. Eight IVF hospitals participated in the study. Women undergoing their first treatment with IVF/ICSI. The Health and Labour Questionnaire (HLQ) was used to estimate the costs of IVF-related absence from work (n=384). Diaries were used to collect background information and reasons for IVF-related absence. Psychological data were derived using the Spielberger State and Trait Anxiety Inventory (STAI), the Beck Depression Inventory for Primary Care (BDI-PC) and the Inventory Social Relations and the Illness Cognition Questionnaire. Regression analyses were performed using two models, one without and one with psychological data, to assess the impact of the different variables on IVF-related absence from work. IVF-related absence from work and the costs of productivity losses due to IVF/ICSI per treatment. Overall absence from work during IVF/ICSI treatment was on average 33 hours, of which 23 hours were attributed to IVF/ICSI. Costs of productivity losses due to IVF/ICSI were euro596 per woman. Significant predictors of IVF-related absence from work were the number of hours of paid work, age and self-reported physical and/or emotional problems due to IFV treatment. Women experiencing emotional complaints and women with physical complaints due to IVF/ICSI reported significantly more IVF-related absence from work.


Retraction: "Computational pulmonary edema: A microvascular model of alveolar capillary and interstitial flow" [APL Bioeng. 6, 046104 (2022)].
[This retracts the article DOI: 10.1063/5.0109107.].


Genome sequence comparison of two United States live attenuated vaccines of infectious laryngotracheitis virus (ILTV).
This study was conducted to identify unique nucleotide differences in two U.S. chicken embryo origin (CEO) vaccines [LT Blen (GenBank accession: JQ083493) designated as vaccine 1; Laryngo-Vac(®) (GenBank accession: JQ083494) designated as vaccine 2] of infectious laryngotracheitis virus (ILTV) genomes compared to an Australian Serva vaccine reference ILTV genome sequence [Gallid herpesvirus 1 (GaHV-1); GenBank accession number: HQ630064]. Genomes of the two vaccine ILTV strains were sequenced using Illumina Genome Analyzer 2X of 36 cycles of single-end reads. Results revealed that few nucleotide differences (23 in vaccine 1; 31 in vaccine 2) were found and indicate that the US CEO strains are practically identical to the Australian Serva CEO strain, which is a European-origin vaccine. The sequence differences demonstrated the spectrum of variability among vaccine strains. Only eight amino acid differences were found in ILTV proteins including UL54, UL27, UL28, UL20, UL1, ICP4, and US8 in vaccine 1. Similarly, in vaccine 2, eight amino acid differences were found in UL54, UL27, UL28, UL36, UL1, ICP4, US10, and US8. Further comparison of US CEO vaccines to several ILTV genome sequences revealed that US CEO vaccines are genetically close to both the Serva vaccine and 63140/C/08/BR (GenBank accession: HM188407) and are distinct from the two Australian-origin CEO vaccines, SA2 (GenBank accession: JN596962) and A20 (GenBank accession: JN596963), which showed close similarity to each other. These data demonstrate the potential of high-throughput sequencing technology to yield insight into the sequence variation of different ILTV strains. This information can be used to discriminate between vaccine ILTV strains and further, to identify newly emerging mutant strains of field isolates.


Multi-omics approaches in psychoneuroimmunology and health research: Conceptual considerations and methodological recommendations.
The field of psychoneuroimmunology (PNI) has grown substantially in both relevance and prominence over the past 40 years. Notwithstanding its impressive trajectory, a majority of PNI studies are still based on a relatively small number of analytes. To advance this work, we suggest that PNI, and health research in general, can benefit greatly from adopting a multi-omics approach, which involves integrating data across multiple biological levels (e.g., the genome, proteome, transcriptome, metabolome, lipidome, and microbiome/metagenome) to more comprehensively profile biological functions and relate these profiles to clinical and behavioral outcomes. To assist investigators in this endeavor, we provide an overview of multi-omics research, highlight recent landmark multi-omics studies investigating human health and disease risk, and discuss how multi-omics can be applied to better elucidate links between psychological, nervous system, and immune system activity. In doing so, we describe how to design high-quality multi-omics studies, decide which biological samples (e.g., blood, stool, urine, saliva, solid tissue) are most relevant, incorporate behavioral and wearable sensing data into multi-omics research, and understand key data quality, integration, analysis, and interpretation issues. PNI researchers are addressing some of the most interesting and important questions at the intersection of psychology, neuroscience, and immunology. Applying a multi-omics approach to this work will greatly expand the horizon of what is possible in PNI and has the potential to revolutionize our understanding of mind-body medicine.


Lack of diurnal variation in maximal symptom-limited exercise test response in chronic stable angina.
Exercise testing is widely used to evaluate the effects of anti-ischemic drugs. Many studies have reported good reproducibility when it is performed in the morning, but little information is available regarding the diurnal variation of exercise test response in patients with chronic stable angina. With the advent of new long-acting anti-ischemic drugs, it has become necessary to perform the exercise testing at various times of the day to determine the duration of action of a given drug. To examine the diurnal variation, exercise tests were performed on 41 patients, aged 53 to 75 years, with established chronic stable angina on 2 occasions 5 days apart at 10 A.M. and 4 P.M. on each day. On day 1, the mean +/- standard error of the mean exercise time was 5.0 +/- 0.4 minutes at 10 A.M. and 5.1 +/- 0.4 minutes at 4 P.M., and on day 5, it was 5.6 +/- 0.4 minutes at 10 A.M. and 5.5 +/- 0.4 minutes at 4 P.M. These values did not differ in statistical significance. Similarly, the time to the development of 1 mm of ST-segment depression did not show any statistically significant change during either test period on either day nor did maximal ST-segment depression. Heart rate at rest was 79 +/- 3 beats/min at 10 A.M., 81 +/- 3 beats/min at 4 P.M. on day 1 and 78 +/- 2 beats/min at 10 A.M. and 80 +/- 3 beats/min at 4 P.M. on day 5 (difference not significant). Similarly, no significant changes were observed in maximal heart rate or rate-pressure product at peak exercise.(ABSTRACT TRUNCATED AT 250 WORDS)


[Health related quality of life in type 1 diabetes mellitus].
The daily impact of DM1 treatment on the psychological aspects of patients, scientifically proven, and the need for preventive and educational approaches in the care processes of this chronic disease, leads to consider the importance of studying the health-related quality of life (HRQOL) during the childhood and adolescence stages. a) To assess the dimensions of HRQoL most affected by the disease, and b) to determine its variation as a function of the school year, sex and number of years from diagnosis. An applied-descriptive study was used. The sample consisted of 126 patients from 6 to 18 years with type 1 diabetes, controlled in four public hospitals in Extremadura. The questionnaire measuring HRQoL is the Spanish version of EQ-5D-Y. The most affected dimension for the total sample is anxiety/depression, with a significant difference in the adolescent group (P=.004). It is necessary to consider the HRQOL assessment should be considered in adolescence, with special attention to the psychological aspects in the proposed treatment and design of educational interventions.


Hormonal influences on seizures: basic neurobiology.
There are sex differences and effects of steroid hormones, such as androgens, estrogens, and progestogens, that influence seizures. Androgens exert early organizational and later activational effects that can amplify sex/gender differences in the expression of some seizure disorders. Female-typical sex steroids, such as estrogen (E2) and progestins, can exert acute activational effects to reduce convulsive seizures and these effects are mediated in part by the actions of steroids in the hippocampus. Some of these anticonvulsive effects of sex steroids are related to their formation of ligands which have agonist-like actions at gamma-aminobutyric acid (GABAA) receptors or antagonist actions at glutamatergic receptors. Differences in stress, developmental phase, reproductive status, endocrine status, and treatments, such as anti-epileptic drugs (AEDs), may alter levels of these ligands and/or the function of target sites, which may mitigate differences in sensitivity to, and/or tolerance of, steroids among some individuals. The evidence implicating sex steroids in differences associated with hormonal, reproductive, developmental, stress, seizure type, and/or therapeutics are discussed.


Esmolol versus ketamine-remifentanil combination for early postoperative analgesia after laparoscopic cholecystectomy: a randomized controlled trial.
Controversy surrounds the optimal technique to moderate pain after laparoscopic cholecystectomy (LC). Opioid analgesics, sympatholytic drugs, and adjuvants, such as ketamine, have all been used. We compared esmolol with a combination of remifentanil plus ketamine in patients undergoing LC to determine the impact of these drugs on morphine requirements and pain control. Sixty American Society of Anesthesiologists physical status I-II patients undergoing LC and anesthetized with sevoflurane were randomized to one of two groups. Group E patients received a bolus of esmolol 0.5 mg·kg(-1) iv at induction followed by an infusion of 5-15 μg·kg(-1)·min(-1), and Group R-K patients received a bolus of ketamine 0.5 mg·kg(-1) iv and remifentanil 0.5 μg·kg(-1) iv at induction followed by a remifentanil infusion titrated over a range of 0.1-0.5 μg·kg(-1)·min(-1). All patients received paracetamol, dexketoprofen, and levobupivacaine via infiltration of laparoscopic port sites. After surgery, a predetermined bolus of morphine was administered according to a verbal numerical rating scale (VNRS) for pain intensity. The primary outcome of interest was postoperative morphine requirement. Median consumption of morphine was higher in Group R-K than in Group E (5 mg [4-6] vs 0 mg [0-2], respectively; P < 0.001). In the postanesthesia care unit, patients in Group R-K had higher pain scores than patients in Group E (difference in maximum VNRS, -11; 95% confidence interval (CI), -19 to -3). The concentration of sevoflurane to maintain a bispectral index~40 was higher in Group E than in Group R-K (between-group difference 0.3%; 95% CI, 0.15 to 0.40). The incidence of postoperative nausea and vomiting was similar between the two groups. Intraoperative esmolol infusion reduces morphine requirements and provides more effective analgesia compared with a combination of remifentanil-ketamine given by infusion in patients undergoing LC.


Stent-supported angioplasty for acute stroke caused by carotid dissection.
Carotid dissection is a less common but important cause of acute ischemic stroke, which has specific treatment implications. We describe the case of a patient with acute, fluctuating neurological symptoms found to be caused by carotid dissection who underwent endovascular stent-supported angioplasty of this lesion with good outcome. Pros and cons of the various treatment options encountered in this case including intravenous thrombolysis, angioplasty and stenting, and antithrombotic therapy are discussed. Endovascular treatment of carotid dissection in acute stroke can be performed safely. Treatment must ultimately be individualized to each specific case.


Analysis of datasets showing which compounds kill which organisms: inferring two systems.
Experiments are sometimes conducted to show which of several compounds is successful at inactivating which of several microorganisms. This paper proposes a method of analysing the datasets obtained. The example refers to 33 compounds (2,4-dihydroxythiobenzanilides) and seven microorganisms (dermatophytes) [data from Eur. J. Med. Chem. 35 (2000) 393]. The conclusion is that two systems or modes of action are needed to explain the data.


Inhibition of MAPK/ERK pathway promotes oligodendrocytes generation and recovery of demyelinating diseases.
Oligodendrocytes (OLs) are the myelinating glia of the central nervous system. Injury to OLs causes myelin loss. In demyelinating diseases, such as multiple sclerosis, the remyelination is hindered principally due to a failure of the oligodendrocyte precursor cells (OPCs) to differentiate into mature OLs. To identify inducers of OPC to OL differentiation, a high-throughput screening based on myelin basic protein expression using neural progenitor cells-derived OPCs has been performed and, PD0325901-an MEK (MAPK kinase) inhibitor-is found to significantly enhance OPC to OL differentiation in a dose- and time-dependent manner. Other MEK inhibitors also display similar effect, indicating blockade of MAPK-ERK signaling is sufficient to induce OPC differentiation into OLs. PD0325901 facilitates the formation of myelin sheaths in OPC-neuron co-culture in vitro. And in experimental autoimmune encephalomyelitis model and cuprizone-induced demyelination model, PD0325901 displays significant therapeutic effect by promoting myelin regeneration. Our results suggest that targeting the MAPK-ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.


Truncated xpt gene present in invasive Streptococcus pneumoniae may have implications for MLST schemes.
A serotype 1 disease-causing pneumococcus possessing a truncated xanthine phosphoribosyltransferase (xpt) housekeeping gene is described. The deletion is within the gene region used for multi-locus sequence typing (MLST) and may have occurred through genetic transformation or capsule switch between clones. The identification of this deletion in a clinical isolate therefore warrants highlighting due to potential errors that may ensue in isolate characterization and due to the fact that deletions may occur in other genes in this or other species characterized by MLST.


Lack of Pharmacokinetic Interaction between Aspirin and Warfarin.
An open-label, randomized, two-phase crossover study was conducted on 36 healthy male volunteers to identify the effects of coadministration of aspirin (acetylsalicylic acid; ASA) and crystalline warfarin sodium (Coumadin((R))) on the elimination and disposition kinetics of ASA, salicylic acid (SA) and R- and S-warfarin enantiomers. Twenty-four subjects were administered single doses of 325 mg of ASA alone and in combination with 10 mg of crystalline warfarin sodium with a 1-week washout between ASA doses. ASA and SA pharmacokinetic parameters were determined after each dose. Twelve subjects were administered single doses of 10 mg of crystalline warfarin sodium alone and in combination with 325 mg of ASA with a 4-week washout between warfarin doses. R- and S-warfarin enantiomer pharmacokinetic parameters were determined after each dose. Pharmacokinetic parameters were compared using analysis of variance and 90% confidence intervals. ASA and SA AUCs (the area under the plasma concentration versus time curve from time zero to time infinity) respectively were 3.28 plus minus 0.80 and 66.99 plus minus 11.73 &mgr;g h ml(minus sign1) (ASA alone), and 3.22 plus minus 0.61 and 69.48 plus minus 15.79 &mgr;g h ml(minus sign1) (ASA with warfarin). R-warfarin and S-warfarin AUCs respectively were 33.9 plus minus 9.3 and 23.9 plus minus 16.0 &mgr;g h ml(minus sign1) (warfarin alone) and 33.6 plus minus 10.2 and 22.6 plus minus 14.7 &mgr;g h ml(minus sign1) (warfarin with ASA). The only pharmacokinetic parameter which was statistically significantly different when the combination was administered was the S-warfarin elimination rate constant (p < 0.05), but the difference (9.2% increase in the presence of ASA) was small and no significant difference was found in S-warfarin clearance. It is concluded that there is no pharmacokinetic interaction when a single dose of ASA 325 mg is coadministered with a single dose of crystalline warfarin sodium 10 mg.


Effect of psilocybin on marble burying in ICR mice: role of 5-HT1A receptors and implications for the treatment of obsessive-compulsive disorder.
Preliminary clinical findings, supported by preclinical studies employing behavioral paradigms such as marble burying, suggest that psilocybin may be effective in treating obsessive-compulsive disorder. However, the receptor mechanisms implicated in the putative anti-obsessional effect are not clear. On this background, we set out to explore (1) the role of serotonin 2A (5-HT2A) and serotonin 1A (5-HT1A) receptors in the effect of psilocybin on marble burying; (2) the effect of staggered versus bolus psilocybin administration and persistence of the effect; (3) the effect of the 5-HT1A partial agonist, buspirone, on marble-burying and the head twitch response (HTR) induced by psilocybin, a rodent correlate of psychedelic effects. Male ICR mice were administered psilocybin 4.4 mg/kg, escitalopram 5 mg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) 2 mg/kg, M100907 2 mg/kg, buspirone 5 mg/kg, WAY100635 2 mg/kg or combinations, intraperitoneally, and were tested on the marble burying test. HTR was examined in a magnetometer-based assay. The results show that (1) Psilocybin and escitalopram significantly reduced marble burying. The effect of psilocybin was not attenuated by the 5-HT2A antagonist, M100907. The 5-HT1A agonist, 8-OH-DPAT, reduced marble burying as did the 5-HT1A partial agonist, buspirone. The effect of 8-OH-DPAT was additive to that of psilocybin, but that of buspirone was not. The 5-HT1A antagonist, WAY100635, attenuated the effect of 8-OH-DPAT and buspirone but not the effect of psilocybin. (2) Psilocybin injections over 3.5 h had no effect on marble burying and the effect of bolus injection was not persistent. (3) Co-administration of buspirone with psilocybin blocked its effect on HTR. These data suggest that neither 5-HT2A nor 5-HT1A receptors are pivotally implicated in the effect of psilocybin on marble burying. Co-administration with buspirone may block the psychedelic effects of psilocybin without impeding its anti-obsessional effects.


Pitcher's elbow: medial elbow pain in the overhead-throwing athlete.
Overhead athletes subject their elbows to significant valgus stresses throughout the throwing cycle. A steady rise in the number of medial-sided elbow injuries over the years has lead to increased awareness regarding the pathophysiology of the "pitcher's elbow." As our understanding of the functional anatomy and throwing biomechanics has become more sophisticated, we have seen a concurrent improvement in the outcomes associated with managing these injuries. Despite this improvement, continued anatomical and biomechanical research is still needed to further optimize outcomes and return to sport.


Telerehabilitation: remote multimedia-supported assistance and mobile monitoring of balance training outcomes can facilitate the clinical staff's effort.
Telerehabilitation can offer prolonged rehabilitation for patients with stroke after being discharged from the hospital, whilst remote diagnostics may reduce the frequency of the outpatient services required. Here, we compared a novel telerehabilitation system for virtual reality-supported balance training with balance training with only a standing frame and with conventional therapy in the hospital. The proposed low-cost experimental system for balance training enabling multiple home systems, real-time tracking of task's performance and different views of captured data with balance training, consists of a standing frame equipped with a tilt sensor, a low-cost computer, display, and internet connection. Goal-based tasks for balance training in the virtual environment proved motivating for the participating individuals. The physiotherapist, located in the remote healthcare center, could remotely adjust the level of complexity and difficulty or preview the outcomes and instructions with the application on the mobile smartphone. Patients using the virtual reality-supported balance training showed an improvement in the task performance time of 45% and number of collisions of 68%, showing significant improvements in the Berg Balance Scale, Timed 'Up and Go', and 10 m Walk Test. The clinical outcomes were not significantly different from balance training with only the standing frame or conventional therapy. The proposed telerehabilitation can facilitate the physiotherapists' work and thus enable rehabilitation to a larger number of patients after release from the hospital because it requires less time and infrequent presence of the clinical staff. However, a comprehensive clinical evaluation is required to confirm the applicability of the concept.


Three-dimensional hydrogel culture conditions promote the differentiation of human induced pluripotent stem cells into hepatocytes.
Human induced pluripotent stem cells (hiPSCs) are becoming increasingly popular in research endeavors due to their potential for clinical application; however, such application is challenging due to limitations such as inferior function and low induction efficiency. In this study, we aimed to establish a three-dimensional (3D) culture condition to mimic the environment in which hepatogenesis occurs in vivo to enhance the differentiation of hiPSCs for large-scale culture and high throughput BAL application. We used hydrogel to create hepatocyte-like cell (HLC) spheroids in a 3D culture condition and analyzed the cell-behavior and differentiation properties of hiPSCs in a synthetic nanofiber scaffold. We found that treating cells with Y-27632 promoted the formation of spheroids, and the cells aggregated more rapidly in a 3D culture condition. The ALB secretion, urea production and glycogen synthesis by HLCs in 3D were significantly higher than those grown in a 2-dimensional culture condition. In addition, the metabolic activities of the CYP450 enzymes were also higher in cells differentiated in the 3D culture condition. 3D hydrogel culture condition can promote differentiation of hiPSCs into hepatocytes. The 3D culture approach could be applied to the differentiation of hiPSCs into hepatocytes for bioartificial liver.


High resolution 3T fMRI in anesthetized monkeys.
Although there are numerous 3T MRI research devices all over the world, only a few functional studies at 3T have been done in anesthetized monkeys. In the past, anesthetized preparations were reported to be misleading when exploring cortical brain regions outside the primary sensory areas. Nonetheless, a great improvement has been achieved in the limited effect of anesthetic agents on the reactivity of the brain. Here, we re-address the feasibility and potential applications of the brain oxygen level dependent (BOLD) fMRI signal in Macaca mulatta monkeys that have been lightly anesthetized with sevoflurane and curarized. The monkeys were studied with commercially available coils and sequences using a 3T clinical magnet. We obtained sagittal T1 scout images, gray matter double inversion recovery, standard gradient echo sequences and gradient echo functional imaging sequences. Given that fMRI signals are most readily identified in the cerebral cortices, we optimized Echo Planar Imaging sequences to reproduce significant changes in the BOLD signal subsequent to a visual stimulation paradigm. Our results provide a satisfactory signal to noise ratio with a limited standard deviation range, when compared with studies on alert macaques. We suggest that the 3T magnet remains a valuable tool to analyze neural pathways in the macaque brain under light anesthesia and report the use of spatially resolved fMRI in higher visual areas of anesthetized monkeys. This methodology avoids the need for time-consuming training of awake monkeys, is stable over many hours, provides reproducible data and could be applied successfully to future functional studies.


Bone marrow edema syndrome of the knee: a case report and review of the literature.
The authors present a 45-year-old man with bone marrow edema syndrome (BMES) of the medial condyle of the knee. Early diagnosis of BMES was based upon clinical, bone scintigraphy and magnetic resonance (MRI) findings. After failure of the conservative treatment, core decompression was performed. Histological examination showed no evidence of osteoporosis or osteonecrosis. Within 2 months after the operation, the patient was pain-free and he resumed his previous activities. At 1-year follow-up examination, MRI showed complete resolution of all signal abnormalities; at 3-year follow-up the patient remained symptom-free and with no functional limitations.


Nanocellulose and Nanocarbons Based Hybrid Materials: Synthesis, Characterization and Applications.
Since the emergence of nanotechnology in recent decades, the development and design of hybrid bio-nanomaterials has become an important field of research [...].


Autophagy and mitochondrial biogenesis impairment contribute to age-dependent liver injury in experimental sepsis: dysregulation of AMP-activated protein kinase pathway.
Age is an independent risk factor of multiple organ failure in patients with sepsis. However, the age-related mechanisms of injury are not known. AMPK is a crucial regulator of energy homeostasis, which controls mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor-γ coactivator-α (PGC-1α) and disposal of defective organelles by autophagy. We investigated whether AMPK dysregulation might contribute to age-dependent liver injury in young (2-3 mo) and mature male mice (11-13 mo) subjected to sepsis. Liver damage was higher in mature mice than in young mice and was associated with impairment of hepatocyte mitochondrial function, structure, and biogenesis and reduced autophagy. At molecular analysis, there was a time-dependent nuclear translocation of the active phosphorylated catalytic subunits AMPKα1/α2 and PGC-1α in young, but not in mature, mice after sepsis. Treatment with the AMPK activator 5-amino-4-imidazolecarboxamide riboside-1-β-d-ribofuranoside (AICAR) improved liver mitochondrial structure in both age groups compared with vehicle. In loss-of-function studies, young knockout mice with systemic deficiency of AMPKα1 exhibited greater liver injury than did wild-type mice after sepsis. Our study suggests that AMPK is important for liver metabolic recovery during sepsis. Although its function may diminish with age, pharmacological activation of AMPK may be of therapeutic benefit.-Inata, Y., Kikuchi, S., Samraj, R. S., Hake, P. W., O'Connor, M., Ledford, J. R., O'Connor, J., Lahni, P., Wolfe, V., Piraino, G., Zingarelli, B. Autophagy and mitochondrial biogenesis impairment contribute to age-dependent liver injury in experimental sepsis: dysregulation of AMP-activated protein kinase pathway.


Imaging the impact of cyclosporin A and dipyridamole on P-glycoprotein (ABCB1) function at the blood-brain barrier: A [(11)C]-N-desmethyl-loperamide PET study in nonhuman primates.
Cyclosporin A (CsA) and dipyridamole (DPy) are potent inhibitors of the P-glycoprotein (P-gp; ABCB1) in vitro. Their efficacy at inhibiting P-gp at the blood-brain barrier (BBB) is difficult to predict. Efficient and readily available (i.e. marketed) P-gp inhibitors are needed as probes to investigate the role of P-gp at the human BBB. In this study, the P-gp inhibition potency at the BBB of therapeutic doses of CsA or DPy was evaluated in baboons using Positron Emission Tomography (PET) imaging with [(11)C]-N-desmethyl-loperamide ([(11)C]dLop), a radiolabeled P-gp substrate. The preparation of dLop as authentic standard and [(11)C]dLop as radiotracer were revisited so as to improve their production yields. [(11)C]dLop PET imaging was performed in the absence (n=3, baseline condition) and the presence of CsA (15mg/kg/h i.v., n=3). Three animals were injected with i.v. DPy at either 0.56 or 0.96 or 2mg/kg (n=1), corresponding to the usual, maximal and twice the maximal dose in patients, respectively, administered immediately before PET. [(11)C]dLop brain kinetics as well as [(11)C]dLop kinetics and radiometabolites in arterial plasma were measured to calculate [(11)C]dLop area-under the time-activity curve from 10 to 30min in the brain (AUCbrain) and in plasma (AUCplasma). [(11)C]dLop brain uptake was described by AUCR=AUCbrain/AUCplasma. CsA as well as DPy did not measurably influence [(11)C]dLop plasma kinetics and metabolism. Baseline AUCR (0.85±0.29) was significantly enhanced in the presence of CsA (AUCR=10.8±3.6). Injection of pharmacologic dose of DPy did not enhance [(11)C]dLop brain distribution with AUCR being 1.2, 0.9 and 1.1 after administration of 0.56, 0.96 and 2mg/kg DPy doses, respectively. We used [(11)C]dLop PET imaging in baboons, a relevant in vivo model of P-gp function at the BBB, to show the P-gp inhibition potency of therapeutic dose CsA. Despite in vitro P-gp inhibition potency, usual doses DPy are not likely to inhibit P-gp function at the BBB.


Cat spinoreticular neurons: locations, responses and changes in responses during repetitive stimulation.
Neurons in the lumbosacral spinal cord which project to the medial pontomedulary reticular formation were studied in the chloralose-anesthetized cat. Such neurons, identified by antidromic activation, were found predominantly in lamina VIII and medial lamina VII, and most were found to project to the contralateral reticular formation. Receptive fields for natural stimuli were generally complex, having various combinations of excitatory and inhibitory areas ipsi- and/or contralaterally. Adequate stimuli ranged from innocuous to noxious, with the stimuli required for decreasing a neuron's activity usually more intense than the stimulus required for increasing it. Electrical stimulation of hindlimb nerves indicated the presence of extensive convergence. Responses of spinoreticular neurons were found to decline during periods of repetitive stimulation. The response decrements were found to have many of the parametric features of behavioral habituation and were similar to response decrements previously observed in the medial pontomedullary reticular formation.


Relation of life events to blood pressure control in the SHEP pilot trial.
The Systolic Hypertension in the Elderly (SHEP) pilot trial was a five-center study in which 551 persons aged 60 years or older with isolated systolic hypertension were given antihypertensive drugs or placebos in order to determine the effects on blood pressure control and possible side effects of therapy. A life events inventory was administered to the cohort one year into the study. Results of this inventory were then compared to blood pressure and changes in blood pressure in the placebo and active therapy groups. One or more of the life events assessed were present in about 65% of the population. Although the sample was too small to detect very subtle effects, there was no evidence in this study that either individual or groups of life events play a major role in blood pressure regulation of persons with isolated systolic hypertension.


Tolerability of antiepileptic drugs: can we determine differences?
Patient tolerability of adverse effects is integral to successful treatment. Although standard antiepileptic drugs (AEDs) are well tolerated by many patients, the promise of newer AEDs has been the potential for diminished burden of problems with similar seizure control. This report reviews the prevalence of systemic and neurological adverse effects reported in clinical trials of AED monotherapy. A central finding in this report was the unidirectional higher prevalence of selected adverse effects from standard compared with newer AEDs. A system of questioning every patient at every visit to elicit information may be helpful when balancing benefit-to-risk ratio of individualized therapy during everyday practice.


Factors associated with ART adherence among HIV-positive adherence club members in Ekurhuleni Metropolitan Municipality, South Africa: A cross-sectional study.
HIV is a leading cause of morbidity and mortality in South Africa that can be managed using antiretroviral therapy (ART). Adherence clubs are interventions that have been introduced to decentralize ART to improve ART adherence and provide social support for club members. However, ART adherence can be suboptimal even among adherence club members. This study aimed to determine the factors affecting ART adherence among people living with HIV/AIDS (PLWHA) attending adherence clubs in Ekurhuleni Metropolitan Municipality. A cross-sectional study was conducted. Ordinal logistic regression was used in univariable and multivariable analyses to determine factors significantly associated with adherence scores. Factors included in the final model were age, comorbidity, ART regimen and club membership duration. The records of 730 participants were analysed. After adjusting for age, participants with comorbidities were half as likely to report high ART adherence scores compared to participants without comorbidities (AOR = 0.5, 95% CI: 0.3-0.8, p = 0.005). The adjusted odds of reporting high levels of adherence among participants on cART were 1.8 times those on a single tablet regimen (AOR = 1.8, 95% CI: 1.0-3.2; p = 0.033). There was a 20% reduction in the adjusted odds of reporting high ART adherence for each additional year of adherence club membership (AOR = 0.8, 95% CI: 0.8-0.9, p<0.001). Increasing years spent as adherence club members, single tablet ART regimens and the presence of comorbidities were all significantly associated with low ART adherence among study participants. Regular assessment of the quality of counselling sessions for ART adherence club members and questionnaires for early screening of treatment fatigue have been suggested as tools for improved adherence in ART adherence club settings.


Looking at scenes while searching for numbers: dividing attention multiplies space.
Observers tend to remember seeing a greater expanse of a scene than was shown (boundary extension [BE]). Is undivided visual attention necessary for BE? In Experiment 1, 108 observers viewed photographs with superimposed numerals (2s and 5s). Each appeared for 750 msec, followed by a masked interval and a test picture (same, closer up, or wider angled). Test pictures were rated as the same, closer, or wider angled on a 5-point scale. Visual attention was manipulated with a search task: The observers reported the number of 5s (zero, one, or two). The observers performed search only, picture rating only, or both (giving search priority). Search accuracy was unaffected by condition. BE occurred in both conditions but was greater with divided attention. The results were replicated using incidental BE tests (Experiments 2 and 3). We propose that anticipatory representation of layout occurs automatically during scene perception, with focal attention serving to constrain the boundary error.


A guide to rational dosing of monoclonal antibodies.
Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Therefore, the dosing paradigm for mAbs should be assessed in the context of these unique characteristics. The objective of this study was to review the current dosing strategy and to provide a scientific rationale for dosing of mAbs using a modelling and simulation approach. In this analysis, the body weight-based or body weight-independent (fixed) dosing regimens for mAbs were systematically evaluated. A generic two-compartment first-order elimination model was developed. Individual or population pharmacokinetic profiles were simulated as a function of the body weight effects on clearance (θ(BW_CL)) and on the central volume of distribution (θ(BW_V1)). The variability in exposure (the area under the serum concentration-time curve [AUC], trough serum concentration [C(min)] and peak serum concentration [C(max)]) was compared between body weight-based dosing and fixed dosing in the entire population. The deviation of exposure for light and heavy subjects from median body weight subjects was also measured. The simulation results were then evaluated with clinical pharmacokinetic characteristics of various mAbs that were given either by body weight-based dosing or by fixed dosing in the case study. Results from this analysis demonstrated that exposure variability was dependent on the magnitude of the body weight effect on pharmacokinetics. In contrast to the conventional assumption, body weight-based dosing does not always offer advantages over fixed dosing in reducing exposure variability. In general, when the exponential functions of θ(BW_CL) and θ(BW_V1) in the population pharmacokinetic model are <0.5, fixed dosing results in less variability and less deviation than body weight-based dosing; when both θ(BW_CL) and θ(BW_V1) are >0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either θ(BW_CL) or θ(BW_V1) is >0.5, the impact on exposure variability is different for each exposure measure. The case study demonstrated that most mAbs had little effect or a moderate body weight effect (θ(BW_CL) and θ(BW_V1) <0.5 or ∼0.5). The difference of variability in exposure between body weight-based and fixed dosing is generally less than 20% and the percentages of deviation for light and heavy subpopulations are less than 40%. The analysis provided insights into the conditions under which either fixed or body weight-based dosing would be superior in reducing pharmacokinetic variability and exposure differences between light and heavy subjects across the population. The pharmacokinetic variability introduced by either dosing regimen is moderate relative to the variability generally observed in pharmacodynamics, efficacy and safety. Therefore, mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs. The dosing strategy in later stages of clinical development could then be determined based on combined knowledge of the body weight effect on pharmacokinetics, safety and efficacy from the early clinical trials.


Intellectual outcomes of extremely preterm infants at school age.
The survival rate of extremely preterm (EP) infants (<28 weeks of gestation) has improved dramatically, and there is great interest in the long-term prognosis. The aim of this study was to elucidate the influence of prenatal and postnatal care on long-term intellectual outcome in EP infants. Subjects were EP infants admitted to the neonatal intensive care unit from 1982 to 2005. The survival rate and neurodevelopmental outcomes at 6 years of age were analyzed for the periods 1982-1991 (period 1) and 1992-2005 (period 2). Logistic regression analysis was performed to examine risk factors for intellectual impairment. Survival rate improved significantly from 84.5% (period 1) to 92.4% (period 2; P = 0.007). Follow-up data were obtained from 92 children in period 1 (69.7% of survivors) and from 245 in period 2 (72.3% of survivors). The incidence of intellectual impairment increased from 16.3% (period 1) to 31.0% (period 2). Significant factors associated with intellectual impairment were period 2 (OR, 3.53; P = 0.007), supplemental oxygen at 36 weeks' corrected age (OR, 2.22; P = 0.012), number of days in the hospital (OR, 1.01; P = 0.012), intraventricular hemorrhage (IVH; OR, 3.05; P = 0.024), and later tube-feeding commencement date (OR, 1.10; P = 0.032). Despite an increase in survival rate, the rate of intellectual impairment increased in period 2. According to risk factor analysis, reducing the incidence of chronic lung disease and/or apnea, IVH, and nutritional deprivation is a key factor in improving the intellectual outcomes of EP infants.


[Does the antireflux operation promote growth of the kidneys? Apropos of 65 surgically treated children with a minimal follow-up of 4 years].
A study in 65 children followed up over at least 4 years after Cohen's operation evaluated renal growth rate using Eklof and Ringertz method. Analysis showed that: small kidneys with corticopapillary lesions were all atrophied; hypertrophic kidneys remained hypertrophic or were within a normal growth rate range; normal size kidneys never hypertrophied but atrophied in 13.5% of cases; the presence of corticopapillary lesions multiplied the risk of degradation of a normal size kidney by a factor of 5.5. These findings are in concordance with documented data, only Willscher et al finding accelerated renal growth rate after surgical relief of reflux.


Biosynthesis of Ag-Pt bimetallic nanoparticles using propolis extract: Antibacterial effects and catalytic activity on NaBH4 hydrolysis.
The critical environmental issues of antibiotic resistance and renewable energies supply urge researching materials synthesis and catalyst activity on hydrogen production processes. Aiming to analyse the antibacterial effect of platinum-silver (Ag-Pt) nanoparticles (NPs) and the catalyst effect on NaBH4 hydrolysis that can be used for hydrogen generation technology, in this work, Ag-Pt NPs were prepared using aqueous propolis extract. Various methods were used for the characterization (Uv-vis Spectroscopy, Transmission Electron Microscopy (TEM), Fourier Transform Infrared Spectroscopy (FTIR), Atomic Force Microscopy (AFM) and X-ray diffraction Spectroscopy (XRD)). The antimicrobial activity of Ag-Pt bimetallic nanoparticles was evaluated in vitro by the microdilution method against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Staphylococcus epidermidis, and Serratia marcescens. The results confirmed the antimicrobial activity of bimetallic NPs Ag-Pt concentrations of (25, 50, and 100 μg/ml). A concentration of 100 μg/ml showed low bacterial viability varying between 22.58% and 29.67% for the six tested bacteria. For the catalyst activity on NaBH4 hydrolysis, the results showed high turnover factor (TOF) and low activation energy of 1208.57 h-1 and 25.61 kJ/mol, respectively, with high hydrogen yield under low temperature. Synthesized Ag-Pt NPs can have great potential for biological and hydrogen storage applications.


Utilization of natural hematite as reactive barrier for immobilization of radionuclides from radioactive liquid waste.
Potential utilization of hematite as a natural material for immobilization of long-lived radionuclides from radioactive liquid waste was investigated. Hematite ore has been characterized by different analytical tools such as Fourier transformer infrared (FTIR), X-ray fluorescence (XRF), powder X-ray diffraction (XRD), thermogravimetry (TG) and differential thermal (DT) analysis, scanning electron microscopy (SEM) and BET-surface area. In this study, europium was used as REEs(III) and as a homolog of Am(III)-isotopes (such as (241)Am of 432.6 y, (242m)Am of 141 y and (243)Am of 7370 y). Micro particles of the hematite ore were used for treatment of radioactive waste containing (152+154)Eu(III). The results indicated that 96% (4.1 × 10(4) Bq) of (152+154)Eu(III) was efficiently retained onto hematite ore. Kinetic experiments indicated that the processes could be simulated by a pseudo-second-order model and suggested that the process may be chemisorption in nature. The applicability of Langmuir, Freundlich and Temkin models was investigated. It was found that Langmuir isotherm exhibited the best fit with the experimental results. It can be concluded that hematite is an economic and efficient reactive barrier for immobilization of long-lived radio isotopes of actinides and REEs(III).


[External irradiation combined with intracavitary brachytherapy for esophageal cancer].
To study the long-term treatment results and acute irradiation response as well as complications following external irradiation combined with intracavitary brachytherapy. After loading intracavitary brachytherapy was used for patients with esophageal cancer. In 92 patients with esophageal cancer, 47 (group A) were treated with external irradiation only, and 45 (group B) with external irradiation and brachytherapy. The doses were 60.0 Gy - 70.0 Gy per 6-7 week for external irradiation, using 8 or 10 MV liner accelerator, and 5.0-8.0 Gy per fraction for intracavitary therapy. There was a significant difference in acute response and complications as well as local recurrence rate between the two groups (P < 0.05). The survival rates of groups A and B at 1,3 and 5 years were 59.6%, 25.6%, 10.6% and 80.0%, 46.7%, 26.7% respectively (P < 0.05 respectively, using chi2 test). The complications related to intracavitary irradiation were esophageal perforation, esophagorrhagia, esophagotracheal fistula and esophageal narrowing. 66 patients died and 9 lost follow-up, giving a follow up rate of 90.2%. External irradiation combined with afterloading intracavitary brachytherapy for esophageal cancer can reduce the local recurrence and enhance the long-term survival but with an increase of complications compared with the patients treated with external irradiation alone.


Molecular mechanisms and treatment responses of pulmonary fibrosis in severe COVID-19.
Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA- (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4, PDE4D, MMP8, CRISP3, and BCL2L15. Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay (pre-DEXA: 42 [29-49] vs. 18 [13-27] days, p < 0.001; DEXA: 42 [28-57] vs. 13 [7-24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes. ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.


Heparin-induced thrombocytopenia--recognition and treatment.
Heparin, an important agent for the prophylaxis and treatment of venous and arterial thromboembolism, also can cause heparin-induced thrombocytopenia (HIT). This medication-induced immune-mediated syndrome is characterized by thrombocytopenia and life- or limb-threatening thrombotic events. The initial presentation of HIT is a decrease in platelet count with or without thrombosis. Heparin-induced thrombocytopenia frequently is overlooked in hospital settings, and it must be distinguished from other causes of thrombocytopenia. New therapies include the use of direct thrombin inhibitors argatroban and hirudin.


Neurophysiology of action anticipation in athletes: A systematic review.
The purpose of this study was to provide a systematic review of action anticipation studies using functional neuroimaging or brain stimulation during a sport-specific anticipation task. A total of 15 studies from 2008 to 2014 were evaluated and are reported in four sections: expert-novice samples, action anticipation tasks, neuroimaging and stimulation techniques, and key findings. Investigators examined a wide range of action anticipation scenarios specific to eight different sports and utilized functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), and transcranial magnetic stimulation (TMS). Expert-novice comparisons were commonly used to investigate differences in action anticipation performance and neurophysiology. Experts tended to outperform novices, and an extensive array of brain structures were reported to be involved differently for experts and novices during action anticipation. However, these neurophysiological findings were generally inconsistent across the studies reviewed. The discussion focuses on strengths and four key limitations. The conclusion posits remaining questions and recommendations for future research.


Regular source of primary care and emergency department use of children in Victoria.
The aim of this paper was to study the prevalence of a regular source of primary care for Victorian children attending one of four emergency departments (EDs) and to determine associated characteristics, including ED use. Responses were collected via an electronic survey from parents attending EDs with their child (≤9 years of age) for a lower-urgency condition. Single, multiple choice, and Likert scale responses were analysed using bivariate and logistic regression tests. Of the 1146 parents who provided responses, 80% stated their child has a regular source of primary care. Of these, care is mostly received by a general practitioner (GP) (95%) in GP group practices (71%). Approximately 20% have changed where their child receives primary care in the last year. No associations were observed between having a regular source of primary care and frequency of ED attendance in the past 12 months, although parents whose child did not have a regular source of primary care were more likely to view the ED as a more convenient place to receive care than the primary care provider (39% without regular source vs. 18% with regular source; P < 0.0001). Children were less likely to have a regular source of primary care if their parents were younger, had a lower household income, lower education, and were visiting a hospital in a lower socio-economic indexes for areas rank. Policy options to improve continuity of care for children may require investigation. Increasing the prevalence of regular source of primary care for children may in turn reduce ED visits.


Actions of Ca2+ antagonists on the guinea-pig ileal myenteric plexus preparation.
The guinea-pig ileal myenteric plexus preparation has been used to compare the actions of three Ca2+ channel antagonists, D 600 (methoxyverapamil), nicardipine and diltiazem, on smooth muscle contractions and acetylcholine release in response to electrical stimulation. Acetylcholine release was not affected by these agents at concentrations of 10(-6)-10(-5)M. In confirmation of previous work, however, the smooth muscle contractile responses were effectively inhibited at these concentrations. Quercetin, a non-Ca2+ channel antagonist, was approximately equieffective in blocking both acetylcholine release and smooth muscle contractions. These data suggest that differences may exist in the antagonist sensitivity of voltage-dependent Ca2+ channels.


Gas Separations using Nanoporous Atomically Thin Membranes: Recent Theoretical, Simulation, and Experimental Advances.
Porous graphene and other atomically thin 2D materials are regarded as highly promising membrane materials for high-performance gas separations due to their atomic thickness, large-scale synthesizability, excellent mechanical strength, and chemical stability. When these atomically thin materials contain a high areal density of gas-sieving nanoscale pores, they can exhibit both high gas permeances and high selectivities, which is beneficial for reducing the cost of gas-separation processes. Here, recent modeling and experimental advances in nanoporous atomically thin membranes for gas separations is discussed. The major challenges involved, including controlling pore size distributions, scaling up the membrane area, and matching theory with experimental results, are also highlighted. Finally, important future directions are proposed for real gas-separation applications of nanoporous atomically thin membranes.


Effect of strychnine on the cutaneous responsiveness of wide-field cerebral neurons after depression by pentobarbital.
A small dose of pentobarbital administered intravenously to a chloralose-anesthetized cat rendered pericruciate wide-field neurons unresponsive to cutaneous stimulation without altering the responsiveness of small-field neurons. Under this condition, topical application of strychnine, which is known to markedly enhance the responses of small-field neurons, was found to restore the responsiveness of the wide-field neurons, but only to stimulation of the topographically focal cutaneous site. Wide-field responsiveness returned only after the effect of pentobarbital had disappeared and the cortex returned to its normal chloralose condition. This result is consistent with the idea that small-field neurons have excitatory synaptic connections with the wide-field neurons in their immediate neighborhood.


Broadening primate genomics: new insights into the ecology and evolution of primate gene regulation.
Comparative analyses have played a key role in understanding how gene regulatory evolution contributes to primate phenotypic diversity. Recently, these studies have expanded to include a wider range of species, within-population as well as interspecific analyses, and research on wild as well as captive individuals. This expansion provides context for understanding genetic and environmental effects on gene regulation in humans, including the importance of the pathogen and social environments. Although taxonomic representation remains biased, inclusion of more species has also begun to reveal the evolutionary processes that explain whether and when gene regulation is conserved. Together, this work highlights how studies in other primates contribute to understanding evolution in our own lineage, and we conclude by identifying promising avenues for future work.


Wavelet coherence analysis of dynamic cerebral autoregulation in neonatal hypoxic-ischemic encephalopathy.
Cerebral autoregulation represents the physiological mechanisms that keep brain perfusion relatively constant in the face of changes in blood pressure and thus plays an essential role in normal brain function. This study assessed cerebral autoregulation in nine newborns with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). These neonates received hypothermic therapy during the first 72 h of life while mean arterial pressure (MAP) and cerebral tissue oxygenation saturation (SctO2) were continuously recorded. Wavelet coherence analysis, which is a time-frequency domain approach, was used to characterize the dynamic relationship between spontaneous oscillations in MAP and SctO2. Wavelet-based metrics of phase, coherence and gain were derived for quantitative evaluation of cerebral autoregulation. We found cerebral autoregulation in neonates with HIE was time-scale-dependent in nature. Specifically, the spontaneous changes in MAP and SctO2 had in-phase coherence at time scales of less than 80 min (< 0.0002 Hz in frequency), whereas they showed anti-phase coherence at time scales of around 2.5 h (~ 0.0001 Hz in frequency). Both the in-phase and anti-phase coherence appeared to be related to worse clinical outcomes. These findings suggest the potential clinical use of wavelet coherence analysis to assess dynamic cerebral autoregulation in neonatal HIE during hypothermia.


Combining loop and thiazide diuretics for acute heart failure across the estimated glomerular filtration rate spectrum: A post-hoc analysis of the CLOROTIC trial.
In patients with acute heart failure (AHF), the addition of hydrochlorothiazide (HCTZ) to furosemide improved diuretic response in the CLOROTIC trial. This work aimed to evaluate if these effects differ across the estimated glomerular filtration rate (eGFR) spectrum. This post-hoc analysis of the CLOROTIC trial analysed 230 patients with AHF and explored the influence of eGFR on primary and secondary endpoints. The median eGFR was 43 ml/min/1.73 m2 (range 14-109) and 23% had eGFR ≥60 ml/min/1.73 m2 (group 1), 24% from 45 to 59 ml/min/1.73 m2 (group 2), and 53% <45 ml/min/1.73 m2 (group 3). Patients treated with HCTZ had greatest weight loss at 72 h in all three groups, but patients in group 1 had a significantly greater response (-2.1 kg [-3.0 to 0.5]), compared to patients in groups 2 (-1.3 kg [-2.3 to 0.2]) and 3 (-0.1 kg [-1.3 to 0.4]) (p-value for interaction = 0.246). At 96 h, the differences in weight were -1.8 kg (-3.0 to -0.3), -1.4 kg (-2.6 to 0.3), and -0.5 kg (-1.3 to -0.1) in groups 1, 2, and 3, respectively (p-value for interaction = 0.256). There were no significant differences observed with the addition of HCTZ in terms of diuretic response, mortality or rehospitalizations, or safety endpoints (impaired renal function, hyponatraemia, and hypokalaemia) among the three eGFR groups (all p-values for interaction were no significant). The addition of eGFR-adjusted doses of oral HCTZ to loop diuretics in patients with AHF improved diuretic response across the eGFR spectrum. ClinicalTrials.gov: NCT01647932; EudraCT number: 2013-001852-36.


Genomic and Transcriptomic Analyses of Malignant Pleural Mesothelioma (MPM) Samples Reveal Crucial Insights for Preclinical Testing.
Cell lines are extensively used to study cancer biology. However, the use of highly passaged commercial cell lines has to be questioned, as they do not closely resemble the originating tumor. To understand the reliability of preclinical models for Malignant pleural mesothelioma (MPM) studies, we have performed whole transcriptome and whole exome analyses of fresh frozen MPM tumors and compared them to cell lines generated from these tumors, as well as commercial cell lines and a preclinical MPM mouse model. Patient-derived cell lines were generated from digested fresh tumors and whole exome sequencing was performed on DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor samples, corresponding patient-derived cell lines, and normal tissue. RNA sequencing libraries were prepared from 10 fresh frozen tumor samples, the 10 corresponding patient-derived cell lines, and 7 commercial cell lines. Our results identified alterations in tumor suppressor genes such as FBXW7, CDKN2A, CDKN2B, and MTAP, all known to drive MPM tumorigenesis. Patient-derived cell lines correlate to a high degree with their originating tumor. Gene expressions involved in multiple pathways such as EMT, apoptosis, myogenesis, and angiogenesis are upregulated in tumor samples when compared to patient-derived cell lines; however, they are downregulated in commercial cell lines compared to patient-derived cell lines, indicating significant differences between the two model systems. Our results show that the genome and transcriptome of tumors correlate to a higher degree with patient-derived cell lines rather than commercial cell lines. These results are of major relevance for the scientific community in regard to using cell lines as an appropriate model, resembling the pathway of interest to avoid misleading results for clinical applications.


Uremic parkinsonism with atypical phenotypes and radiologic features.
Uremic encephalopathy with bilateral basal ganglia lesions has been reported as an acute neurometabolic disease which shows reversible clinical course and brain imaging features. The exact nature and pathophysiology have not been well established. We encountered two patients who showed a relapsing and aggravating course and an atypical phenotype including parkinsonism with paroxysmal dystonic head tremor and acute onset monoparesis of the lower extremity. They also showed unusual radiological findings which revealed combined lesions in the basal ganglia and cortex, persistent hemorrhagic transformation, and focal ischemic lesion in the internal capsule. Herein, we present the unusual phenomenology with atypical radiologic findings and suggest the possible multifactorial pathogenesis of uremic encephalopathy.


Bronzino's Claw Hand.
Lancet recently published an article concerning a work of art by Bronzino (1503-1572). Apart from incorrectly identifying Bronzino as a Renaissance artist, Vein and Mouret (2018) make an extraordinary medical claim based on their observation of the artistic image of the left hand of the sitter in Bronzino's Mannerist Portrait of Bartolomeo Panciatichi (1540s). In short, seemingly without even a basic understanding of the tenets of Mannerist painting or the specifics of Bronzino's enormous oeuvre, Vein and Mouret (2018) claim that Bronzino's subject, Bartolomeo Panciatichi (1507-1582) was suffering from "a unilateral ulnar pathology." The author analyses the image of Bartolomeo Panciatichi from an art historical perspective involving both formal analysis and stylistic analysis. The specific portrayal of Panciatichi's "claw hand" is more correctly a product of creative genius, designed to elicit an emotional response of "disquiet" from the informed spectator. There is in fact no portrayal of a unilateral ulnar pathology. If it were, then it means that many of Bronzino's subjects suffered from exactly the same condition.


GDC-0980 (apitolisib) treatment with gemcitabine and/or cisplatin synergistically reduces cholangiocarcinoma cell growth by suppressing the PI3K/Akt/mTOR pathway.
Since conventional chemotherapy (gemcitabine and cisplatin) has marginal survival benefit in patients with advanced cholangiocarcinoma (CCA), an effective targeted therapeutic agent is urgently required. Activation of the PI3K/Akt/mTOR signaling pathway is frequently observed in CCA, and thus, PI3K and mTOR are promising therapeutic targets in CCA. Recently a new dual PI3K/mTOR inhibitor GDC-0980 (apitolisib) was introduced. This study was undertaken to examine the activity of apitolisib against CCA cells in vitro and in vivo. Apitolisib treatment strongly reduced Akt and mTOR active phosphorylation levels and attenuated cell growth in two different CCA cell lines (SNU478 and SNU1196). In addition, the cytotoxic activity of apitolisib enhanced the effects of gemcitabine or cisplatin in vitro and increased PARP cleavage. Moreover, we observed these co-treatments significantly reduced colony formation by SNU478 and SNU1196 cells and potently inhibited tumor growth in a mouse xenograft model. The results of the present study show that apitolisib effectively reduces CCA cell growth by suppressing the PI3K/Akt/mTOR pathway. In addition, co-treatments with apitolisib and gemcitabine or cisplatin synergistically enhanced apitolisib activity, which suggests a means of improving the chemotherapeutic sensitivity of CCA.


The size of cytoplasmic lipid droplets varies between tumour cell lines of the nervous system: a 1H NMR spectroscopy study.
Cytoplasmic lipid droplets (LDs) are dynamic cellular organelles; their accumulation is associated with several cellular processes, such as cell proliferation, apoptosis and necrosis. (1)H Nuclear Magnetic Resonance (NMR) spectroscopy detects resonances from lipids present in cytoplasmic (LDs); an understanding of the relationship between LD characteristics and NMR lipid signals is important. In this study, five nervous system cancer cell lines were investigated. Nile red staining was used to measure the diameter of LDs. High-resolution magic angle spinning NMR (HR-MAS) was performed on harvested cell pellets to quantify the patterns of lipid signals. LDs were present in all five cell lines with different morphology. An average LD diameter of approximately 0.2 μm was found in all cell types. Diameter of the largest LDs varied across the cell lines. The intensity of NMR lipid signals varied greatly between cell types, and a good correlation was found between total volume of LDs and the proton NMR lipid signal intensity at 0.9 and 1.3 ppm. The correlation implied that little NMR signal is detected from LDs of diameters less than approximately 0.34 μm, most likely due to restriction of rotational motion of the lipids.


Neuroendocrinological investigations during sleep deprivation in depression. I. Early morning levels of thyrotropin, TH, cortisol, prolactin, LH, FSH, estradiol, and testosterone.
Measurements of 12 hormones were conducted in patients with major depressive disorder at 8 AM on the morning before and at 8 AM on the morning after total sleep deprivation (SD). Thyrotropin (TSH), thyroxine (T4), triiodothyronine (T3), and free T3 (fT3) were measured in 50 patients, free T4 in 39 patients, reverse T3, cortisol, prolactin, luteinizing hormone, and follicle-stimulating hormone in 21, estradiol in 20 (women), and testosterone in 14 (men). After SD, there was a significant rise in TSH, T4, T3, and fT3 concentrations and a significant fall in testosterone levels. The increases in TSH levels were significantly correlated to clinical response. Responders to SD had higher T4, fT4, rT3, and testosterone concentrations before SD. Neither age, gender, polarity, nor antidepressant medication had a clearly significant effect on the response to SD.


Capturing the cardiac effects of racial discrimination: Do the effects "keep going"?
Racial discrimination negatively impacts cardiac functioning, but few studies examine the more distal cardiac effects of racial discrimination experiences. The present study examined the momentary and prolonged impact of lab-based intergroup and intragroup racial discrimination on heart rate variability (HRV) and heart rate (HR) in a sample (N = 42) of African American (AA) women across two days. On day one, the women were exposed to simulated racial discrimination from either a European American (EA) or AA confederate in the lab. On day two, the women returned to the lab for additional physiological recording and debriefing. Women insulted by the EA confederate exhibited lower HRV on day one and marginally lower HRV on day two. These women also exhibited marginally higher HR on day two. The HRV and HR effects on day two were not mediated by differences in perseveration about the stressor. The findings indicate that racial discrimination - particularly intergroup racial discrimination - may have both momentary and prolonged effects on cardiac activity in AAs.


Subtypes of anorgasmia via mathematical taxonomy.
Seventy-six women who presented with a principal complaint of anorgasmia were partitioned into four distinct subtypes on the basis of psychosexual and psychological symptoms using hierarchical cluster analysis, a mathematical taxonomic method. The classification was accomplished with data from the Derogatis Sexual Functioning Inventory (DSFI) and the Brief Symptom Inventory (BSI). Comparisons involving age, race, marital status, and social class demonstrated no significant differences between the four subtypes; however, statistical analyses of psychosexual, psychological symptom, and chart-review variables (including psychiatric diagnosis) revealed very significant distinctions between the four groups. From the resulting typology, anorgasmic subtypes were presumptively identified as "low desire" (n = 21), "histrionic/marital conflict" (n = 20) "psychiatric disorder" (n = 12) and "constitutional" (n = 16). Implications of the typology for etiologic and optimal treatment decisions concerning anorgasmia are discussed.


Clavines. New antibiotics with cytostatic activity.
The cytostatic potentials of ten ergolines were determined in the L5178y mouse lymphoma cell system; six of them belong to the clavines (agroclavine, 1-propyl-agroclavine, 1-propyl-festuclavine, 1-allyl-festuclavine, 6-cyano-6-nor-festuclavine and 1-hydroxymethyl-festuclavine) and four to the lysergic acid derivatives (methylergometrine, lysergic acid amide, isolysergic acid amide and lysergic acid diethylamide). It is shown that agroclavine (ED50: 3.9 microM), 1-propyl-agroclavine (3.5 microM), 1-propylfestuclavine (4.3 microM) and 1-allyl-festuclavine (4.3 microM) are potent cytostatic agents. Up to 2 X ED50 concentration the inhibitory effect was completely reversible. Incorporation studies suggested that the compounds inhibit DNA synthesis; this assumption was also supported by the findings which revealed that after incubation with these clavines, the cells showed slight 'unbalanced growth'. 6-Cyano-6-nor-festuclavine was less inhibitory (ED50 11.8 microM). 1-Hydroxymethyl-festuclavine and all lysergic acid derivatives tested were without any detectable activity.


Notoedric and sarcoptic mange in free-ranging lynx from Switzerland.
Between March and December 1999, five free-ranging lynx (Lynx lynx) affected by mange were found dead or shot by game wardens in the Swiss Alps. In the first two cases, Notoedres cati was isolated from the skin; in the third and fourth case, Sarcoptes scabiei was the cause of the infection; and in the fifth case, a mixed infection was diagnosed. Red foxes (Vulpes vulpes) affected with sarcoptic mange and domestic cats infested with N. cati are likely to be the sources of infection. It seems improbable that mange will occur as an epidemic in lynx in Switzerland, but losses due to infections with N. cati and/or S. scabiei may have an impact on this small, geographically limited lynx population. This is the first report of notoedric mange in a free-ranging lynx and the first report of mange in lynx from Switzerland.


Studies of malformation syndromes of man VB: the hypertelorism-hypospadias (BBB) syndrome. Case report and review.
We describe a boy with the hypertelorism-hypospadias (BBB) syndrome. His mother and his maternal grandmother showed minor manifestations suggestive of the syndrome. The BBB syndrome is a syndrome of multiple congenital anomalies with mental retardation due a segregating mendelian mutation, either X-linked or autosomal. This paper reviews the literature on the subject and emphasizes the problem of identifying females at high risk of transmitting the condition.


The role of extracorporeal membrane oxygenation in COVID-19.
An extracorporeal membrane oxygenation (ECMO) program is an important component in the management of patients with COVID-19, but it is imperative to implement a system that is well-supported by the institution and staffed with well-trained clinicians to both optimize patient outcomes and to keep providers safe. There are many unknowns related to COVID-19, and one of the most challenging aspects for clinicians is the lack of predictive knowledge as to why some patients fail medical therapy and require advanced support such as ECMO. These factors can create challenges during a time of resource scarcity and interruptions in the supply chain. In the current environment, in which resources are limited and an ongoing pandemic, healthcare practitioners need to focus on evidence-based best practice for supportive care of patients with COVID-19 in refractory respiratory or cardiac failure. with As experience is gained, a greater understanding will develop in this cohort of patients regarding need and timing of ECMO. As this pandemic continues, it will be important to compile and analyze multicentered data pertaining to patient-specific outcomes to help guide clinicians caring for patients with COVID-19 undergoing ECMO support. In this paper, the authors demonstrate the strategies utilized by a major quaternary care center in the utilization and management of ECMO for patients with COVID-19.


The Multi-Institutional Experience in Single-Port Robotic Transvesical Simple Prostatectomy for Benign Prostatic Hyperplasia Management.
Single-port (SP) robotic-assisted simple prostatectomy (RASP) through the transvesical approach is a novel surgical option in the management of large prostatic glands. We present the first multi-institutional study to further assess the perioperative and postoperative outcomes of SP RASP. From February 2019 to November 2021, 91 consecutive patients of 3 separate institutions underwent transvesical RASP using the da Vinci® SP robotic surgical system. Surgeries were performed by 3 experienced surgeons. Through a suprapubic incision and transvesical access, the SP robot is docked directly into the bladder, and the prostatic enucleation is performed. Prospective data collection, including baseline characteristics, perioperative and postoperative outcomes, was performed. The mean followup period was 4.6 months. The mean (SD) prostate volume was 156 (62) ml. The mean (SD) total operative time was 159 (45) minutes, and the median (IQR) estimated blood loss was 100 (50, 200) cc. The median (IQR) postoperative hospital stay was 21.0 (6.5, 26.0) hours; however, 42% of all patients were discharged the same day. The median (IQR) Foley catheter duration was 5 (5, 7) days. Only 3 patients (3%) developed Clavien grade 2 postoperative complications. At 9-month followup, the median (IQR) International Prostate Symptom Score and quality of life score were 4 (2, 5) and 0 (0, 1), respectively, with a mean (SD) maximum flow rate and post-void residual of 21 (17) ml/second and 40 (55) ml, respectively. In a multi-institutional setting, the SP RASP promotes a pain-free procedure, same-day discharge, short Foley catheter duration, low complication rate and quick recovery.


A spatial and temporal analysis of dorsal root and sympathetic ganglion formation in the avian embryo.
The present study explores the formation of the dorsal root and sympathetic ganglia in the trunk of the avian embryo. Particular emphasis was given to the timing of gangliogenesis and the relative positions of the neural crest-derived ganglia with respect to the somites. Neural crest cells and their derivatives were recognized by the HNK-1 antibody. The time at which neural crest cell coalesced to form ganglia was assessed by the state of cellular aggregation. The state of ganglionic differentiation was assessed by the expression of neurofilament proteins and the neural cell adhesion molecule (N-CAM). At the level of the 15th somite, neural crest cells were observed in the rostral half of the somite at stage 15, during active neural crest migration, and occupied the rostral two-thirds of the somite at progressive stages. HNK-1 positive cells appeared to be organized in three to four streams of cells oriented mediolaterally and dorsoventrally. The dorsal root ganglia and sympathetic ganglia were first detectable at stages 20 and 21, respectively. Both ganglionic rudiments were aligned with the rostral portion of the somite. The dorsal root ganglia occupied the rostral two-thirds of each somite, whereas cells in the sympathetic ganglia occupied a region corresponding to approximately one-third of each somite. At the time of condensation of the dorsal root ganglia, abundant neurofilament staining was observed within the ganglia. However, no N-CAM immunoreactivity was detected until three stages later at stage 23. In contrast, the sympathetic ganglia demonstrated both neurofilament and N-CAM immunoreactivity at the time of condensation. The observation that both dorsal root and sympathetic ganglia form in register with the rostral portion of somite suggests that cues localized at these axial levels, perhaps within the rostral somite, may influence the position where neural crest cells condense to form ganglia. In sensory ganglia, N-CAM expression does not correlate with the onset of gangliogenesis, suggesting that molecules other than N-CAM may play an important role in the aggregation of some neuronal populations.


Antibacterial activity of G6-quaternary ammonium derivatives of a lipophilic vancomycin analogue.
A series of G6-amino derivatives of a lipophilic vancomycin analogue was prepared. Antibacterial activity of the analogues was inversely proportional to the degree of substitution of the G6-nitrogen. The fully substituted (quaternary) analogues were essentially inactive against vanA phenotype VREF strains but retained substantial activity against other bacteria, a profile reminiscent of teicoplanin.