Labor and Birth Care Satisfaction Associated With Medical Interventions and Accompaniment During Labor Among Chilean Women.
Satisfaction with care during labor and birth has been associated with various obstetric variables. The purpose of this study was to determine which labor and birth procedures are significant predictors of maternal patient satisfaction in a large cross-sectional sample. An observational, cross-sectional study of 1660 women giving birth in Chilean public hospital facilities was conducted from 2012 to 2013. Data were collected from 9 different hospitals in 8 regions of Chile using 2 instruments, including the American College of Nurse-Midwives Intrapartum Care Data Set and a locally validated measure of maternal well-being. Women were eligible if they arrived at the labor and delivery unit during early labor (2-3 centimeters dilated) and spent at least 4 hours in labor at the facility. In the current analysis, odds ratios were calculated using ordinal logistic regression for association with a less optimal well-being score (possible outcome values were optimal, adequate, and minimal). Odds ratios were adjusted for age, education, single status, and parity (nulliparous vs multiparous). Stepwise regression was used to identify the procedural factors that were significantly associated with labor and birth care satisfaction. Factors significantly associated with lower satisfaction were cesarean birth (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.7), pharmacologic pain management (OR, 1.3; 95% CI, 1.02-1.7), continuous fetal heart rate monitoring (OR. 1.4; 95% CI, 1.2-1.8), and episiotomy (OR, 1.4; 95% CI, 1.1-1.7). Nulliparity was also associated with minimal maternal satisfaction (OR, 1.3; 95% CI, 1.0-1.5). Greater satisfaction was associated with accompaniment by a companion of choice during labor (OR, 0.49: 95% CI, 0.40-0.60). This study is one of the first to provide empirical evidence that maternal patient satisfaction is negatively affected by many common obstetric procedures in the Latin American context. These findings are consistent with World Health Organization recommendations regarding judicious and necessary, rather than routine, use of obstetric interventions.


The histopathological pattern of primary IgA nephropathy in a Malaysian patient population.
In the 10-year period from October 1977 to July 1987, 149 cases of primary IgA nephropathy were histologically confirmed through renal biopsies in the Department of Pathology, University Hospital, Kuala Lumpur. The ages of these patients ranged from 5 to 72 years, with the majority in the 20-30 year age group. There was no sex preponderance. The ethnic distribution showed a significant predominance of Chinese with 107 (71.8%) Chinese, 24 (16.1%) Malays, 15 (10.1%) Indians and 3 others. A wide range of renal glomerular pathology was seen, the commonest being diffuse mesangioproliferative glomerulonephritis (59.1%). Focal proliferative glomerulonephritis (14.1%) followed by minimal change glomerulonephritis (10.7%) were next in order of frequency. Immunofluorescence studies consistently demonstrated heavy and predominant IgA deposition in the mesangium. Weak deposition of C3, IgG and IgM were also observed in various combinations.


The Eph tyrosine kinase receptors EphB2 and EphA2 are novel proteolytic substrates of tissue factor/coagulation factor VIIa.
Tissue factor (TF) binds the serine protease factor VIIa (FVIIa) to form a proteolytically active complex that can trigger coagulation or activate cell signaling. Here we addressed the involvement of tyrosine kinase receptors (RTKs) in TF/FVIIa signaling by antibody array analysis and subsequently found that EphB2 and EphA2 of the Eph RTK family were cleaved in their ectodomains by TF/FVIIa. We used N-terminal Edman sequencing and LC-MS/MS analysis to characterize the cleaved Eph isoforms and identified a key arginine residue at the cleavage site, in agreement with the tryptic serine protease activity of FVIIa. Protease-activated receptor 2 (PAR2) signaling and downstream coagulation activity was non-essential in this context, in further support of a direct cleavage by TF/FVIIa. EphB2 was cleaved by FVIIa concentrations in the subnanomolar range in a number of TF expressing cell types, indicating that the active cellular pool of TF was involved. FVIIa caused potentiation of cell repulsion by the EphB2 ligand ephrin-B1, demonstrating a novel proteolytical event to control Eph-mediated cell segregation. These results define Eph RTKs as novel proteolytical targets of TF/FVIIa and provide new insights into how TF/FVIIa regulates cellular functions independently of PAR2.


Renin, aldosterone, and vasopressin responses to hypoxia during 6 hours of mild exercise.
The effect of hypoxia (H) on plasma renin (PRA), aldosterone (PA), and arginine vasopressin levels (AVP) was evaluated during 6 h of mild exercise (treadmill: 0 grade, 1 mph). A crossover study was performed on seven male volunteers during steady state conditions of H2O, Na+ and K+ balance while breathing 12.5% O2 (PaO2 42 +/- 3 mm Hg) and room air (N, 21% O2). After exercise there were no significant differences in body weight, hematocrit, calculated plasma volumes, serum or urine osmolality, urine Na+ or K+ excretion or AVP. Mean arterial pressure (MAP) while exercising was reduced during hypoxia (86 +/- 2 vs. 92 +/- 4 mm Hg), p less than 0.05. Normal diurnal variation in serum cortisol was lost during exercise (N and H). Plasma renin and aldosterone levels fell with exercise in both groups: PRA N 3.3 to 2.4 vs. H 4.9 to 2.3 ng X ml-1 X h-1; PA N 6.5 to 2.8 vs. H 9.3 to 2.3 ng X dl-1 (p less than 0.05). Hypoxia per se did not exert influence beyond mild exercise regarding serum osmolality, urine osmolality or Na+ or K+ excretion. Sustained hypoxia during 6 h of mild exercise despite a lower MAP failed to elevate PRA, aldosterone, or AVP levels when normal hydration is maintained.


Children as visionary change agents in Danish school health promotion.
This paper describes children's perceptions and visions for a healthier social and physical environment in the setting of a primary school on the Danish island of Bornholm. Guided by an everyday-life perspective and applying participatory action research methods including social imagination and visual techniques within the framework of future creating workshops, the study engaged 50 children aged 6-9 years in creative processes of identifying health-related problem areas and solutions in their school setting. The study observed that the children were very capable of articulating their thoughts, ideas and visions for a better and healthier school environment. Identified problem areas and solutions differed widely and represented a broad perspective of health including social, physical, environmental and emotional aspects. The paper discusses advantages and challenges of involving children in decision-making processes and concludes that children are visionary and creative agents of change in health promotion projects provided that applied participatory methods are appealing to the children.


Effect of an Antenatal Lifestyle Intervention on Dietary Inflammatory Index and Its Associations with Maternal and Fetal Outcomes: A Secondary Analysis of the PEARS Trial.
We investigated the effect of an antenatal lifestyle intervention of a low-glycaemic index (GI) diet and physical activity on energy-adjusted dietary inflammatory index (E-DIITM) and explored its relationship with maternal and child health in women with overweight and obesity. This was a secondary analysis of 434 mother-child pairs from the Pregnancy Exercise and Nutrition Study (PEARS) trial in Dublin, Ireland. E-DIITM scores were calculated for early (10-16 weeks) and late (28 weeks) pregnancy. Outcomes included lipids, inflammation markers, insulin resistance, mode of delivery, infant size, pre-eclampsia, and gestational diabetes. T-tests were used to assess changes in E-DIITM. Chi-square, correlations, and multiple regression were employed to investigate relationships with outcomes. The mean (SD) age of participants was 32.45 (4.29) years with median (IQR) BMI 28.25 (26.70, 31.34) kg/m2. There was no change in E-DIITM in the controls (-0.14 (1.19) vs. -0.07 (1.09), p = 0.465) but E-DIITM reduced by 10% after the intervention (0.01 (1.07) vs -0.75 (1.05), p < 0.001). No associations were found between early pregnancy E-DIITM and maternal and child outcomes, except for increased odds of adverse cardiometabolic phenotype in women who delivered male (OR = 2.29, p = 0.010) but not female infants (OR = 0.99, p = 0.960). A low-GI antenatal intervention can reduce the inflammatory potential of diets. Sex differences should be explored further in future research.


Antimicrobial efficacy and durability of copper formulations over one year of hospital use.
To evaluate 3 formulations of copper (Cu)-based self-sanitizing surfaces for antimicrobial efficacy and durability over 1 year in inpatient clinical areas and laboratories. Randomized control trial. We assessed 3 copper formulations: (1) solid alloy 80% Cu-20% Ni (integral copper), (2) spray-on 80% Cu-20% Ni (spray-on) and (3) 16% composite copper-impregnated surface (CIS). In total, 480 coupons (1 cm2) of the 3 products and control surgical grade (AISI 316) stainless steel were inserted into gaskets and affixed to clinical carts used in patient care areas (including emergency and maternity units) and on microbiology laboratory bench work spaces (n = 240). The microbial burden and assessment of resistance to wear, corrosion, and material compatibility were determined every 3 months. Participants included 3 tertiary-care Canadian adult hospital and 1 pediatric-maternity hospital. Copper formulations used on inpatient units statistically significantly reduced bacterial bioburden compared to stainless steel at months 3 and 6. Only the integral copper product had significantly less bacteria than stainless steel at month 12. No statistically significant differences were detected in microbial burden between copper formulations and stainless-steel coupons on microbiology laboratory benches where bacterial counts were low overall. All mass changes and corrosion rates of the formulations were acceptable by engineering standards. Copper surfaces vary in their antimicrobial efficacy after 1 year of hospital use. Frequency of cleaning and disinfection influence the impact of copper; the greatest reduction in microbial bioburden occurred in clinical areas compared to the microbiology laboratory where cleaning and disinfection were performed multiple times daily.


Factors influencing culture positivity in pyogenic vertebral osteomyelitis patients with prior antibiotic exposure.
We conducted a retrospective cohort study to evaluate factors influencing tissue culture positivity in patients with pyogenic vertebral osteomyelitis exposed to antibiotics before diagnosis. Tissue culture was positive in 48.3% (28/58) of the patients, and the median antibiotic-free period was 1.5 days (range, 0.7 to 5.7 days). In a multivariate analysis, a higher C-reactive protein (CRP) level (adjusted odds ratio [aOR], 1.18; 95% confidence interval, 1.07 to 1.29) and open surgical biopsy (aOR, 6.33; 95% confidence interval, 1.12 to 35.86) were associated with tissue culture positivity.


Epidemiology, pathophysiology and clinical presentation of gram-negative sepsis.
To review the epidemiology and pathophysiology of gram-negative sepsis and the new consensus terminology describing the clinical signs of sepsis. Review of the medical literature and compiled data from animal and clinical trials. Members of the Society of Critical Care Medicine, American College of Chest Physicians and American Association of Critical-Care Nurses with expertise on the subject of sepsis and its complications. Preconference and general sessions were offered at the National Teaching Institutes of the American Association of Critical-Care Nurses, with the goal of clarifying the epidemiology, risk factors and pathophysiology of gram-negative sepsis. In addition, current terminology and new (1992) consensus terminology describing the clinical signs of sepsis were presented. Special emphasis was placed on the role of the healthcare provider in the prevention and recognition of sepsis and the role of the septic mediators in the septic cascade. If the incidence of sepsis is to be reduced, the healthcare provider must be aware of the risk factors for sepsis and methods of reducing nosocomial infections. A thorough understanding of the role of mediators and consensus terminology used to describe sepsis, severe sepsis, septic shock and multiple organ dysfunction syndrome is necessary to recognize early or progressive signs of sepsis and to initiate state-of-the-art therapy.


Including oral health training in a health system strengthening program in Rwanda.
Rwanda's Ministry of Health, with the Clinton Health Access Initiative, implemented the Human Resources for Health (HRH) Program. The purpose of the program is to train and retain high-quality health care professionals to improve and sustain health in Rwanda. In May 2011, an oral health team from Rwanda and the United States proposed that oral health be included in the HRH Program, due to its important links to health, in a recommendation to the Rwandan Ministry of Health. The proposal outlined a diagonal approach to curriculum design that supports the principles of global health through interconnected training for both treatment and collaborative prevention, rather than discipline-based fragmented training focused on isolated risk factors. It combined 'vertical' direct patient care training with 'horizontal' interdisciplinary training to address common underlying risk factors and associations for disease through primary care, program retention, and sustainability. The proposal was accepted by the Ministry of Health and was approved for funding by the US Government and The Global Fund. Rwanda's first Bachelor of Dental Surgery program, which is in the planning phase, is being developed. Competencies, the training curriculum, insurance and payment schemes, licensure, and other challenges are currently being addressed. With the Ministry of Health supporting the dental HRH efforts and fully appreciating the importance of oral health, all are hopeful that these developments will ultimately lead to more robust oral health data collection, a well-trained and well-retained dental profession, and vastly improved oral health and overall health for the people of Rwanda in the decades to come.


Alignment, Classification, Clinical Evaluation, and Surgical Treatment for Adult Cervical Deformity: A Complete Guide.
Adult cervical deformity management is complex and is a growing field with many recent advancements. The cervical spine functions to maintain the position of the head and plays a pivotal role in influencing subjacent global spinal alignment and pelvic tilt as compensatory changes occur to maintain horizontal gaze. There are various types of cervical deformity and a variety of surgical options available. The major advancements in the management of cervical deformity have only been around for a few years and continue to evolve. Therefore, the goal of this article is to provide a comprehensive review of cervical alignment parameters, deformity classification, clinical evaluation, and surgical treatment of adult cervical deformity. The information presented here may be used as a guide for proper preoperative evaluation and surgical treatment in the adult cervical deformity patient.


The costs of managing advanced colorectal cancer: a broad perspective.
Cancer care is expensive, consuming between 5 and 10% of health-care resources in industrialized countries. Therefore increasing emphasis is being placed on the value of treatment interventions. Colorectal cancer is the second most common cancer in the Western world and nearly two-thirds of patients will require palliative treatment. Only limited data are available on the cost of palliative chemotherapy for patients with advanced disease. The profile of raltitrexed ('Tomudex', formerly ZD1694) suggests that it may reduce costs associated with the administration of chemotherapy. Recent studies demonstrate that the total monthly cost of raltitrexed is lower or about the same as a variety of commonly used 5-fluorouracil-based regimens and offers potential savings for hospitals in terms of demand on specialist facilities, physician, nursing and pharmacy time, and overnight bed occupancy. The personal cost borne by patients and their carers for travelling and time off work is reduced with raltitrexed compared with the widely used Mayo regimen. However, there may be disincentives within certain national health-care systems to the introduction of a more resource-efficient drug such as raltitrexed. Physicians will need information on both the benefits and costs of drug treatments to be able to make informed decisions on the provision of high quality, cost-effective patient care, and it is likely that health economic assessment will be incorporated into increasing numbers of clinical trials.


Molecular Dynamics Study of the Influence of Nano SiO2 on the Thermodynamic Properties of PMIA Composites.
The poly-m-phenyleneisophthalamide (PMIA) is widely used in the electrical field due to its numerous favorable characteristics, but its poor thermal conductivity limits its application. In this study, PMIA was modified with nano-silica (SiO2) to improve its thermal and mechanical properties. Using iso-phthalic acid and m-phenylenediamine as monomers, the changes in the thermodynamic properties and microstructure parameters of SiO2-modified PMIA were analyzed using molecular dynamics before and after modification in the temperature range of 250~450 K. It was found that adding SiO2 improves the Young's modulus and Shear modulus of PMIA, and the mechanical properties of PMIA, and SiO2/PMIA composites deteriorate with increasing temperature, but the mechanical properties of SiO2/PMIA composites are always better than those of pure PMIA in the temperature range of electrical equipment. Meanwhile, after doping SiO2 with the radius of 8 Å, the glass transition temperature of PMIA increases by 27.11 K, and its thermal conductivity increases from 0.249 W m-1 K-1 to 0.396 W m-1 K-1. When SiO2 is added to PMIA, the thermal expansion coefficient of PMIA will decrease in both glass and rubber states, and its thermal stability will improve. In terms of microstructure parameters, the free volume distribution of the SiO2/PMIA model is less easily dispersed than that of the PMIA model, indicating that the addition of SiO2 can improve the related properties of PMIA by hindering the movement of molecular chains.


Update on Radiotherapy Changes of Nasopharyngeal Carcinoma Tumor Microenvironment.
The utilization of radiotherapy (RT) serves as the principal approach for managing nasopharyngeal carcinoma (NPC). Consequently, it is imperative to investigate the correlation between the radiation microenvironment and radiation resistance in NPC. PubMed and China National Knowledge Infrastructure (CNKI) databases were accessed to perform a search utilizing the English keywords "nasopharyngeal cancer", "radiotherapy", and "microenvironment". The search time spanned from the establishment of the database until January 20, 2023. A total of 82 articles were included. The post-radiation tumor microenvironment (TME), or the radiation microenvironment, includes several components, such as the radiation-immune microenvironment and the radiation-hypoxic microenvironment. The radiation-immune microenvironment includes various factors like immune cells, signaling molecules, and extracellular matrix. RT can reshape the TME, leading to immune responses with both cytotoxic effects (T cells, B cells, natural killer (NK) cells) and immune escape mechanisms (regulatory T cells (Tregs), macrophages). RT enhances immune responses through DNA release, type I interferons, and immune cell recruitment. Radiation-hypoxic microenvironment affects metabolism and molecular changes. RT-induced hypoxia causes vascular changes, fibrosis, and vessel compression, leading to tissue hypoxia. Hypoxia activates hypoxia-inducible factor (HIF)-1α/2α, promoting angiogenesis and glycolysis in tumor cells. TME changes due to hypoxia also involve immune suppressive cells like myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Tregs. The radiation microenvironment is involved in radiation resistance and holds a significant effect on the prognosis of patients with NPC. Exploring the radiation microenvironment provides new insights into RT and NPC research.


Nifedipine maintenance tocolysis and perinatal outcome: an individual participant data meta-analysis.
Preterm birth is the leading cause of neonatal mortality and morbidity in developed countries. Whether continued tocolysis after 48 hours of rescue tocolysis improves neonatal outcome is unproven. To evaluate the effectiveness of maintenance tocolytic therapy with oral nifedipine on the reduction of adverse neonatal outcomes and the prolongation of pregnancy by performing an individual patient data meta-analysis (IPDMA). We searched PubMed, Embase, and Cochrane databases for randomised controlled trials of maintenance tocolysis therapy with nifedipine in preterm labour. We selected trials including pregnant women between 24 and 36(6/7) weeks of gestation (gestational age, GA) with imminent preterm labour who had not delivered after 48 hours of initial tocolysis, and compared maintenance nifedipine tocolysis with placebo/no treatment. The primary outcome was perinatal mortality. Secondary outcome measures were intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), infant respiratory distress syndrome (IRDS), prolongation of pregnancy, GA at delivery, birthweight, neonatal intensive care unit admission, and number of days on ventilation support. Pre-specified subgroup analyses were performed. Six randomised controlled trials were included in this IPDMA, encompassing data from 787 patients (n = 390 for nifedipine; n = 397 for placebo/no treatment). There was no difference between the groups for the incidence of perinatal death (risk ratio, RR 1.36; 95% confidence interval, 95% CI 0.35-5.33), intraventricular haemorrhage (IVH) ≥ grade II (RR 0.65; 95% CI 0.16-2.67), necrotising enterocolitis (NEC) (RR 1.15; 95% CI 0.50-2.65), infant respiratory distress syndrome (IRDS) (RR 0.98; 95% CI 0.51-1.85), and prolongation of pregnancy (hazard ratio, HR 0.74; 95% CI 0.55-1.01). Maintenance tocolysis is not associated with improved perinatal outcome and is therefore not recommended for routine practice. Nifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation.


Mosquito swarms shear harden.
Recently Cavagna et al. (Sci Rep 13(1): 8745, 2023) documented the swarming behaviors of laboratory-based Anopheles gambiae mosquitoes. Here key observations from this 3D-video tracking study are reproduced by a minimally structured (maximum entropy) stochastic trajectory model. The modelling shows that in contrast with midge swarms which are a form of collective behavior, unperturbed mosquito swarms are more like collections of individuals that independently circulate around a fixed location. The modelling predicts the observed response Anopheles gambiae mosquitoes in wild swarms to varying wind speeds (Butail et al. in J Med Entomol 50(3): 552-559, 2013). It is shown that this response can be attributed to shear hardening. This is because mosquitoes are found to be attracted to the centre of the swarm by an effective force that increases with increasing flight speed. Mosquitoes can therefore better resist the influence of environmental disturbances by increasing their flight speeds. This contrasts with other emergent mechanical-like properties of swarming which arise accidentally without a change in an individual's behavior. The new results add to the growing realization that perturbations can drive swarms into more robust states.


Factors affecting the formation of chlorotrifluoroethane and chlorodifluoroethylene from halothane.
Since CF3CH2Cl and CF2CHCl are probably the products of reactive intermediates formed during the reductive metabolism of halothane (CF3CHClBr), factors affecting their in vitro and in vivo formation were investigated. In vitro studies with rat hepatic microsomes showed that CF3CH2Cl and CF2CHCl are produced by cytochrome P-450 mediated reductive pathways which were inhibited by the presence of CO. Under conditions of exposure known to promote halothane hepatotoxicity in phenobarbital treated rats (1 per cent halothane, 14 per cent oxygen), the hepatic and blood concentrations of the volatile metabolites were enhanced. Central venous levels of the volatile metabolites were much higher than he concentration in peripheral vessels. The CF3CH2Cl/CF2CHCl ratio in blood was approximately three, whereas the ratio in vitro was almost unity. Liver levels of the two volatile metabolites greatly exceeded the blood levels, but interestingly they were present in equivalent concentrations. The differences in the ratio of CF3CH2Cl to CF2CHCl may be explained by the fact that CF2CHCl is further degraded under oxidative conditions, whereas CF3CH2Cl appears relatively stable. Measurement of these metabolic products in patients undergoing halothane anesthesia may permit rapid detection of an unusually high level of halothane biotransformation along its hepatotoxic pathway.


Transient synovitis of the hip : is systematic radiological screening necessary for the detection of Perthes disease?
Current imaging guidelines in Belgium advise a systematic X-ray screening of the hips after an episode of transient synovitis of the hip, in order to detect Perthes disease. The aim of this study was to analyze whether systematic radiological screening is necessary for all children or whether the X-ray indication could be guided by clinical symptoms. A retrospective single center study including all children with the diagnosis of transient synovitis of the hip between 2013 and 2018 was performed. 242 patients with the diagnosis of one or more transient synovitis episodes were included, 102 of whom underwent a follow up X-ray. Persistence or recurrence of symptoms were recorded for all patients, as well as the results of follow-up hip X-rays. 12 children did not remain symptom-free after the episode of transient synovitis. Of these patients 10 had a normal follow-up X-ray and 3 were diagnosed with Perthes disease. 1 patient of those 3 had a normal X-ray but was diagnosed with Perthes disease on MRI. Of the children which remained symptom-free after the episode of transient synovitis, none were diagnosed with Perthes disease afterwards. A follow-up X-ray to exclude Perthes disease after a diagnosis of transient hip synovitis appears to be necessary only in patients with persistent or recurrent symptomatology.


Acoustic Energy Release During the Laboratory Seismic Cycle: Insights on Laboratory Earthquake Precursors and Prediction.
Machine learning can predict the timing and magnitude of laboratory earthquakes using statistics of acoustic emissions. The evolution of acoustic energy is critical for lab earthquake prediction; however, the connections between acoustic energy and fault zone processes leading to failure are poorly understood. Here, we document in detail the temporal evolution of acoustic energy during the laboratory seismic cycle. We report on friction experiments for a range of shearing velocities, normal stresses, and granular particle sizes. Acoustic emission data are recorded continuously throughout shear using broadband piezo-ceramic sensors. The coseismic acoustic energy release scales directly with stress drop and is consistent with concepts of frictional contact mechanics and time-dependent fault healing. Experiments conducted with larger grains (10.5 μm) show that the temporal evolution of acoustic energy scales directly with fault slip rate. In particular, the acoustic energy is low when the fault is locked and increases to a maximum during coseismic failure. Data from traditional slide-hold-slide friction tests confirm that acoustic energy release is closely linked to fault slip rate. Furthermore, variations in the true contact area of fault zone particles play a key role in the generation of acoustic energy. Our data show that acoustic radiation is related primarily to breaking/sliding of frictional contact junctions, which suggests that machine learning-based laboratory earthquake prediction derives from frictional weakening processes that begin very early in the seismic cycle and well before macroscopic failure.


Conformation- and fusion-defective mutations in the hypothetical phospholipid-binding and fusion peptides of viral hemorrhagic septicemia salmonid rhabdovirus protein G.
Fourteen single and two double point mutants in the highly conserved region (positions 56 to 159) of the G gene of viral hemorrhagic septicaemia virus (VHSV), a salmonid rhabdovirus, were selected and obtained in plasmids by site-directed mutagenesis. Fish cell monolayers transfected with the mutant plasmids were then assayed for protein G (pG) expression, conformation-dependent monoclonal antibody (MAb) reactivity, and cell-cell fusion. Some mutations located in the phospholipid-binding p2 peptide (positions 82 to 110; mutants P86A, A96E, G98A, and R107A) abolished both MAb recognition and fusion activity, while others (P79A, L85S, and R103A) abolished MAb recognition but retained fusion at similar or lower pHs compared to those for the wild type. Phospholipid-binding assays of p2-derived synthetic peptides suggested that phosphatidylserine binding was not affected by the mutations studied. On the other hand, three (P79A, L85S, and T135E) of the four mutants retaining fusion activity mapped around two locations showing amino acid variation in 22 VHSV isolates and in neutralizing MAb-resistant mutants described previously. Mutations located in the hypothetical fusion peptide (positions 142 to 159; mutants F147K, P148K, and W154K) abolished both MAb recognition and fusion activity. The existence of mutants with altered conformation and defective fusion in both p2 and fusion peptides provides further evidence in favor of the participation of these and adjacent regions in some of the steps of the VHSV fusion processes, as suggested by previous studies. In addition, because the studied region induced strong immunological responses in trout, some of the mutants described here might be used to design attenuated VHSV vaccines.


A comparison of epidermal growth factor receptor-mediated mitogenic signaling in response to transforming growth factor alpha and epidermal growth factor in cultured fetal rat hepatocytes.
We compared the ability of Epidermal Growth Factor (EGF) and Transforming Growth Factor alpha (TGF alpha) to transduce a mitogenic signal via their common receptor, the EGF receptor, in primary cultures of fetal rat hepatocytes. Mitogenic potency, measured as DNA synthesis, was similar in response to EGF and TGF alpha although signal initiation, measured as EGF receptor tyrosine phosphorylation, was more than 3-fold higher in response to EGF compared to TGF alpha. Downstream signal transduction events including Shc tyrosine phosphorylation, Shc/Grb2 complex formation and MAP kinase activation were similar in response to EGF and TGF alpha, thus indicating a dissociation between potency for receptor activation versus signal propagation. These data suggest that TGF alpha may preferentially activate an EGF receptor population linked to the Ras/MAP kinase pathway. In contrast, EGF shows no such selectivity, thereby reducing the mitogenic potency of EGF relative to its ability to activate the EGF receptor.


Leg muscle activity during whole-body vibration in individuals with chronic stroke.
It has been previously shown that whole-body vibration (WBV) can augment muscle activity in young healthy adults. However, the EMG response of leg muscles during WBV in individuals with stroke is unknown. The objective of this study was to determine the influence of WBV on the activity of the vastus lateralis (VL) and gastrocnemius (GS) muscles during the performance of different exercises in chronic stroke patients. Forty-five chronic stroke patients were studied. Each subject was exposed to three WBV conditions of 1) no WBV, 2) low-intensity WBV protocol (peak acceleration: 0.96 unit of gravitational constant [g]), and 3) high-intensity WBV protocol (peak acceleration: 1.61g) while performing eight different static exercises involving upright standing, semisquat, deep squat, weight shifted forward, weight shifted backward, weight shifted to the side, forward lunge, and single-leg standing. Bilateral VL and GS muscle activity was recorded with surface EMG and expressed as a percentage of the EMG amplitude recorded during a maximal voluntary contraction of the respective muscles. Two-way repeated-measures ANOVA revealed that exposure to WBV (low- and high-intensity protocols) significantly increased VL and GS EMG amplitude (large effect size, partial η = 0.135-0.643, P < 0.001) on both the paretic and nonparetic sides in different exercise conditions compared with no WBV. No significant difference in EMG magnitude was found between the high- and the low-intensity WBV protocols (P > 0.05). With a few exceptions, WBV enhanced EMG activity in the paretic and nonparetic leg muscles to a similar extent in different exercise conditions. Leg muscle activity was increased significantly with the addition of WBV. Further clinical trials are needed to determine the effectiveness of different WBV protocols for strengthening leg muscles in chronic stroke patients.


Childhood Adversity, Resilience, and Mental Health: A Sequential Mixed-Methods Study of Chinese Young Adults.
Resilience is a key health protective factor for those with adverse childhood experiences (ACEs), but little research has explored how it manifests in early adulthood or across cultures. The purpose of this study was to generate a fuller understanding of resilience and its contribution to the relationships between mental health problems and ACEs among Chinese young adults in Hong Kong. Using a sequential explanatory mixed-methods design, 433 Chinese young adults aged 18 to 24 years were surveyed online to examine the relationships between ACEs, resilience, and mental health problems (depression, anxiety, maladjustment, and posttraumatic stress symptoms). Among them, 34 participants with ACEs were purposively selected and interviewed to explore cultural factors that influenced their resilience. Quantitative data were analyzed using multiple hierarchical regression analyses; qualitative data were analyzed using a qualitative descriptive approach. Higher cumulative ACE exposure was associated with higher severity of adjustment disorder and odds for screening positive for posttraumatic stress disorders, but not for symptoms of depression or anxiety. Resilience significantly contributed to explaining variances across all mental health outcomes over and beyond ACEs and in a protective fashion. Four themes emerged from qualitative interviews: (a) Privacy, emotional restraint, and "saving face"; (b) Conforming to preserve harmony; (c) A will to excel; and (d) Viewing adversity as a matter of luck. These findings suggest Chinese young adults' resilience was influenced by cultural norms of restraint, conformity, competition, and superstition. The present study provides a model for future studies using a mixed-methods design to deeply examine resilience among younger people exposed to early adversities within sociocultural, historical, or geographical contexts.


History of chickenpox and shingles and prevalence of antibodies to varicella-zoster virus and three other herpesviruses among adults with glioma and controls.
Whether viruses or immunologic factors might cause or prevent human brain cancer is of interest. Statistically significant inverse associations of adult glioma with history of chickenpox and immunoglobulin G antibodies to varicella-zoster virus have been reported. The authors evaluate associations of immunoglobulin G antibodies to varicella-zoster virus and three other herpesviruses among 229 adults with glioma and 289 controls in the San Francisco Bay Area Adult Glioma Study (1997-2000). Cases were less likely than controls to report a history of chickenpox (for self-reported cases vs. controls: the age-, gender-, and ethnicity-adjusted odds ratio = 0.59, 95% confidence interval: 0.40, 0.86), and they also had lower levels of immunoglobulin G to varicella-zoster virus (for being in the highest quartile vs. the lowest quartile: the age-, gender-, and ethnicity-adjusted odds ratio = 0.41, 95% confidence interval: 0.24, 0.70). The inverse association with anti-varicella-zoster virus immunoglobulin G was most marked for glioblastoma multiforme cases versus controls and was only somewhat attenuated by excluding subjects taking high-dose steroids and other medications. Cases and controls did not differ notably for positivity to three other herpesviruses, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus. Cohort studies may help to clarify the nature of the association between immunity to and/or clinical manifestations of varicella-zoster virus and glioblastoma.


Chronic critical illness: the growing challenge to health care.
The chronically critically ill (CCI) comprise a rapidly growing population of patients who have survived acute critical illness, only to be left with ongoing organ dysfunctions requiring high levels of specialized care for months or years. In many ways, CCI is an "iatrogenic" process, reflecting the ability of modern life support technologies to keep patients alive for prolonged periods of time despite ongoing life threatening illness. Venues of care for the CCI patient include acute care hospitals (both ICU and step-down facilities), specialized long term acute care hospitals, and, less commonly, skilled nursing facilities, or even the home. Importantly, CCI patients transition among these venues frequently, reflecting the nature of CCI to be punctuated with episodes of acute critical illness. Management of the CCI population requires a special combination of intensive care and rehabilitative skills.


Alcohol Promotes Exosome Biogenesis and Release via Modulating Rabs and miR-192 Expression in Human Hepatocytes.
Exosomes are membrane vesicles released by various cell types into the extracellular space under different conditions including alcohol exposure. Exosomes are involved in intercellular communication and as mediators of various diseases. Alcohol use causes oxidative stress that promotes exosome secretion. Here, we elucidated the effects of alcohol on exosome biogenesis and secretion using human hepatocytes. We found that alcohol treatment induces the expression of genes involved in various steps of exosome formation. Expression of Rab proteins such as Rab1a, Rab5c, Rab6, Rab10, Rab11, Rab27a and Rab35 were increased at the mRNA level in primary human hepatocytes after alcohol treatment. Rab5, Rab6 and Rab11 showed significant induction in the livers of patients with alcohol-associated liver disease. Further, alcohol treatment also led to the induction of syntenin, vesicle-associated membrane proteins (VAMPs), and syntaxin that all play various roles in exosome biogenesis and secretion. VAMP3, VAMP5, VAPb, and syntaxin16 mRNA transcripts were increased in alcohol treated cells and in the livers of alcohol-associated liver disease (ALD) patients. Induction in these genes was associated with increases in exosome secretion in alcohol treated hepatocytes. We found that hepatocyte enriched miR-192 and miR-122 levels were significantly decreased in alcohol treated hepatocytes whereas their levels were increased in the cell-free supernatant. The primary transcripts of miR-192 and miR-122 were reduced in alcohol treated hepatocytes, suggesting alcohol partially affects these miRNAs at the transcriptional level. We found that miR-192 has putative binding sites for genes involved in exosome secretion. Inhibition of miR-192 in human hepatoma cells caused a significant increase in Rab27a, Rab35, syntaxin7 and syntaxin16 and a concurrent increase in exosome secretion, suggesting miR-192 regulates exosomes release in hepatocytes. Collectively, our results reveal that alcohol modulates Rabs, VAMPs and syntaxins directly and partly via miR-192 to induce exosome machinery and release.


Deep Sequencing Reveals Central Nervous System Compartmentalization in Multiple Transmitted/Founder Virus Acute HIV-1 Infection.
HIV-1 disseminates to a broad range of tissue compartments during acute HIV-1 infection (AHI). The central nervous system (CNS) can serve as an early and persistent site of viral replication, which poses a potential challenge for HIV-1 remission strategies that target the HIV reservoir. CNS compartmentalization is a key feature of HIV-1 neuropathogenesis. Thus far, the timing of how early CNS compartmentalization develops after infection is unknown. We examined whether HIV-1 transmitted/founder (T/F) viruses differ between CNS and blood during AHI using single-genome sequencing of envelope gene and further examined subregions in pol and env using next-generation sequencing in paired plasma and cerebrospinal fluid (CSF) from 18 individuals. Different proportions of mostly minor variants were found in six of the eight multiple T/F-infected individuals, indicating enrichment of some variants in CSF that may lead to significant compartmentalization in the later stages of infection. This study provides evidence for the first time that HIV-1 compartmentalization in the CNS can occur within days of HIV-1 exposure in multiple T/F infections. Further understanding of factors that determine enrichment of T/F variants in the CNS, as well as potential long-term implications of these findings for persistence of HIV-1 reservoirs and neurological impairment in HIV, is needed.


Community-level socioeconomic status and outcomes of patients with out-of-hospital cardiac arrest: A systematic review and meta analysis.
The aim of this systematic review and meta-analysis was to investigate the associations of community-level socioeconomic status (SES) on outcomes of patients with out-of hospital cardiac arrest (OHCA). A systematic literature review was conducted using PubMed, EMBASE, and the Cochrane database according to guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We included literature that presented the outcomes based on community-level SES among patients with OHCA. SES indicators included economic indicators such as income, wealth, and occupation, as well as combined indicators, where any of these indicators were integrated. Outcomes were bystander cardiopulmonary resuscitation (CPR) and survival to discharge. From 1394 titles, 10 cross-sectional observational studies fulfilled inclusion and exclusion criteria, representing 118,942 patients with OHCA. The odds ratios (ORs) of bystander CPR and survival to discharge for lower community-level SES patients were lower than those for higher community-level SES by economic SES indicators (bystander CPR OR 0.67; 95% CI 0.51-0.89, survival to discharge OR 0.60; 95% CI 0.35-1.02). Based on combined SES indicators the results showed similar patterns (bystander CPR OR 0.80; 95% CI 0.75-0.84, survival to discharge OR 0.76; 95% CI 0.63-0.92). In this meta-analysis, community-level SES was significantly associated with bystander CPR and survival among patients with OHCA.


Monitoring And Managing Depression In Adolescents With Epilepsy: Current Perspectives.
Epilepsy is associated with a significantly increased risk of developing depressive disorder during adolescence. On the other hand, depression is highly detected in adolescents with epilepsy. These findings highlight the importance of early identification and proper management of comorbid depression in adolescent age. The prevalence of depressive disorders in adolescents with epilepsy ranges between 8 and 35% and is higher than the general population of the same age. The relationship between epilepsy and depression is complex and potentially bidirectional, thereby suggesting a common underlying pathophysiology. Furthermore, failure to detect and treat depressive disorder mostly in adolescence could lead to several negative implications such as an increased risk of suicidal ideation or behavior and poor quality of life. A number of methods are available to detect depressive disorder, such as psychiatric or psychological assessments, structured or semi-structured interviews, and self-report screening tools. Thus, physicians should be able to regularly screen depressive symptoms in youths with epilepsy. Recently, the NDDI-E-.Y inventory has been developed from the adult NDDI-E, and has been validated in many countries. NDDI-E-Y has showed reliable validity, being a brief screening tool (12 items) that can be easily included in routine epilepsy care. The first step to be considered for the management of depressive disorder in adolescents with epilepsy is to consider potential reversible causes of anxiety and depression (i.e., a new AEDs; seizure control). Secondly, great attention has to be given to the education of the child/adolescent and his/her family, trying to improve knowledge about epilepsy as well as to decrease parental stress and improving the child's sense of competence. Pharmacological treatment should also be considered in adolescents diagnosed with depression.


3-O-sulfo-β-D-galactose moiety of endogenous sulfoglycolipids is a potential ligand for immunoglobulin-like receptor LMIR5.
Axonal Guillain-Barré syndrome (GBS) is an autoimmune neuropathy characterized by limb weakness and/or paralysis due to the presence of autoantibodies against brain glycolipids. The immune receptors that recognize these autoimmune targets have not been described. In this study, 12 C-type lectin and 10 immunoglobulin-like receptors were screened for their potential ligands from the brain glycolipids, which are the binding targets for GBS autoantibodies. These glycolipids were GM1, GM2, GD1a, GD1b, GQ1b, crude gangliosides, and 3-O-sulfo-β-D-galactosylceramide C24:1 (designated as C24:1). A direct interaction between ligand and receptor was examined using an ELISA-based binding assay. C-type lectin (CLEC5a, SIGNR3) and immunoglobulin-like receptors (TREM2, TREM3, LMIR2, LMIR5, LMIR7, LMIR8) interacted with C24:1. In addition, TREM3 did bind to GQ1b. LMIR5 interacted with GD1a, GQ1b, and crude gangliosides. Binding with highest affinity was observed for the LMIR5-C24:1 interaction, which was selected for further verification. C24:1 was found to induce MCP-1 production, but not proinflammatory cytokines, in basophils. C24:1-induced MCP-1 production was significantly reduced in DAP12(-/-) basophils. Importantly, LMIR5 ligation by C24:1 resulted in NFAT activation through DAP12 in LMIR5-expressing reporter cells. Structural analysis showed that LMIR5 recognized the 3-O-sulfo-β-D-galactose moiety of C24:1. The findings indicated that C24:1 is a potential ligand for DAP12-coupled LMIR5.


Doubly Strapped Redox-Switchable 5,10,15,20-Tetraaryl-5,15-diazaporphyrinoids: Promising Platforms for the Evaluation of Paratropic and Diatropic Ring-Current Effects.
This paper presents a novel series of chemically stable and redox-switchable 20π, 19π, and 18π 5,10,15,20-tetraaryl-5,15-diazaporphyrinoids (TADAPs) that have two alkyl-chain straps above and below the diazaporphyrin ring. Three types of doubly strapped TADAPs were prepared as nickel(II) complexes using meso-N-(2,6-dihydroxyphenyl)-substituted TADAP and the corresponding aliphatic diacids as precursors. Theoretical calculations revealed that regardless of their oxidation states, all strapped TADAPs had essentially flat π-planes. It was found that the alkyl-chain straps slightly affected the optical and electrochemical properties of the DAP rings, particularly in the oxidized forms. 1H NMR spectroscopy was used to evaluate the antiaromatic character of the 20π TADAPs and the aromatic character of the 18π TADAP dications, and it was observed that they displayed paratropic and diatropic ring-current effects, respectively, on the chemical shifts of methylene protons in the spatially separated alkyl chains. The degree of shielding and deshielding depended on the position of the methylene units; it decreased with increase in separation from the π-plane and central axis of the porphyrin ring. The NMR experiments also revealed that the degree of the diatropic ring currents was clearly related to the π-electron density of the porphyrin ring; the ring-current effects decreased as the charge increased from 0 to +2. These findings are also qualitatively supported by the nucleus-independent chemical shifts.


Pharmacokinetics, metabolism and toxicity of the plant-derived photoxin alpha-terthienyl.
The plant-derived insecticide, alpha-terthienyl was prepared by synthesis as 3',4'-di[14C]-alpha-terthienyl for pharmacokinetic and metabolism studies. When administered orally to rats at a single dose of 50 mg/kg, excretion of the labelled material was maximal one day after administration and declined to no measurable quantities by day 4. Two metabolites [1,4-di(2'-thienyl)1,4-butadione and 2-2'-bithiophene-5-carboxylic acid] and trace quantities of the parent material were isolated from the urine and chemically identified. These represent the first metabolites of alpha-terthienyl identified. In pilot acute and subacute trials, unlabelled alpha-terthienyl was non-toxic when administered orally to rats as the "ready to use" formulation (0.1% active ingredient). The pure compound had an LD50 of 110 mg/kg when administered intraperitoneally to rats. The results suggest that there is considerable separation with respect to mosquito larvae and non-target mammal sensitivity.


Markers of Kidney Tubule Dysfunction and Major Adverse Kidney Events.
Serum creatinine and albuminuria are primary markers of glomerular function and injury, respectively. Tubular secretion, acid-base homeostasis, protein reabsorption, among other tubular functions, are largely ignored. This mini-review aimed to discuss how two tubular functions, secretion, and acid-base homeostasis are associated with major adverse kidney events (MAKEs). Proximal tubular secretion is an essential function that allows the elimination of endogenous substances and drugs. Recently discovered endogenous markers in urine and plasma allow a noninvasive way of assessing tubular secretion markers. Several studies have found an association between these markers and a higher risk of chronic kidney disease (CKD) progression and mortality. In a study we recently performed among patients with CKD and at risk of cardiovascular events, lower tubular secretion was associated with an increased risk of acute kidney injury and metabolic acidosis, independent of baseline eGFR and albuminuria. The kidney tubules also play a crucial role in acid-base homeostasis. Although the standard clinical assessment of acidosis consists of measuring serum bicarbonate, urinary ammonium excretion decreases before over metabolic acidosis. Urinary ammonium excretion is associated with CKD progression, a higher risk of kidney failure, and an increased mortality risk, independent of baseline eGFR and albuminuria. Novel biomarkers of kidney tubular health consistently associate with MAKEs, above and beyond baseline eGFR, albuminuria, and other CKD risk factors. Tubular markers may provide new opportunities to improve kidney prognosis, drug dosing, and monitoring for adverse events.


Beneficial Root Endophytic Fungi Increase Growth and Quality Parameters of Sweet Basil in Heavy Metal Contaminated Soil.
How interactions between plants, the rhizosphere, and contaminated soil affect environmental sustainability is still under research. We tested the effects of two root endophytic fungi, the arbuscular mycorrhiza fungus (AMF) Rhizophagus irregularis and the beneficial endophyte Serendipita indica, on sweet basil (Ocimum basilicum) growing on soil contaminated with lead and copper in a pot experiment under defined greenhouse conditions. Both fungi caused an increase in shoot and root dry weight of sweet basil plants under all conditions and decreased the amount of lead in shoots. The amount of copper was reduced by S. indica, while the AM fungus showed this effect only when the soil is contaminated with both copper and lead. Furthermore the AMF, but not the endophyte S. indica caused a strong increase on the concentrations of the essential oils linalool and eucalyptol even on sweet basil growing on contaminated soils. Hence, cultivating sweet basil in combination with beneficial fungi in case of difficult environmental conditions could be of interest for industry located in countries with widespread land pollution, because quantity and quality of plants are increased while the amount of heavy metals is generally reduced.


Adverse drug event notification on a semantic interoperability framework.
Adverse drug events (ADEs) are common, costly and one of the most important issues in contemporary pharmacotherapy. Current drug safety surveillance methods are largely based on spontaneous reports. However, this is known to be rather ineffective. There is a lack of automated systems checking potential ADEs on routine data captured in electronic health records (EHRs); present systems are usually built directly on top of specific clinical information systems through proprietary interfaces. In the context of the European project "SALUS", we aim to provide an infrastructure as well as a tool-set for accessing and analyzing clinical patient data of heterogeneous clinical information systems utilizing standard methods. This paper focuses on two components of the SALUS architecture: The "Semantic Interoperability Layer" (SIL) enables an access to disparate EHR sources in order to provide the patient data in a common data model for ADE detection within the "ADE Detection and Notification Tool" (ANT). The SIL in combination with the ANT can be used in different clinical environments to increase ADE detection and reporting rates. Thus, our approach promises a profound impact in the domain of pharmacovigilance.


Additive and synergistic effects of bFGF and hypoxia on leporine meniscus cell-seeded PLLA scaffolds.
Injuries to avascular regions of menisci do not heal and result in significant discomfort to patients. Current treatments, such as partial meniscectomy, alleviate these symptoms in the short term but lead to premature osteoarthritis as a result of compromised stability and changes in knee biomechanics. Thus, tissue engineering of the meniscus may provide an alternative treatment modality to overcome this problem. In this experiment, a scaffold-based tissue-engineering approach was utilized to regenerate the meniscus. Meniscus cells were cultured on poly-L-lactic acid scaffolds in normoxic (approximately 21% oxygen) or hypoxic (approximately 2% oxygen) conditions in the presence or absence of the growth factor, basic fibroblast growth factor (bFGF). At t = 4 weeks, histological sections of constructs showed presence of collagen and glycosaminoglycan (GAG) in all groups. Immunohistochemical staining showed the presence of collagen I in all groups and collagen II in groups cultured under hypoxic conditions. bFGF in the culture medium significantly increased cell number/construct by 25%, regardless of culture conditions. For GAG/construct, synergistic increases were observed in constructs cultured in hypoxic conditions and bFGF (two-fold) when compared to constructs cultured in normoxic conditions. Compressive tests showed synergistic increases in the relaxation modulus and coefficient of viscosity and additive increases in the instantaneous modulus for constructs cultured under hypoxic conditions and bFGF, when compared to constructs cultured under normoxic conditions. Overall, these results demonstrate that bFGF and hypoxia can significantly enhance the ability of meniscus cells to produce GAGs and improve the compressive properties of tissue-engineered meniscus constructs in vitro.


Stereotactic Body Radiation Therapy and Abiraterone Acetate for Patients Affected by Oligometastatic Castrate-Resistant Prostate Cancer: A Randomized Phase II Trial (ARTO).
ARTO (ClinicalTrials.gov identifier: NCT03449719) is a multicenter, phase II randomized clinical trial testing the benefit of adding stereotactic body radiation therapy (SBRT) to abiraterone acetate and prednisone (AAP) in patients with oligometastatic castrate-resistant prostate cancer (CRPC). All patients were affected by oligometastatic CRPC as defined as three or less nonvisceral metastatic lesions. Patients were randomly assigned 1:1 to receive either AAP alone (control arm) or AAP with concomitant SBRT to all the sites of disease (experimental arm). Primary end point was the rate of biochemical response (BR), defined as a prostate-specific antigen (PSA) decrease ≥50% from baseline measured at 6 months from treatment start. Complete BR (CBR), defined as PSA < 0.2 ng/mL at 6 months from treatment, and progression-free survival (PFS) were secondary end points. One hundred and fifty-seven patients were enrolled between January 2019 and September 2022. BR was detected in 79.6% of patients (92% v 68.3% in the experimental v control arm, respectively), with an odds ratio (OR) of 5.34 (95% CI, 2.05 to 13.88; P = .001) in favor of the experimental arm. CBR was detected in 38.8% of patients (56% v 23.2% in the experimental v control arm, respectively), with an OR of 4.22 (95% CI, 2.12 to 8.38; P < .001). SBRT yielded a significant PFS improvement, with a hazard ratio for progression of 0.35 (95% CI, 0.21 to 0.57; P < .001) in the experimental versus control arm. The trial reached its primary end point of biochemical control and PFS, suggesting a clinical advantage for SBRT in addition to first-line AAP treatment in patients with metastatic castration-resistant prostate cancer.


Dual-axes confocal microscopy with post-objective scanning and low-coherence heterodyne detection.
We present a dual-axes confocal microscope that employs postobjective scanning and low-coherence heterodyne detection to collect vertical cross-sectional images from biological tissue with high axial resolution, reduced noise from scattered light, deep tissue penetration, and a large dynamic range. This architecture can be scaled down to millimeter dimensions with microelectromechanical systems technology for performance of in vivo optical biopsy.


Reflections on death and mourning in relation to Dickens' novel Our Mutual Friend.
Both Bion and Jung indicate in their theories of oscillating cycles of coniunctio/mortificatio and Ps<-->D that the toleration of psychic states of disintegration is both dangerous and essential to new development and that change is resisted and feared. Our fear of growth and development is described by Jung in the mortificatio phase of the coniunctio cycles where movement can be forward towards coniunctio or backwards into disiunctio and by Bion in his delineation of a grid, with its negative grid, where the normal direction of growth may be permanently reversed. Both highlight the inevitability of elements destructive to thought being present in the psyche and the need to know these forces. This paper relates their ideas to the difficult processes of mourning explored by Dickens in his novel Our Mutual Friend.


Current state of metabolic control achieved in a New Zealand diabetes clinic.
To report on current degree of metabolic control achieved in diabetic patients in a New Zealand diabetes clinic. All metabolic data were reviewed for patients attending the Waikato diabetes clinic from 1 January 1992 to 1 January 1995. Values were obtained from 409 insulin treated patients (IDDM), with a mean age of 39 (SD 15 yr); 200 patients who transferred from diet or pills to insulin (NIDDM-I) with a mean age of 59 (SD 12 yr); and 290 noninsulin dependent patients (NIDDM), mean age 54 (SD 13 yr). Results. Percentage of fructosamine values in the normal range: IDDM 10%, NIDDM-I 12.5% and NIDDM 37.9%. Mean values (SD). IDDM group: fructosamine 376 (78) mmol/L, cholesterol 5.24 (1.1) mmol/L, HDL cholesterol 1.47 (0.45) mmol/L, triglycerides 1.71 (1.35) mmol/L. NIDDM-I group: fructosamine 359 (67) mmol/L, cholesterol 5.82 (1.1) mmol/L, HDL cholesterol 1.21 (0.45) mmol/L, triglycerides 2.92 (3.8) mmol/L. NIDDM group: fructosamine, 312 (73) mmol/L, cholesterol 5.83 (1.24) mmol/L, HDL cholesterol 1.1 (0.33) mmol/L, triglycerides 3.11 (3.59) mmol/L. Percentage of smokers in each group: IDDM 24%, NIDDM-I 8.5%, NIDDM 17.2%. the majority of patients fail to achieve normal fructosamine values. Lipid control is poor, other than in the IDDM group. A significant number of patients continue to smoke. Considerable scope for improvement is noted.


Excision of beta-D- and beta-L-nucleotide analogs from DNA by the human cytosolic 3'-to-5' exonuclease.
The cytosolic 3'-to-5' exonuclease from chronic lymphocytic leukemia cells was highly purified, and its ability to remove beta-D- and beta-L-nucleotide analogs from the 3'-end of DNA was determined. The relative rate of excision of beta-D-ddCMP, beta-L-ddCMP, beta-L-FddCMP, beta-L-SddCMP, beta-L-Fd4CMP, and beta-L-OddCMP from the 3'-end of a single-stranded oligonucleotide primer or a primer annealed with complementary DNA and/or RNA templates was assessed. The rate of excision of beta-D-nucleotides from the 3'-end of DNA was higher than that of beta-L-nucleotides, which could be partly attributable to the affinity of the enzyme to beta-D-nucleotide-terminated DNA being 5-fold higher compared with that of beta-L-nucleotide-terminated DNA. The rate of removal of beta-L-Fd4CMP and beta-L-OddCMP from the 3'-end of DNA was at least 8 to 10 times lower compared with that of beta-L-SddCMP. HIV reverse transcriptase could elongate DNA primers after the removal of chain terminators by the cytosolic exonuclease. Concentrations of nucleoside 5'-monophosphate analogs that inhibit the cytosolic exonuclease by 50% were estimated. Among the nucleoside 5'-monophosphate analogs examined, beta-L-Fd4CMP appeared to be the most effective inhibitor of the cytosolic exonuclease, with an ID(50) value of 38 microM.


The effect of education on the assessment of optic nerve head photographs for the glaucoma diagnosis.
To evaluate the effect of one lesson of continuing medical education (CME) of subjective assessment of optic nerve head appearance on sensitivity and specificity for the diagnosis of glaucoma. Ophthalmologists and residents in ophthalmology attending an international glaucoma meeting arranged at Malmö University Hospital, Malmö, Sweden, were asked to grade optic nerve head (ONH) photographs of healthy and glaucomatous subjects at two sessions separated by a lecture on glaucoma diagnosis by ONH assessment. Each grader had access to an individual portfolio of 50 ONH photographs randomly selected from a web-based data bank including ONH photographs of 73 glaucoma patients and 123 healthy subjects. The individual portfolio of photographs was graded before and after the lecture, but in different randomized order. Ninety-six doctors, 91% of all attending the meeting, completed both assessment sessions. The number of correct classifications increased from 69 to 72% on the average. Diagnostic sensitivity increased significantly (p < 0.0001) from 70% to 80%, and the number of photographs classified as uncertain decreased significantly (p < 0.0001) from 22% to 13%. Specificity remained at 68%, and intra-grader agreement decreased. CME had only a small effect on the assessment of ONH for the glaucoma diagnosis. Sensitivity increased and the amount of uncertain classifications decreased, while specificity was unchanged.


Elusive Roles of the Different Ceramidases in Human Health, Pathophysiology, and Tissue Regeneration.
Ceramide and sphingosine are important interconvertible sphingolipid metabolites which govern various signaling pathways related to different aspects of cell survival and senescence. The conversion of ceramide into sphingosine is mediated by ceramidases. Altogether, five human ceramidases-named acid ceramidase, neutral ceramidase, alkaline ceramidase 1, alkaline ceramidase 2, and alkaline ceramidase 3-have been identified as having maximal activities in acidic, neutral, and alkaline environments, respectively. All five ceramidases have received increased attention for their implications in various diseases, including cancer, Alzheimer's disease, and Farber disease. Furthermore, the potential anti-inflammatory and anti-apoptotic effects of ceramidases in host cells exposed to pathogenic bacteria and viruses have also been demonstrated. While ceramidases have been a subject of study in recent decades, our knowledge of their pathophysiology remains limited. Thus, this review provides a critical evaluation and interpretive analysis of existing literature on the role of acid, neutral, and alkaline ceramidases in relation to human health and various diseases, including cancer, neurodegenerative diseases, and infectious diseases. In addition, the essential impact of ceramidases on tissue regeneration, as well as their usefulness in enzyme replacement therapy, is also discussed.


Leishmaniasis in the United States military veterinary patient population.
To describe the presence of Leishmania infection within the animal population receiving care from US Army Veterinary Services. 629 canine, feline, and equine patients of US Army Veterinary Services from 2014 to 2017. Personnel at the US Army Public Health Center ran a query within the Remote Online Veterinary Record system using previously validated search terms (eg, liesh, leish, and lesh) and returned data on any patient for which the master problem list included those terms. Next, a query was run to identify all leishmaniasis testing. Records identified by queries were reviewed manually, and data were collected on patient signalment, indication for and type of testing, location of testing, and previous locations or country of the patient. Only dogs (n = 378), not cats or horses, had been tested for leishmaniasis, 54 (14.3%) of which tested positive for Leishmania infection. More specifically, 39 of 104 (37.5%) privately owned dogs tested positive, compared with 15 of 274 (5.6%) government-owned dogs. Overall, 186 dogs had no clinical signs, 12 (6.5%) of which tested positive. Forty-four of the 54 (81%) test-positive dogs were located in or had traveled to an endemic area. The prevalence of leishmaniasis in the various subpopulations of dogs suggested the need for additional prevalence studies. Many animals travel in and out of the US, and repeated introduction of Leishmania spp could lead to this vector-borne disease becoming endemic in the US animal and human populations. Consequently, US veterinarians need to ensure proper testing and follow-up to protect one health.


New Dipyrroloquinones from a Plant-Derived Endophytic Fungus Talaromyces sp.
Two new dipyrroloquinones, namely talaroterreusinones A (1) and B (2), together with four known secondary metabolites, terreusinone A (3), penicillixanthone A (4), isorhodoptilometrin (5), and chrysomutanin (6), were isolated from the solid culture of the endophytic fungus Talaromyces sp. by integrating mass spectrometry-based metabolic profiling and a bioassay-guided method. Their planar structures and stereochemistry were elucidated by comprehensive spectroscopic analysis including NMR and MS. The absolute configuration at C-1″ of terreusinone A (1) was established by applying the modified Mosher's method. Compounds 1-6 were evaluated for anti-inflammatory activity and cytotoxicity. As a result, 1-3 inhibited the LPS-stimulated NO production in macrophage RAW264.7 cells, with IC50 values of 20.3, 30.7, and 20.6 µM, respectively. Penicillixanthone A (4) exhibited potent cytotoxic activity against Hep G2 and A549 cell lines, with IC50 values of 117 nM and 212 nM, respectively, and displayed significant antitumour effects in A549 cells by inhibiting the PI3K-Akt-mTOR signalling pathway.


Quantifying the contribution of statins to the decline in population mean cholesterol by socioeconomic group in England 1991 - 2012: a modelling study.
Serum total cholesterol is one of the major targets for cardiovascular disease prevention. Statins are effective for cholesterol control in individual patients. At the population level, however, their contribution to total cholesterol decline remains unclear. The aim of this study was to quantify the contribution of statins to the observed fall in population mean cholesterol levels in England over the past two decades, and explore any differences between socioeconomic groups. This is a modelling study based on data from the Health Survey for England. We analysed changes in observed mean total cholesterol levels in the adult England population between 1991-92 (baseline) and 2011-12. We then compared the observed changes with a counterfactual 'no statins' scenario, where the impact of statins on population total cholesterol was estimated and removed. We estimated uncertainty intervals (UI) using Monte Carlo simulation, where confidence intervals (CI) were impractical. In 2011-12, 13.2% (95% CI: 12.5-14.0%) of the English adult population used statins at least once per week, compared with 1991-92 when the proportion was just 0.5% (95% CI: 0.3-1.0%). Between 1991-92 and 2011-12, mean total cholesterol declined from 5.86 mmol/L (95% CI: 5.82-5.90) to 5.17 mmol/L (95% CI: 5.14-5.20). For 2011-12, mean total cholesterol was lower in more deprived groups. In our 'no statins' scenario we predicted a mean total cholesterol of 5.36 mmol/L (95% CI: 5.33-5.40) for 2011-12. Statins were responsible for approximately 33.7% (95% UI: 28.9-38.8%) of the total cholesterol reduction since 1991-92. The statin contribution to cholesterol reduction was greater among the more deprived groups of women, while showing little socio-economic gradient among men. Our model suggests that statins explained around a third of the substantial falls in total cholesterol observed in England since 1991. Approximately two thirds of the cholesterol decrease can reasonably be attributed non-pharmacological determinants.


A case of primary small cell carcinoma of the breast.
We report a rare case of primary small cell carcinoma of the breast. A 44-year-old woman was admitted to our hospital with a mass in her left breast. Fine-needle biopsy revealed small cell carcinoma with neuroendocrine differentiation resembling small cell carcinoma of the lung. Systemic computed tomography (CT) and magnetic resonance imaging (MRI) revealed no primary site in the lung or any other organ. A modified radical mastectomy with removal of the axillary lymph node (Bt + Ax, R2) was performed. Histological examination revealed that the tumor was composed of small round to oval cells with a large nuclear-cytoplasmic ratio. The tumor cells were positive for neuroendocrine differentiation markers such as synaptophysin, CD56, and neuron-specific enolase (NSE), but negative for thyroid transcription factor-1 (TTF-1), leukocyte common antigen (LCA), estrogen receptor (ER), and progesterone receptor (PR). Interestingly, the tumor cells lacked immunoreactivity for epithelial markers, including cytokeratin AE1/3, CAM5.2, and epithelial membrane antigen (EMA). The patient was given adjuvant chemotherapy for axillary lymph node metastasis. There were no signs of recurrence 22 months after surgery.


Microplastics in the context of regulation of commercial shellfish aquaculture operations.
Shellfish aquaculture in the Salish Sea (encompassing the Strait of Juan de Fuca, Puget Sound, and the Georgia Strait) is a major source of clams, oysters, and mussels in the United States and Canada. Plastic gear is necessary for the viability of many of these operations. During the past few years, shellfish farm permits issued in Washington State have been challenged on various bases that have included allegations that the plastic gear is releasing microplastics, commonly defined as particles less than 5 mm in diameter. Published survey data on sources of marine plastic debris demonstrate the very limited contribution of aquaculture gear. Both permits and industry codes of practice provide procedures to minimize loss of gear to the marine environment. Plastic gear is also designed specifically to maintain its integrity and not degrade in the marine environment. Plastic degradation is greatest on beaches with high UV exposure, whereas aquaculture gear is mostly underwater and/or covered by biofoulants. Available data for microplastics in water, sediment, and biota of the Salish Sea do not suggest significant release of microplastics from shellfish aquaculture operations. Integr Environ Assess Manag 2017;13:522-527. © 2017 SETAC.


In vivo magnetic resonance imaging of the blue crab, Callinectes sapidus: effect of cadmium accumulation in tissues on proton relaxation properties.
Nuclear magnetic resonance imaging (MRI) has been used to visualize the internal anatomy of a living blue crab. The resolution obtained in these studies was sufficient to distinguish individual organs by the differences in their proton densities and proton relaxation properties. T1 (spin-lattice relaxation time)-weighted imaging revealed the lipid-rich nature of the hepatopancreas and gonadal tissue. To evaluate the effect of metal-induced stress on the different organs, crabs were exposed to elevated levels of cadmium in their diet, which resulted in increased concentrations of both cadmium and copper in the hepatopancreas. The spin-spin relaxation time, T2, of mobile protons in the metal-exposed tissue was significantly greater than T2 in the control tissues. These measurements suggest that the excess copper in the exposed tissues was diamagnetic [Cu(I)], since the presence of paramagnetic copper [Cu(II)] would result in a decrease of observed T2 values. We hypothesize that the increased T2 value is a reflection of increased free water in the hepatopancreas. These studies show that magnetic resonance imaging is an important nondestructive tool for the study of morphological and physiological changes that occur in marine invertebrates in response to anthropogenic and natural stresses.


Mouse taste cells with G protein-coupled taste receptors lack voltage-gated calcium channels and SNAP-25.
Taste receptor cells are responsible for transducing chemical stimuli from the environment and relaying information to the nervous system. Bitter, sweet and umami stimuli utilize G-protein coupled receptors which activate the phospholipase C (PLC) signaling pathway in Type II taste cells. However, it is not known how these cells communicate with the nervous system. Previous studies have shown that the subset of taste cells that expresses the T2R bitter receptors lack voltage-gated Ca2+ channels, which are normally required for synaptic transmission at conventional synapses. Here we use two lines of transgenic mice expressing green fluorescent protein (GFP) from two taste-specific promoters to examine Ca2+ signaling in subsets of Type II cells: T1R3-GFP mice were used to identify sweet- and umami-sensitive taste cells, while TRPM5-GFP mice were used to identify all cells that utilize the PLC signaling pathway for transduction. Voltage-gated Ca2+ currents were assessed with Ca2+ imaging and whole cell recording, while immunocytochemistry was used to detect expression of SNAP-25, a presynaptic SNARE protein that is associated with conventional synapses in taste cells. Depolarization with high K+ resulted in an increase in intracellular Ca2+ in a small subset of non-GFP labeled cells of both transgenic mouse lines. In contrast, no depolarization-evoked Ca2+ responses were observed in GFP-expressing taste cells of either genotype, but GFP-labeled cells responded to the PLC activator m-3M3FBS, suggesting that these cells were viable. Whole cell recording indicated that the GFP-labeled cells of both genotypes had small voltage-dependent Na+ and K+ currents, but no evidence of Ca2+ currents. A subset of non-GFP labeled taste cells exhibited large voltage-dependent Na+ and K+ currents and a high threshold voltage-gated Ca2+ current. Immunocytochemistry indicated that SNAP-25 was expressed in a separate population of taste cells from those expressing T1R3 or TRPM5. These data indicate that G protein-coupled taste receptors and conventional synaptic signaling mechanisms are expressed in separate populations of taste cells. The taste receptor cells responsible for the transduction of bitter, sweet, and umami stimuli are unlikely to communicate with nerve fibers by using conventional chemical synapses.


Psychotropic, Anticonvulsant, and Opioid Use in Assisted Living Residents Before and During the COVID-19 Pandemic.
To examine the associations between COVID-19 pandemic waves (1-4) and prevalent antipsychotic, antidepressant, benzodiazepine, anticonvulsant, and opioid use among assisted living (AL) residents, by setting (dementia care vs other). Population-based, repeated cross-sectional study. Linked clinical and health administrative databases for residents of all publicly subsidized AL homes (N = 256) in Alberta, Canada, examined from January 2018 to December 2021. Setting-specific quarterly cohorts of residents were derived for pandemic (starting March 1, 2020) and comparable historical (2018/2019 combined) periods. The quarterly proportion of residents dispensed an antipsychotic, antidepressant, benzodiazepine, anticonvulsant, or opioid was examined for each setting and period. Log-binomial generalized estimating equations models estimated prevalence ratios (PR) for period (pandemic vs historical quarterly periods), setting (dementia care vs other AL), and period-setting interactions. On March 1, 2020, there were 2874 dementia care and 6611 other AL residents (mean age 82.4 vs 79.9 years, 68.2% vs 66.1% female, 93.5% vs 42.6% with dementia, respectively). Antipsychotic use increased during waves 2 to 4 for residents of both settings, but this increase was significantly greater for dementia care than other AL residents during waves 3 and 4 (eg, wave 3, PR 1.21, 95% CI 1.14-1.27 vs PR 1.12, 95% CI 1.07-1.17, interaction term P = .029). In both settings, there was a significant but modest increase in antidepressant use and a significant decrease in benzodiazepine use during several pandemic waves. For other AL residents only, there was a small statistically significant increase in anticonvulsant use during waves 2 to 4. No significant pandemic effect was observed for prevalent opioid use in either setting. The persistence of the pandemic-associated increase in antipsychotic, antidepressant, and anticonvulsant use in AL residents, and greater increase in antipsychotic use for dementia care settings, raises concerns about the attendant risks for residents, especially those with dementia.


Liquid-diet with alcohol alters maternal, fetal and placental weights and the expression of molecules involved in integrin signaling in the fetal cerebral cortex.
Maternal alcohol consumption during pregnancy causes wide range of behavioral and structural deficits in children, commonly known as Fetal Alcohol Syndrome (FAS). Children with FAS may suffer behavioral deficits in the absence of obvious malformations. In rodents, the exposure to alcohol during gestation changes brain structures and weights of offspring. The mechanism of FAS is not completely understood. In the present study, an established rat (Long-Evans) model of FAS was used. The litter size and the weights of mothers, fetuses and placentas were examined on gestation days 18 or 20. On gestation day 18, the effects of chronic alcohol on the expression levels of integrin receptor subunits, phospholipase-Cγ and N-cadherin were examined in the fetal cerebral cortices. Presence of alcohol in the liquid-diet reduced the consumption and decreased weights of mothers and fetuses but increased the placental weights. Expression levels of β(1) and α(3) integrin subunits and phospholipase-Cγ(2) were significantly altered in the fetal cerebral cortices of mothers on alcohol containing diet. Results show that alcohol consumption during pregnancy even with protein, mineral and vitamin enriched diet may affect maternal and fetal health, and alter integrin receptor signaling pathways in the fetal cerebral cortex disturbing the development of fetal brains.


Prejudice and Ethnic Bullying Among Children: The Role of Moral Disengagement and Student-Teacher Relationship.
The identification of factors associated with ethnic bullying within multiethnic schools is a timely social issue. Up to now, ethnic prejudice has been found to facilitate aggression triggered by schoolmates' cultural background. Yet, there is still a dearth of research about the mechanisms underlying this relation among children. In order to fill this gap, by adopting a social-cognitive developmental perspective on prejudice and morality, this paper investigated the mediating role of moral disengagement in the association between ethnic prejudice and ethnic bullying, as well as the moderating role of closeness with the teacher. A mediation model and a moderated mediation model were applied to data collected from 552 primary school children aged 8-10years. Ethnic prejudice, ethnic bullying, and moral disengagement were assessed through self-reported questionnaires, whereas a questionnaire was administered to teachers to assess the level of closeness with their pupils. Results indicated that ethnic prejudice was directly and positively related to ethnic bullying and that moral disengagement partially mediated this association. This indirect link was particularly strong for children with low levels of closeness with their teachers, whereas it resulted not significant for pupils with high levels of closeness, suggesting that closeness with the teacher might restrain morally disengaged children from enacting ethnic bullying. Implications for research and practice aimed at reducing prejudice and moral disengagement, as well as at promoting positive relationships among children and between pupils and teachers, are discussed.


In vitro generation of functional lens-like structures with relevance to age-related nuclear cataract.
To investigate the capacity of lens epithelial cells, maintained in a modified explant culture system, to mimic normal patterns of lens cell differentiation and to regenerate lens structure and function. Lens epithelial explants were set up in pairs with their apical surfaces facing each other. These explant pairs (EPs) were then cultured in vitreous for up to 43 days to promote their growth and differentiation. Immunohistochemistry and conventional light and electron microscopy were used to assess structural and functional properties of the lens-like structures that developed from EPs. EPs that were asymmetrically exposed to vitreous routinely produced biconvex, lens-like structures composed of ordered epithelial and fiber cells that were transparent and had some focusing and magnifying ability. In addition, characteristic of the lens in vivo, fiberlike cells that were peripherally situated in EPs contained markers of the relatively early stages of fiber differentiation, whereas centrally situated cells contained markers of terminally differentiated fibers. During long-term culture of the EPs, a central opacity appeared that had structural features similar to those reported for the early stages of human, age-related nuclear cataract. This study shows that, given appropriate culture conditions, lens epithelial cells can regenerate ordered lens-like structures with functional properties. This system represents a valuable new tool for the investigation of factors involved in the generation of normal lens structure and function and lens opacification.


Is there a doctor in the house?
The two cases presented deal with urgent situations experienced by persons unknown to the dentist in the area. It is likely that dentists, physicians, nurses, and other medical professionals will encounter persons in urgent need of medical attention in other venues. Certainly, it is possible for someone to experience an emergency in a ballpark, grocery store, church, or other public gathering. While these settings may not offer the advantage of a medical emergency kit, they do pose the same ethical requirement for those trained in medical management of urgent problems to step forward, identify themselves, and attempt to help the ill person. Fortunately, most non-air settings usually allow for contacting emergency medical help and prompt transport to hospitals. The public may never reach a general understanding of the extent to which doctors other than physicians are trained to handle medical emergencies. Similarly, when someone in a crowded theater yells, "Is there a doctor in the house?" he or she most likely is thinking about a physician. This does not mean that a dentist is excused from acting as a medically trained Good Samaritan. The ethical obligation of specific beneficence requires dentists to minister to the ill in medical emergencies unless a more qualified health care provider is present and identifies himself or herself. The ethical obligation of general beneficence requires dentists and other citizens to assist those in urgent circumstances whose needs do not call upon specialized knowledge or training. Fortunately, the law in this country is designed to protect those who do attempt to help those in need.


Youth access to tobacco: policies and politics.
The late 1980s marked the beginning of a sea change in research and intervention on tobacco use by young people, when the first studies were published demonstrating the ease with which adolescents could purchase cigarettes. Since then concern with the commercial availability of tobacco products to youth has grown, becoming deeply entrenched in both research and policy efforts. This paper reviews the history of restrictions on youth access to tobacco, the evidence that commercial sources of tobacco are available and important to adolescents, and the rationale for various components of policies to restrict access. We also review the recent expansion of policies addressing youth access to tobacco at all levels of government, the tobacco industry response to this expansion, and issues that have arisen as this expansion has developed.


[Aggregation of 4-vinyl-protochlerophyll and protochlorophyll in solutions].
The addition of water to dioxane solution of protochlorophyll (PChl) and 4-vinyl-protochlorophyll (4VPChl) results in a number of transformations related with pigment molecule associations into polymer formations and with their conversion. By variation of pigment concentration and composition of binar mixture of solvents a set of aggregated forms with different electronic spectra can be obtained. At the first stage the monomeric pigment converts into polymer with long-wavelenght absorption maximum of 633 nm (P633). During 1-3 hours P633 converts into other aggregated forms: either P639 or P645 depending on the proportion of dioxane and water. The pigment aggregates are characterized by fluorescence (quantum yield less than or equal to 1%) with maxima close to the main maxima of absorption spectra. Alongside with the main aggregated forms of PChl and 4VPChl the presence of a small number of longer-wavelength aggregates in solutions is established by fluorescence spectra. The investigation of dependence of fluorescence spectra on excitation wavelength, as well as of fluorescence excitation spectra of pigments in binary mixture shows that the long-wavelength aggregates can form part of complex associate and be effective trapping centres of electronic excitation of shorter wavelength aggregated forms. The phenomenon of 4VPChl association in concentrated solutions of castor oil (c greater than-10(-2) m/l) is discovered, which is especially marked after a long storage of the solutions at lower temperature (t=-2 degrees C). Under these conditions the two aggregated forms P640 and P650 alongside with monomer are present. The aggregate P650 is characterized by fluorescence with maximum of 655 nm and spectrally similar to the natural form of photoactive protochlorophyll. The experimental data show that the protochlorophyll pigments form a set of aggregated forms and that the medium conditions favour the predominance of some of the forms and their interconversion. The results obtained evidence that the main reason of the long-wavelength shift of electronic spectra for PChl natural forms is the intermolecular interaction related with the association of pigment monomeric molecules.


Interpretation of karyotype evolution should consider chromosome structural constraints.
Comparative genetics, genomics and cytogenetics provide tools to trace the evolutionary history of extant genomes. Yet, the interpretation of rapidly increasing genomic data is not always done in agreement with constraints determined by chromosome structural features and by insights obtained from chromosome mutagenesis. The terms 'non-reciprocal chromosome translocation', 'chromosome fusion' and 'centromere shift' used to explain genomic differences among organisms are misleading and often do not correctly reflect the mechanisms of chromosome rearrangements underlying the evolutionary karyotypic variation. Here, we (re)interpret evolutionary genome alterations in a parsimonious way and demonstrate that results of comparative genomics and comparative chromosome painting can be explained on the basis of known primary and secondary chromosome rearrangements. Therefore, some widespread terms used in comparative and evolutionary genomics should be either avoided (e.g. non-reciprocal translocation) or redefined (e.g. chromosome fusion and centromere shift).


RNIE: genome-wide prediction of bacterial intrinsic terminators.
Bacterial Rho-independent terminators (RITs) are important genomic landmarks involved in gene regulation and terminating gene expression. In this investigation we present RNIE, a probabilistic approach for predicting RITs. The method is based upon covariance models which have been known for many years to be the most accurate computational tools for predicting homology in structural non-coding RNAs. We show that RNIE has superior performance in model species from a spectrum of bacterial phyla. Further analysis of species where a low number of RITs were predicted revealed a highly conserved structural sequence motif enriched near the genic termini of the pathogenic Actinobacteria, Mycobacterium tuberculosis. This motif, together with classical RITs, account for up to 90% of all the significantly structured regions from the termini of M. tuberculosis genic elements. The software, predictions and alignments described below are available from http://github.com/ppgardne/RNIE.


The treatment of patellofemoral pain by combined rotation and elevation of the tibial tubercle.
An operation designed to achieve simultaneous decompression and realignment of the patella has been used by the senior one of us (B. J. M.) for the treatment of selected patients with patellofemoral pain since 1978. The procedure isolates the tibial tubercle as a pedicle and simultaneously rotates it medially and anteriorly. Patellar tracking is then checked intraoperatively, and no bone graft is required. This paper reports the results of the procedure in thirty-eight knees in twenty-nine patients. The minimum length of follow-up was 2.5 years. Twenty-one knees were graded as excellent; twelve, as good; and five were considered to be failures. Of the twenty-five knees that were followed for four years or more, twenty-one were rated as excellent or good and four were failures.


Incorporation of H2O and CO2 into a BN-embedded 3aH-3a1H-acephenanthrylene derivative.
A fused tetracyclic BN-species 1 featuring nucleophilic nitrogen and electrophilic boron centers behaves as a reactive N/B frustrated Lewis pair (FLP) for small molecule activation. Specifically, the O-H and C[double bond, length as m-dash]O bonds have been cleaved by 1 with the formation of fused borinic acid 2, borenium species 3, anionic boranuidacarboxylic acid 4 and oxadiazaborolidinone 5, respectively. Quantum-mechanical calculations are conducted to comprehensively understand the activation processes of small molecules by 1.


Clear cell carcinoma of minor salivary gland of the tongue.
The case of a clear cell carcinoma of a minor salivary gland, at the basis of the tongue, is described, which represents 1% of malignant tumours of salivary glands. The biological behaviour is not very aggressive and development, which is very slow, is usually asymptomatic, and, indeed, the tumour often reaches considerable dimensions before being diagnosed. There are rare cases of local recurrence and distant metastases. Cases of salivary glands which have become sites of secondary localization of a clear cell tumour, originating in the kidneys, have been described. The interest in the form described here stems from the slow evolution and the considerable dimensions reached by the tumour before being diagnosed, despite development in a breathing or digestive area such as the oralpharyngeal tract. In the present case, computed axial tomography and nuclear magnetic resonance were used to reach the diagnosis. The patient was submitted to surgical treatment. In the differential diagnosis, it is necessary, from a pathological point of view, to take into consideration other neoplastic formations, such as acinar cell adenocarcinoma, epithelial-myoepithelial carcinoma, clear cell oncocytoma, sebaceous adenoma and sebaceous carcinoma.


Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis.
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data. Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan. This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.


The COVID-19 pandemic is intricately linked to biodiversity loss and ecosystem health.
The ongoing COVID-19 pandemic, caused by zoonotic SARS-CoV-2, has important links to biodiversity loss and ecosystem health. These links range from anthropogenic activities driving zoonotic disease emergence and extend to the pandemic affecting biodiversity conservation, environmental policy, ecosystem services, and multiple conservation facets. Crucially, such effects can exacerbate the initial drivers, resulting in feedback loops that are likely to promote future zoonotic disease outbreaks. We explore these feedback loops and relationships, highlighting known and potential zoonotic disease emergence drivers (eg, land-use change, intensive livestock production, wildlife trade, and climate change), and discuss direct and indirect effects of the ongoing pandemic on biodiversity loss and ecosystem health. We stress that responses to COVID-19 must include actions aimed at safeguarding biodiversity and ecosystems, in order to avoid future emergence of zoonoses and prevent their wide-ranging effects on human health, economies, and society. Such responses would benefit from adopting a One Health approach, enhancing cross-sector, transboundary communication, as well as from collaboration among multiple actors, promoting planetary and human health.


Assessment of complement C4 gene copy number using the paralog ratio test.
The complement C4 locus is in the class III region of the MHC, and exhibits copy number variation. Complement C4 null alleles have shown association with a number of diseases including systemic lupus erythematosus (SLE). However, most studies to date have used protein immunophenotyping and not direct interrogation of the genome to determine C4 null allele status. Moreover, a lack of accurate C4 gene copy number (GCN) estimation and tight linkage disequilibrium across the disease-associated MHC haplotypes has confounded attempts to establish whether or not these associations are causal. We have therefore developed a high throughput paralog ratio test (PRT) in association with two restriction enzyme digest variant ratio tests (REDVRs) to determine total C4 GCN, C4A GCN, and C4B GCN. In the densely genotyped CEU cohort we show that this method is accurate and reproducible when compared to gold standard Southern blot copy number estimation with a discrepancy rate of 9%. We find a broad range of C4 GCNs in the CEU and the 1958 British Birth Cohort populations under study. In addition, SNP-C4 CNV analyses show only moderate levels of correlation and therefore do not support the use of SNP genotypes as proxies for complement C4 GCN.