Critical amino acids of p21 protein are located within beta-turns: further evaluation.
It has been shown that malignant activation of ras proto-oncogenes was mediated by point mutations which resulted in the single amino acid conversions at positions 12, 13 or 61 of the ras gene products (p21 proteins). By analyzing randomly mutated ras genes, it has been demonstrated that amino acid substitutions at residues 12, 13, 59 and 63 activated p21. Furthermore, it has been shown that residues 16, 116 and 119 in p21 played critical roles in the guanine nucleotide binding and, consequently, the ability of the protein to induce changes characteristic of cellular transformation. By using the protein conformational prediction method of Chou and Fasman, the present work predicts that these critical amino acids, except glutamic acid at position 63, are located within beta-turns. The major "hot spots" for ras activation are codons 12 and 61. The author has predicted in an earlier paper that the single amino acid conversions at positions 12 and 61 would occur at beta-turn conformation consisting of residues 10-13 and 58-61, respectively. In the present study, probabilities of beta-turn occurrence at residues 10-13 or 58-61 of the p21 proteins encoded by various ras genes are compared. The probability for the normal p21 containing glycine as residue 12 is greatest, and the cancer-associated variants show less probabilities. The single amino acid substitutions at position 61 do not cause so decreased probabilities of beta-turn potential at residues 58-61, except the replacement by histidine. Histidine at position 61 is not predicted as occurring within a beta-turn.(ABSTRACT TRUNCATED AT 250 WORDS)


Internal limiting membrane flap with viscoelastic device for lamellar hole surgery with no postoperative positioning.
To propose a novel technique of an internal limiting membrane (ILM) flap using ophthalmic viscoelastic device (OVD) with no requirement for postoperative head posture for the treatment of lamellar macular hole (LMH) repair. A retrospective analysis of 16 consecutive eyes of LMH patients who underwent vitrectomy with ILM flap with OVD. Best-corrected visual acuity (BCVA), central macular thickness (CMT), simultaneous cataract extraction, and ellipsoid zone disruption preoperatively and at the final follow-up were compared. The mean age was 73.19 ± 7.26 years, and ten patients (62%) were females. The mean follow-up was 5.06±1.43 months (range 3-6). For all patients, BCVA was significantly improved at the final visit, from 0.65±0.36 logMAR units to 0.42±0.29 (p < 0.001). None of the patients had visual loss. Six patients had epiretinal membrane (ERM) foveoschisis, and the rest had LMH with epiretinal proliferation. Both subgroups presented a significant improvement in their BCVA with a trend for better improvement in the latter (p=0.09). Ellipsoid zone disruption was seen in 7 patients including one patient with a macular scar. There was no significant effect of ellipsoid zone disruption on the final BCVA (p=0.33). Twelve eyes (75%) underwent simultaneous cataract extraction. Mean BCVA at the final postoperative visit improved regardless of whether the eyes underwent simultaneous cataract surgery (p=0.39). CMT was also significantly improved at the final visit, from 200.06±46.8 μm preoperatively to 305.00±85.5 μm (p<0.001). No full-thickness macular holes were developed postoperatively. No intraoperative or postoperative complications were observed. Treatment of LMH with ILM flap with OVD showed promising anatomical and functional results with no postoperative head position requirements.


Behavioral Activation as a Mechanism of Change in Residential Treatment for Mood Problems: A Growth Curve Model Analysis.
Research on the efficacy, effectiveness, and dissemination potential of behavioral activation (BA)-focused interventions for depression and comorbid disorders has expanded rapidly. However, research that examines how BA interventions work has seen less growth. A primary purported mechanism of BA is activation, which reflects a person's meaningful (re)engagement in life. BA theory posits that depression will decrease as activation increases, and that changes in the mechanism variable will lead to changes in outcome. The current study aims to investigate activation as a potential mechanism of change in the context of a BA-focused residential treatment intervention for mood problems using repeated measures of self-reported activation and depression from a large comorbid sample (N = 578). Growth curve modeling was used to examine between-person differences in within-person change over time. Findings suggest that self-reported activation increases and depression decreases over time. Moreover, results show both linear and quadratic growth and that the rate of change in activation predicts the rate of change of depression. BA-focused residential treatment may facilitate activation, which exerts an effect on depression among residents with diagnostically complex presentations.


Municipal solid waste management in Pudong New Area, China.
The increase in population, the rapid economic growth and the rise in community living standards accelerate municipal solid waste (MSW) generation in developing cities. This problem is especially serious in Pudong New Area, Shanghai, China. The daily amount of MSW generated in Pudong was about 1.11 kg per person in 2006. According to the current population growth trend, the solid waste quantity generated will continue to increase with the city's development. In this paper, we describe a waste generation and composition analysis and provide a comprehensive review of municipal solid waste management (MSWM) in Pudong. Some of the important aspects of waste management, such as the current status of waste collection, transport and disposal in Pudong, will be illustrated. Also, the current situation will be evaluated, and its problems will be identified.


Developments in hearing aid fitting and delivery. A decade of revolution.
The socioeconomic changes and technological advances that have occurred in the field of hearing aid dispensing are chronicled. The various instruments available to aid the hearing-impaired person, including digital electronics and programmable hearing aids, are described. The qualifications required of those who deliver hearing aids are also discussed.


Distribution of gunshot residues--the influence of weapon type.
Gunshot residue (GSR) analysis is a frequently used forensic method for investigating shooting events. In this process, GSR-particles are detected on pertinent objects, often the hands of a suspect, with energy dispersive X-ray microanalysis in a scanning electron microscope. The question asked in court is usually the following: "… has or has not a given shot been fired by the suspect (at a certain place and time)?" Unfortunately, this question frequently cannot be answered by the analyst. Only the presence or absence of "characteristic" GSR-particles on the investigated sample can be stated with confidence. All other assumptions are inherently biased by many factors that are usually only known by the culprit or are generally unknown. In order to draw more profound conclusions from GSR analytical results, the dynamics of GSR particles have to be considered, i.e., how these particles reach a suspect. Consequently, the formation of the plume after firing was investigated for eleven different firearms with high speed-video analysis. The results show that a vast scope exists between revolvers - distributing many particles near the shooter - and e.g. shotguns that are quite sealed. These differences between the various weapon types should be considered for interpretation of the results of GSR-analysis.


Over-Expression of p190RhoGEF Regulates the Formation of Atherosclerotic Plaques in the Aorta of ApoE-/- Mice via Macrophage Polarization.
The RhoA-specific guanine nucleotide exchange factor p190RhoGEF has been implicated in the control of cell morphology, focal adhesion formation, and cell motility. Previously, we reported that p190RhoGEF is also active in various immune cells. In this study, we examined whether over-expression of p190RhoGEF could affect atherosclerotic plaque formation in mouse aortae. For that purpose, transgenic (TG) mice over-expressing p190RhoGEF were cross-bred with atherosclerosis-prone apolipoprotein E (ApoE)-/- mice to obtain p190RhoGEF-TG mice with ApoE-/- backgrounds (TG/ApoE-/-). Aortic plaque formation was significantly increased in TG/ApoE mice-/- at 30 to 40 weeks of age compared to that in ApoE-/- mice. Serum concentrations of inflammatory cytokines (IL-6 and TNF-α) were greater in TG/ApoE-/- mice than in ApoE-/- mice at ~40 weeks of age. Furthermore, TG/ApoE-/- mice had a greater proportion of peritoneal macrophages within the M1 subset at 30 to 40 weeks of age, together with higher production of inflammatory cytokines and stronger responses to bacterial lipopolysaccharide than ApoE-/- mice. Collectively, these results highlight a crucial role of enhanced p190RhoGEF expression in atherosclerosis progression, including the activation of pro-inflammatory M1 macrophages.


Changes in grip strength in a randomized study of carpal tunnel release by three different techniques.
Carpal tunnel release is frequently followed by weak grasp but recently, endoscopy has been claimed to avoid this pitfall. 277 patients representing 303 CT were enrolled in a prospective randomized study to assess changes in grasp after classical open CTR (Group I - 77 cases), ligamentoplasty (Group II - 133 cases) and an Agee endoscopic CTR (Group III - 99 cases). Grasp was measured pre-operatively and post-operatively every month for six months to analyse strength recovery according to technique, dominance, sex, motor conduction velocity, job, and leisure activity.There were no complications in the series except one RSD and six open conversions in the Agee group due to technical problems.Pre-operative CT was accompanied by an average loss of strength of 18%. In the postoperative period, the contralateral side had an increase in strength from 2% to 12.5%. These data plus the frequent bilaterality of CT explained the bias of any post-operative study without pre-operative measurement.Strength recovered faster and better in Group II and III. At three months, the percentage of patients having recovered was 38% in Group I, 54% in Group II, 58% in Group III. An explanation of similarity in the last two groups could be found in the modification of Agee procedure preserving an intermediate fascia, avoiding full separation of the two edges of the ligament, as in the ligamentoplasty.


TNF-α derived from arsenite-induced microglia activation mediated neuronal necroptosis.
Arsenic, an identified environmental toxicant, poses threats to the health of human beings through contaminated water and food. Recently, increasing reports focused on arsenic-induced nerve damage, however, the underlying mechanism remains elusive. Microglia are important immune cells in the nervous system, which produce a large number of inflammatory factors including TNF-α when activated. Recent reports indicated that TNF-α is involved in the process of necroptosis, a new type of programmed cell death discovered recently. Although there were evidences suggested that arsenic could induce both microglia activation and TNF-α production in the nervous system, the mechanism of arsenic-induced neurotoxicity due to microglia activation is rarely studied. In addition, the role of microglia-derived TNF-α in response to arsenic exposure in necroptosis has not been documented before. In this study, we found that arsenite induced microglial activation through p38 MAPK signaling pathway, leading to the production of TNF-α. Microglia-derived TNF-α further induced necroptosis in the neuronal cells. Our findings suggested that necroptosis induced by microglia-derived TNF-α upon arsenite exposure partially played a role in arsenic-induced cell death which underlie the fundamental event of arsenic-related neurotoxicity.


Introduction to a Special Section on the Effects of the Dating Matters Model on Secondary Outcomes: Results from a Comparative Effectiveness Cluster Randomized Controlled Trial.
Teen dating violence (TDV) affects millions of young people in the USA each year (Basile et al. 2020) and is associated with a myriad of negative consequences across the lifespan, including placing individuals at greater risk for experiencing intimate partner violence (IPV) in their more permanent relationships in adulthood (Exner-Cortens et al. Pediatrics 131(1):71-78 Exner-Cortens et al. 2013; Exner-Cortens et al. Journal of Adolescent Health 60(2):176-183 Exner-Cortens et al. 2017). The CDC developed the Dating Matters®: Strategies to Promote Healthy Teen Relationships comprehensive prevention model to prevent TDV and its consequences among young people, and it was found to be effective at reducing TDV perpetration and victimization compared with another evidence-based program (Niolon et al. American Journal of Preventive Medicine 57(1):13-23 Niolon et al. 2019). Dating Matters addresses multiple risk and protective factors for TDV through its multiple components, many of which are shared risk and protective factors for other forms of violence and risk behaviors among adolescents. This article introduces this special section, which includes three papers examining these secondary outcomes of the Dating Matters comparative effectiveness, multi-site, longitudinal cluster randomized controlled trial and concludes with an invited commentary by Debnam and Temple (2020). This introduction briefly discusses the Dating Matters comprehensive prevention model, the comparative effectiveness trial used to evaluate effectiveness, the outcomes examined by the three papers included in this special section and the commentary from external reviewers. This special section makes an important contribution to the field of violence prevention, highlighting a preventive intervention for TDV that addresses a constellation of risk and protective factors and demonstrating its effects on multiple adolescent risk and violence outcomes.


A Retrospective Study on Profile of Patients with Faciomaxilary Fractures in a Tertiary Care Center.
Maxillofacial injuries in general occur quite commonly following trauma and these injuries if not properly managed can negatively influence both the psychosocial and functional activities of the patient. This is as a result of the centrality of the facial region as a key factor in human identity, aesthetics, and general well-being. Fractures involving the facial skeleton may be isolated or complex. High velocity trauma is usually seen in urban and semi-urban areas while low velocity trauma is the common setting in rural areas. The pattern of faciomaxillary fractures vary with geographical area, socioeconomic condition, enforcements of law and order of a country. Trauma to the faciomaxillary region mandates special attention as important sensory systems are contained within the face (e.g. vision, auditory, somatic sensation, gustatory, olfaction and vestibular), also, vital structures in the head and neck region are intimately associated (airway, blood vessels, nerves and gastrointestinal tracts. It should be noted that the treatment outcome of maxillofacial fractures is mainly dependent among other things on the degree of injury, type of fracture, the expertise of the surgeon, and available technology. The aim of this study is to find out the incidence of faciomaxillary injuries resulting from various etiological factor Classification of facial bone fractures; Diagnosis and different treatment modalities. This is a prospective cross sectional study comprising of 75 patients who were having different faciomaxillary fractures and visited to L.G. hospital from December 2020 to April 2022. Patients were evaluated thoroughly by history taking, proper examination and routine investigations. In general examination consciousness, orientation to time, place and person, neck movements, and general mobility of the patients were checked. In local examination- facial oedema, facial asymmetry, skin lacerations, deep cuts, decreased mouth opening, improper teeth occlusion, teeth loss, nasal bleeding, black eye, eyeball movements and redness of eyes were checked. In specialized radiological investigations x- rays, 2D & 3D Computed Tomography (CT) of Facial bones were done in all cases. CT Brain and CT Cervical spine were done in patients if needed. From our study, it seems reasonable to assume that road traffic accident remains the leading cause of faciomaxillary fractures and is closely followed by fall especially among men in their productive years. It is necessary to diagnose faciomaxillary fracture at the earliest to prevent the complications of fractures such as infection and malocclusion, for that thorough clinical examination and radiological investigations are very important. 3D CT face is the gold standard investigation in case of different faciomaxillary fractures. In isolated fractures nasal bone fractures remains the most affected bone of the facial skeleton followed by mandible. Among the different sites of mandibular fractures body of the mandible is the most common site for mandibular fractures.


Evaluation of choroidal parameters in eyes at the first onset of acute anterior uveitis.
Little is known about choroidal involvement in anterior uveitis. The aim of our study was to evaluate changes in choroidal thickness and volume in eyes with acute anterior uveitis (AAU) using enhanced depth imaging-optical coherence tomography (EDI-OCT) at baseline and after treatment, which were compared with healthy fellow eyes. For the study, 35 individuals with unilateral acute AAU at the first onset were enrolled. Subfoveal thickness and choroidal volume were measured with EDI-OCT in nine Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields before and after the completion of treatment. Moreover, axial length measurements of both eye bulbs were determined by optical biometry. No statistically significant differences in choroidal thickness or choroidal volume were detected between AAU eyes at baseline and after treatment and fellow eyes. Positive correlations between the values of anterior chamber flare and absolute CT changes in both temporal and inferior ETDRS fields, as well as in superior outer ring were detected. Negative correlations between age and both choroidal thickness and choroidal volume were detected in AAU eyes at baseline and after treatment, as well as in fellow eyes. Evaluation of the choroid with EDI-OCT does not appear to be a reliable tool for the treatment monitoring of eyes with anterior uveitis.


Liver or blood-stage arrest during malaria sporozoite immunization: the later the better?
So far, the best immunization strategies to achieve high levels of protection against malaria are based on whole parasites. Complete sterile protection can be obtained in rodent models after immunization with sporozoites and chemoprophylaxis, or with sporozoites attenuated either genetically or by radiation. These approaches target specific stages, with arrests occurring at different time-points of the parasite life cycle. Here, we review these different approaches in relation to their capacity to induce protection in both Plasmodium berghei and Plasmodium yoelii models. The combined data suggest that maximal liver-stage exposure without further development into blood stages may induce the most efficient protection in mice.


Evaluation of intrathecal baclofen delivery system malfunction by computed tomography scan.
To describe the computed tomography (CT) findings encountered when catheter patency is questionable. The role of CT in directing treatment is evaluated. Records of children with intrathecal baclofen pump management were reviewed. Only patients with CT evaluation who had revision pump/catheter surgery were included. From 295 patients, 27 had CT contrast study; in three of them, baclofen could not be aspirated and the procedure was stopped, eight had normal scan and did not need surgery and 16 patients were reported. Four patients had normal CT (free contrast formed a perfect crescent shape), and had surgery because the pump battery was close to expiration. Five patients had inadequate fluid pooling (fluid was seen without a crescent shape). Five patients had fluid leak (fluid was seen around the pump or in the lumbar canal below catheter entrance level or outside the canal in the lumbar region). Two patients had catheter occlusion (fluid loculation around the catheter tip with no free flow). CT contrast study is safe and effective for locating defects in intrathecal baclofen delivery system. When catheter patency is questionable, CT plays an important role in directing the next step of management.


Tetrachloroethane (TeCA) removal through sequential graphite-mixed metal oxide electrodes in a bioelectrochemical reactor.
Electro-bioremediation offers a promising approach for eliminating persistent pollutants from groundwater since allows the stimulation of biological dechlorinating activity, utilizing renewable electricity for process operation and avoiding the injection of chemicals into aquifers. In this study, a two-chamber microbial electrolysis cell has been utilized to achieve both reductive and oxidative degradation of tetrachloroethane (TeCA). By polarizing the graphite granules cathodic chamber at -650 mV vs the standard hydrogen electrode and employing a mixed metal oxide (MMO) counter electrode for oxygen production, the reductive and oxidative environment necessary for TeCA removal has been established. Continuous experiments were conducted using two feeding solutions: an optimized mineral medium for dechlorinating microorganisms, and synthetic groundwater containing sulphate and nitrate anions to investigate potential side reactions. The bioelectrochemical process efficiently reduced TeCA to a mixture of trans-dichloroethylene, vinyl chloride, and ethylene, which were subsequently oxidized in the anodic chamber with removal efficiencies of 37 ± 2%, 100 ± 4%, and 100 ± 5%, respectively. The introduction of synthetic groundwater with nitrate and sulphate stimulated reductions in these ions in the cathodic chamber, leading to a 17% decrease in the reductive dechlorination rate and the appearance of other chlorinated by-products, including cis-dichloroethylene and 1,2-dichloroethane (1,2-DCA), in the cathode effluent. Notably, despite the lower reductive dechlorination rate during synthetic groundwater operation, aerobic dechlorinating microorganisms within the anodic chamber completely removed VC and 1,2-DCA. This study represents the first demonstration of a sequential reductive and oxidative bioelectrochemical process for TeCA mineralization in a synthetic solution simulating contaminated groundwater.


Examining the impacts of economic and demographic aspects on the ecological footprint in South and Southeast Asian countries.
The re-examination of the existing economic and environmental policies in the South and Southeast Asian countries seems to be necessary, as these countries are struggling to achieve the goals of sustainable development. For designing a long-term environmental policy, we intended to examine whether the selected economic and demographic indicators have influenced the ecological footprint in the eight developing countries of Asia from 1990 to 2015. The use of pooled mean group (PMG) approach allowed driving the long-run common coefficients, which may facilitate us to develop a common policy framework for fortifying the environmental quality. The computed results confirmed that the selected variables are cointegrated in the long run, and the variables, i.e., per capita income, nonrenewable energy usage, urbanization, fertility rate, and population density are observed as the significant drivers of the environmental pollution. Moreover, the consumption of renewable energy restored the environmental quality in these countries. Based on the results, we recommended the need for the diversification of the energy-basket for enhancement of the use of renewable energy resources. Further, through sensitization of the necessity of environmental conservation, the governments should promote less carbon-intense economic and demographic practices across the industries and sectors.


Molecular assessment of minimal residual disease in PBSC harvests provides prognostic information in neuroblastoma.
As almost all patients with high-risk neuroblastomas have autograft, we aimed to determine if minimal residual disease (MRD) quantified by RT-PCR for tyrosine hydroxylase in PBSC is prognostic in neuroblastomas. PBSC harvests from 38 children were analyzed. Seven had harvests positive for TH-mRNA. Patients with a positive MRD had a lower 2-year-overall-survival compared to those with negative MRD (P = 0.04) regardless of whether or not PBSC were re-infused. Patients in CR/VGPR group with positive MRD have hazard ratio of death at 7.3 [1.3-40.5]. In conclusion, molecular MRD status in PBSC of good response group may be of interest as a survival prognostic factor in high-risk neuroblastomas.


Scanning electron microscopic evidence for neural differentiation in Ewing's sarcoma cell lines.
A number of recent studies have suggested a relationship between Ewing's sarcoma (ES) and other small round cell tumours of childhood such as peripheral neuroepithelioma (PN). We report scanning electron microscopic studies on the character of induced neural differentiation in ES, neuroblastoma, PN, osteosarcoma and colon carcinoma. We found evidence of neural differentiation in both neural lines and in one of two Ewing's lines before treatment. After differentiation, both Ewing's and neural lines developed neuritic processes with varicosities and little arborization, except for the initially undifferentiated Ewing's line (A4573) which displayed extensive lateral sprouting from neuritic processes after differentiation. Neither treated nor untreated osteosarcoma or colon carcinoma displayed any evidence of neural differentiation. Further, neuroblastoma cells are easily distinguished from ES and PN by virtue of their single, unbranched neurites and lack of lateral sprouting or filopodia. These results provide further evidence for the neural character and close relationship between ES and PN.


A new fluoroquinolone derivative exhibits inhibitory activity against human immunodeficiency virus type 1 replication.
The inhibitory activity of several fluoroquinolone antibiotics against human immunodeficiency virus type 1 (HIV-1) replication was investigated. R-71762, (+/-) 9-fluoro-3-fluoromethyl-2, 3-dihydro-10-[4-(2-pyridyl)-1-piperazinyl]-7-oxo-7H-pyrido[1,2, 3-de][1,4]benzoxazine-6-carboxylic acid, protected MT-4 cells from HIV-1-induced cytopathic effects. Furthermore, the compound inhibited virus replication both in acutely and in chronically HIV-1-infected cells. On the other hand, ofloxacin, levofloxacin, ciprofloxacin, norfloxacin and enoxacin, that were previously reported to be protective against HIV-1-induced cytopathic effects, did not show any protective activity in our assay system. These results indicate that R-71762 is a novel inhibitor of HIV-1 replication and is effective even in HIV-1 chronically infected cells.


[Achievement motivation in children with migraine and their healthy siblings].
Psychosocial variables like stress or a high achievement motivation are discussed as a possible contributory factor to an attack in migraine. The aim of our study was to examine, whether children with migraine may be at risk for impaired achievement motivation. 37 children with migraine and their 17 non-affected siblings, were examined by means of an especially developed test for achievement motivation and by the Kaufman-Assessment-Battery for Children (K-ABC). There were no significant differences in achievement motivation and cognition between both groups. Children with migraine and their siblings demonstrated a neurocognitive performance within the average normal test range. There was a slight positive correlation between an atypical achievement motivation and the duration of migraine attacks. In general there are no signs of a pathologically elevated achievement motivation in children with migraine, but we found evidence that there might be a subgroup of patients, within whom an atypical achievement motivation might serve as a trigger variable, and who might profit from relaxation techniques and psychological-educational counselling.


Comparison of the direct effects of halothane and isoflurane on large and small coronary arteries isolated from dogs.
Relaxant responses to halothane and isoflurane were compared in helical strips of dog epicardial coronary arteries of different sizes: proximal large coronary arteries with outside diameters (OD) larger than 2.5 mm and distal small arteries with 0.7-0.9 mm OD. Responses to pharmacologic vasodilators, including nitroglycerin (NTG) and adenosine, were also studied for comparison. The relaxation induced by halothane in concentrations of 0.8-2.3% and by NTG (10(-9)-10(-5) M) was greater in proximal large coronary arteries than in distal small ones contracted with 20 mM KCl. In contrast, the relaxation by isoflurane (1.2-3.5%) and by adenosine (10(-8)-10(-4) M) was greater in small coronary arteries than in large ones. These results suggest that isoflurane is, like adenosine, preferentially a small artery dilator.


Association of Abnormal Findings on Neonatal Cranial Ultrasound With Neurobehavior at Neonatal Intensive Care Unit Discharge in Infants Born Before 30 Weeks' Gestation.
Cranial ultrasound (CUS) findings are routinely used to identify preterm infants at risk for impaired neurodevelopment, and neurobehavioral examinations provide information about early brain function. The associations of abnormal findings on early and late CUS with neurobehavior at neonatal intensive care unit (NICU) discharge have not been reported. To examine the associations between early and late CUS findings and infant neurobehavior at NICU discharge. This prospective cohort study included infants enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants Study between April 2014 and June 2016. Infants born before 30 weeks' gestational age were included. Exclusion criteria were maternal age younger than 18 years, maternal cognitive impairment, maternal inability to read or speak English or Spanish, maternal death, and major congenital anomalies. Overall, 704 infants were enrolled. The study was conducted at 9 university-affiliated NICUs in Providence, Rhode Island; Grand Rapids, Michigan; Kansas City, Missouri; Honolulu, Hawaii; Winston-Salem, North Carolina; and Torrance and Long Beach, California. Data were analyzed from September 2019 to September 2021. Early CUS was performed at 3 to 14 days after birth and late CUS at 36 weeks' postmenstrual age or NICU discharge. Abnormal findings were identified by consensus of standardized radiologists' readings. Neurobehavioral examination was performed using the NICU Network Neurobehavioral Scale (NNNS). Among the 704 infants enrolled, 675 had both CUS and NNNS data (135 [20.0%] Black; 368 [54.5%] minority race or ethnicity; 339 [50.2%] White; 376 [55.7%] male; mean [SD] postmenstrual age, 27.0 [1.9] weeks). After covariate adjustment, lower attention (adjusted mean difference, -0.346; 95% CI, -0.609 to -0.083), hypotonicity (mean difference, 0.358; 95% CI, 0.055 to 0.662), and poorer quality of movement (mean difference, -0.344; 95% CI, -0.572 to -0.116) were observed in infants with white matter damage (WMD). Lower attention (mean difference, -0.233; 95% CI, -0.423 to -0.044) and hypotonicity (mean difference, 0.240; 95% CI, 0.014 to 0.465) were observed in infants with early CUS lesions. In this cohort study of preterm infants, certain early CUS lesions were associated with hypotonicity and lower attention around term-equivalent age. WMD was associated with poor attention, hypotonicity, and poor quality of movement. Infants with these CUS lesions might benefit from targeted interventions to improve neurobehavioral outcomes during their NICU hospitalization.


Dynamic stiffness and crossbridge action in muscle.
Small sinusoidal vibrations at 300 HZ were applied to frog sartorius muscle to measure the dynamic stiffness (Young's modulus) throughout the course of tetanus. For a peak-to-peak amplitude of 0.4% the dynamic Young's modulus increased from 1.5 X 10(5) Nm-2 in the resting state to 2 X 10(7) Nm-2 in tetanus. After correction for the external connective tissue, the dynamic Young's modulus of the muscle was almost directly proportional to the tension throughout the development of tetanus. The ratio of dynamic Young's modulus to tensile stress thus remained constant (with a value at 300 Hz of approximately 100), consistently with Huxley and Simmon's identification of the crossbridges as the source of both tension and stiffness. For a single crossbridge the ratio of stiffness to tension was 8.2 X 10(7) m-1 at 300 Hz; it is deduced from literature data that the limiting value at high frequencies is about 1.6 X 10(8) m-1. This ratio is interpreted on Harrington's (1971) model to show that crossbridge action can be explained by a helix-coil transition of about 80 out of the 260 residues in each S-2 myosin strand. It is also shown that a helix-coil model can account for the observed rapid relaxation of muscle without invoking any complex behaviour of the crossbridge head.


The role of restraint omission in alcohol-related traffic fatalities.
Fatal traffic accidents affect thousands of people in the US alone every year. Alcohol consumption has been identified as a strong predictor of traffic fatalities. This result is hardly surprising as drivers who decide to consume alcohol and then drive are more likely to exhibit poor driving performance. In this paper, I argue that alcohol consumption can lead to traffic fatalities by increasing restraint omission. I analyzed individual-level data about victims (n=488,829) of fatal traffic accidents that occurred in the US between January 1, 1999 and December 31, 2015 from the Fatality Analysis Reporting System of the National Highway Traffic and Safety Administration. There is a strong relationship between alcohol consumption and restraint use. Both vehicle drivers and occupants are far less likely to be restrained when inebriated. Additional analyses show that part of the effect of alcohol consumption on traffic fatalities can be attributed to restraint omission. There is a significant relationship between alcohol consumption and restraint omission for both drivers and occupants of vehicles that were involved in fatal traffic accidents in the US between January 1999 and December 2015. Past public health campaigns have focused on preventing traffic fatalities by persuading drivers to refrain from getting behind the wheel after consuming alcohol. My data suggest that public health campaigns should inform both drivers and occupants of vehicles about the relationship between alcohol and restraint omission in order to minimize future casualties.


Treatment and outcomes in pheochromocytomas and paragangliomas: a study of 110 cases from a single center.
Many pheochromocytomas and paragangliomas (PPGLs) are nowadays diagnosed as incidentalomas or by screening. This may have changed outcomes. We reviewed 110 consecutive cases of PPGLs. Two cases with concurrent ectopic ACTH-syndrome were excluded. Sixty-five percent had presented as incidentalomas, 30% as symptomatic PPGLs, and 5% had been screened (previously diagnosed MEN2A). Doxazosin was used in 79%, phenoxybenzamine in 18%, intravenous phentolamine in 1%, and no alpha-blockade in the rest. Laparoscopic surgery was performed in 70%, but 11% were converted to open surgery. Complications of surgery were seen in 20%, and length of stay after surgery was 4 days (2-8) with no correlation with alpha-blockade dose or time. In the whole cohort glycemic disturbances decreased by surgery (47% vs. 9%, P < 0.001). During 9.6 ± 7.2-year (median 8[4-13]) follow-up, 7% developed a new PPGL, 5% a PPGL-metastasis (KI67 > 2% n = 2; KI67 ≤ 1% n = 3; tumor size ≥ 95 mm n = 4), and 13% died (metastatic pheochromocytoma n = 2, hypertensive crisis n = 1, heart failure n = 2, other malignancies n = 5, and unclear n = 4). Surgery improved blood pressure and glycemic disturbances in the incidentaloma and the symptomatic PPGL. Recurrence was more common in the screening group. The symptomatic PPGL group was more likely to die of a PPGL-related cause. Surgery was more challenging in the paragangliomas, with less improvement in glycemic control than in the pheochromocytoma group. However, blood pressure and long-term outcomes were similar. The outcomes seemed slightly better than previous studies. Long-term prognosis was similar between pheochromocytomas and paragangliomas.


Recruitment strategies for a post cessation weight management trial: A comparison of strategy cost-effectiveness and sample diversity.
Effective recruitment of representative and diverse samples in research trials is important to the generalizability of findings and in describing access to behavioral interventions. The current study evaluated the effectiveness of local and national recruitment strategies for a smoking cessation and weight management-focused randomized controlled trial (Fit & Quit). The overall cost-effectiveness of recruitment strategies was also evaluated. The study initially recruited participants locally in the Memphis, TN area and later transitioned to national recruitment, necessitated by the transition to remote assessment strategies due to the COVID-19 pandemic. The study evaluated effective recruitment strategies for randomized participants (n = 305) across gender, race, rurality, and recruitment method, as well as the cost-effectiveness of methods used during the recruitment period of this study. The most effective recruitment strategies were local postcards, local radio advertisements, word-of-mouth referrals, and national internet advertisements, which resulted in a combined 71.8% (n = 219) of the total randomized sample (n = 305). Radio advertisements were the best method for recruiting Black participants. Electronic recruitment strategies were the most effective method for non-urban participants. Additionally, gender, recruitment method, race, and rurality predicted randomization. Overall, electronic media methods were more cost-effective ($430.97 per participant) compared to traditional media methods ($931.43 per participant); however, traditional media methods resulted in a greater number of recruited and randomized participants. Results provide information on effective and cost-effective local and national recruitment methods for recruiting underrepresented groups of participants in behavioral clinical intervention studies.


Placental weight in diabetic pregnancies.
The placenta from 30 women with diabetes mellitus were examined and weighed at delivery. Nineteen of these were from women with overt and eleven from women with gestational diabetes. Eleven placentae from normal pregnancies served as controls. There was no difference between the mean +/- s.d. placental weight for the diabetic group and the control group (609 +/- 148 versus 591 +/- 93 g, NS). The mean placental weight ratios for the diabetic group and the control group were also similar (0.98 +/- 0.23 versus 0.89 +/- 0.15, NS). Moreover, there was no difference between the weights and weight ratios of placentae from women with overt (622 +/- 173 g, 1.02 +/- 0.27) and those with gestational diabetes (586 +/- 90 g, versus 0.90 +/- 0.13). Placental weights correlated with birthweights (r = 0.70, P less than 0.01) and with skinfold thickness measurements fo the infants (r = 0.40, P less than 0.05), but neither with gestational ages (r = 0.15, NS) nor with maternal glycosylated haemoglobin levels in the third trimester (r = 0.24, NS). Among the women with overt diabetes, placental weights were greater in those in White's class B and C than those in class D and R (689 +/- 143 versus 530 +/- 177 g; P less than 0.05). In general, placentae from well controlled diabetic patients were not heavier than those from normal pregnant women, although there was an increase in placental weight in White's class B and C, as compared with those in class D and R.


Conformational behavior of cyclic CCK-related peptides determined by 400-MHz 1H-NMR: relationships with affinity and selectivity for brain receptors.
The conformational study of a homogenous series of cyclic analogues of CCK8, selective for central receptors, such as Boc-X-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2, where X = L-Glu, D-Glu, or gamma-D-Glu, was performed by 400-MHz 1H-nmr. The regular increase in affinity for central receptors when going from [L-Glu] to [gamma-D-Glu] is correlated to (a) an enhancement in internal flexibility of the cyclic moiety, (b) an external orientation of the tyrosine side chain, and (c) a restructuring of the C-terminal part of the peptide. All these results could permit a modeling of biologically active conformation of CCK8 for both receptors types to be performed.


On the tip calibration for accurate modulus measurement by contact resonance atomic force microscopy.
Accurate quantitative elastic modulus measurements using contact resonance atomic force microscopy require the calibration of geometrical and mechanical properties of the tip as well as the choice of a suitable model for describing the cantilever-tip-sample system. In this work, we demonstrate with both simulations and experiments that the choice of the model influences the results of the calibration. Neglecting lateral force results in the underestimation of the tip indentation modulus and in the overestimation of the tip-sample contact radius. We propose a new approach to the calibration and data analysis, where lateral forces and cantilever inclination are neglected (which simplifies the calculations) and the tip parameters are assumed as fictitious.


Bulk, surface and blood-contacting properties of polyether polyurethanes modified with polydimethylsiloxane macroglycols.
The bulk, surface and blood-contacting properties of a series of polyether polyurethanes, modified with three different polydimethylsiloxane (PDMS) macroglycol segments, were evaluated. The PDMS oligomers were terminated with hydroxy-tipped end groups of varying polarity. The effect of substituting the polytetramethylene oxide (PTMO) soft segment of a base polyurethane with 5 and 15 wt% of these PDMS-containing polyols was investigated. The ultimate tensile strength and elongation at break appeared to be the bulk properties most significantly affected by the addition of the PDMS-containing polyols. Underwater contact angle data indicate that the block copolymer surface became more hydrophilic with increasing PDMS content. In a vacuum, as determined from the ESCA data, the relatively non-polar PDMS soft segments preferentially oriented at the surface with increasing PDMS incorporation. Despite the variation in the surface properties, the blood compatibility of these polymers was not significantly affected by the addition of the PDMS-containing polyols.


Efficacy of electrical stimulation for treatment of migraine.
The objective of this study is to assess the efficacy of electrical stimulation (ES) for the treatment of patients with migraine. MEDLINE, EMBASE, Cochrane Library, CINAHL, PsycINFO, Scopus, Web of Science, Allied and Complementary Medicine Database, ProQuest Nursing and Allied Health, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure will be searched for eligible studies. All electronic databases will be searched from inception to the present with no language restriction. Two authors will independently carry out study selection, data collection, and study quality assessment, respectively. RevMan 5. 3 software will be used for statistical analysis. This study will summarize high quality evidence on the efficacy and safety of ES for the treatment of migraine. This study will establish the accurate results of ES for migraine to facilitate the clinical practice and guideline development. PROSPERO CRD42019147480.


Surface-guided radiotherapy overview: Technical aspects and clinical applications.
In radiotherapy, patient positioning has long been ensured by ionizing imaging (kV or MV). Over the past ten years, surface-guided radiotherapy has appeared in radiotherapy departments. It is a continuous three-dimensional acquisition of the surface of the patient, based on the use of several optical cameras. The acquired surface is compared to an expected surface (usually taken from the planning scanner). Operators can constantly appreciate poor position, anatomical deformity or patient shift. Thus, the system allows an aid to the positioning of the patient, possibly without tattooing, but also a follow-up of the patient during the duration of the session. The most obvious contribution of the system concerns the treatment of the breast. In fact, for this location, the bone registration is not ideal and the target is visible in surface-guided radiotherapy. These systems also make it possible to treat in deep inspiration breath hold. But several other locations can benefit from it (pelvis, thorax, etc.).


Similarity of the oxidation products of L-cystathionine by L-amino acid oxidase to those excreted by cystathioninuric patients.
L-Cystathionine is oxidized by snake venom L-amino acid oxidase at a rate about half that with L-leucine at pH 8.5. The appearance of an absorbance at 296 nm and quantitation of the products of oxidation in the presence of catalase indicate formation in the solutions of a seven-membered ketimine ring produced by cyclization of the monoamino monoketo derivative of cystathionine. A limited double deamination has also been observed. In the absence of catalase, S-(carboxymethyl)homocysteine and S-(beta-carboxyethyl)cysteine have been identified together with ninhydrin-unreactive compounds yielding the above mentioned carboxy compounds upon hydrolysis with HCl. Authentic samples of the monoamino monoketo analogs of cystathionine have been prepared and compared with the enzymatic products. Cyclization of the synthetic products into the ketimine ring is pH-dependent as established by UV spectrum and other assays. Compounds derived from either the oxidation or the reduction of the ketimine have been prepared. It was found that many products of enzymatic and chemical changes of cystathionine and its ketimine described in the present paper are identical with those identified in the urine of cystathioninuric patients. This result indicates the occurrence in humans of secondary metabolic routes of cystathionine centered on the production of cystathionine ketimine, in equilibrium with the open form, which in cystathioninurics is revealed by the lack of cystathionase.


Improving the Initial Breast Cancer Consultation.
Research shows providing cancer patients with adequate information has many benefits, but how do nurse practitioners know whether the initial consultation meets the information needs of their patients? Furthermore, how can the initial consultation be improved? A low-cost continuous quality improvement process centered on decreasing distress and increasing information satisfaction was piloted to determine its effectiveness and feasibility. Immediately before and after an initial consultation with a breast cancer surgeon, 59 women completed a questionnaire to measure distress and specific problems they were having. They then completed a questionnaire to measure information satisfaction. Pre-post changes in the distress score and number of problems were analyzed, as was information satisfaction. Feasibility was qualitatively examined. For the study sample, pre-post median distress scores decreased significantly (from 5 to 3, Chi-square = 5.73, p < .017). Information dissatisfaction scales were identified. The process was deemed feasible. This effective and feasible process may help the nurse practitioner continuously improve the initial consultation process. (a) the initial breast cancer consultation is important, (b) a novel process for improving the initial breast cancer consultation is proposed, and (c) this feasible, low-cost process should be embedded into normal practice operations.


Design and synthesis of novel 1-substituted 3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine analogs as selective BTK inhibitors for the treatment of mantle cell lymphoma.
Ibrutinib (IBN), a first-in-class BTK-inhibitor, was approved by the FDA for the treatment of mantle cell lymphoma (MCL). Although IBN shows excellent performance as an anti-lymphoma agent, it has some undesirable side effects due to its off-target activities. Our studies yielded a novel series of 3-(6-phenoxypyridin-3-yl)-4-amine-1H-pyrazolo[3,4-d]pyrimidine derivatives capable of potent inhibition of Bruton's tyrosine kinase (BTK). Notably, compound 13e explained potent BTK inhibitory activity and could completely inhibit the phosphorylation of BTK and PLCγ2 in Z138 cells at low micromolar concentration. Compared with IBN, compound 13e improved anti-proliferative activities 3-40 folds in MCL cell lines with IC50 values lower than 1 μM. Low micromolar doses of 13e could induce strong cell apoptosis in Jeko-1 and Z138 cells. In addition, compound 13e showed greater BTK selectivity and higher stability in human liver microsomes than IBN and potential safety improvement for the treatment of MCL.


Characterisation of a messenger RNA selectively expressed in human breast cancer.
A complementary DNA library from MCF-7 cells was screened using 32P-cDNA derived from a breast carcinoma and from normal breast tissue. From 10(5) plaques (20% of library) we obtained a clone (Md2) which was differentially expressed in the carcinoma. The distribution of its corresponding transcript of 6-700 nucleotides was examined in normal and neoplastic cells, by filter and in situ hybridisation. We observed localisation of 35S-Md2 to the tumour cells of breast cancers with no significant reaction over stromal or vascular elements or on normal ductal epithelia. M13 sequencing showed Md2 to be 250 nucleotides in length, of which 197 were homologous to the 3'-untranslated region and a short open reading frame of the pS2 gene (Masiakowski et al., 1982). Md2 mRNA was found principally in breast carcinoma cell lines and tumours, with low levels in benign breast disease and no expression in non-breast squamous cell lines. Approximately 43% (23/54) of carcinomas contained this mRNA (varying from + to + + + + level); it was present in 20/38 (53%) of ER positive carcinomas compared to 3/16 (19%) of ER negative carcinomas. In 21 patients who had undergone primary endocrine therapy for recurrent disease expression of Md2 in the primary tumour correlated with the subsequent response to treatment (P = 0.041) and was of similar predictive value as ER status. Both tests correctly predicted outcome in about 76% of cases.


Alterations of norepinephrine metabolism in rat locus coeruleus neurons in response to axonal injury.
Adult male Sprague-Dawley rats were injected in the right cerebral hemisphere with the neurotoxin 6-hydroxydopamine (6-OHDA) at a site which interrupted the noradrenergic axons ascending from the locus coeruleus (LC). Distal to the injection site ('posterior cortex'), levels of norepinephrine (NE), dopamine-beta-hydroxylase (D beta H) and tyrosine hydroxylase (TH) fell to 39-42% of control levels ipsilateral to the lesion over the first 25 days, while contralateral levels fell to 32-73% of control during this time. These changes were paralleled by a 63% decrease in the high affinity uptake of [3H]NE in the ipsilateral posterior cortex at 12 days after the lesion. Both ipsilateral and contralateral levels of NE and D beta H fell in the LC during this time, while LC TH showed variable increases and decreases in activity. At 3 months after right cortical 6-OHDA injections, posterior cortical levels of NE, D beta H and TH, as well as the high affinity uptake of [3H]NE, had returned to control levels suggesting that some type of regeneration or axonal sprouting had occurred. Axonal transport of D beta H and TH was assessed by measuring the accumulation of enzyme activity proximal to a 6-OHDA lesion made in the more caudal portion of these same LC axons. Transport of D beta H fell to 7-40% of control from 2 to 24 days and rose to 160% of control by 3 months after the lesion. TH transport was decreased to only 61% of control only at 24 days and returned to control levels by 3 months. These studies document that there is independent regulation of the metabolism of the NE synthetic enzymes, D beta H and TH, during the degeneration and subsequent regeneration or collateral sprouting of injured distal axons of LC noradrenergic neurons.


Time-dependent response of both ventricles after septal ablation: implications for biventricular support after left ventricular assist device placement.
An ovine model of septal ablation was studied to elucidate the mechanisms involved in right ventricular failure when commencing left ventricular mechanical assistance. The disruption of ventricular interdependence after acute and chronic septal injury was examined. Twelve sheep underwent percutaneous transluminal septal myocardial ablation using 0.6 mL ethanol. Twelve other sheep underwent a sham procedure. Left ventricular and right ventricular pressure and volume (conductance) response 15 minutes and 4 weeks postinjury were measured. Ultrasonic crystals measured chamber dimensions and wall movement. Areas at risk and infarct zones were quantified. Compared with sham, ablation chronically reduced systolic interventricular septal thickening (18.4% +/- 5.8% vs 7.3% +/- 3.1%; P < .001) and acutely increased right ventricular ejection fraction (37.6% +/- 8.5% vs 69.9% +/- 7.2%; P < .001), preload recruitable stroke work (42.0 +/- 4.4 erg x 10(3) vs 48.7 +/- 2.0 erg x 10(3), P < .001), end-systolic elastance (1.03 +/- 0.19 mm Hg mL(-1) vs 1.31 +/- 0.18 mm Hg mL(-1); P < .001), and Tau (24.9 +/- 3.8 ms vs 29.6 +/- 8.2 ms; P < .001). In contrast, for left ventricular ejection fraction (55.5% +/- 5.9% vs 38.9% +/- 7.7%; P < .001), preload recruitable stroke work (85.9 +/- 10.6 mm Hg vs 66.5 +/- 9.6 mm Hg; P < .001) and elastance (2.13 +/- 0.51 mm Hg mL(-1) vs 1.81 +/- 0.44 mm Hg mL(-1); P < .001) were reduced, but Tau increased (22.0 +/- 3.5 ms vs 28.9 +/- 5.8 ms; P < .001) and remained elevated at 4 weeks compared with sham. The area at risk was the same between groups, and injury was limited to the septum (17.2% +/- 2.7% vs 2.9% +/- 5.8%; P < .001). Acute and chronic hemodynamic responses are distinctly different after septal injury; the acute response demonstrates a paradoxical motion. Resolution of this motion at 4 weeks is suggestive of reduced septal compliance and buttressing. Ventricular interactions after placement of a left ventricular assist device will vary depending on the injury duration.


"Learned" changes in the responses of the rat barrel field neurons.
The effect of pairing two vibrissa stimulations on unit responses of the barrel field of the somatosensory cortex were studied in partially restrained but awake and undrugged rats. Before pairing, one of the stimulations (S2) evoked a stable, short-latency and excitatory response from the recorded unit. Depending on the neuron, the other stimulation (S1), preceding S2 by 500 ms, did or did not have an effect before pairing. In a number of cases, the S1-S2 association produced significant changes in the unit responses: (1) the appearance of an excitatory response to S1 when that stimulus was ineffective before pairing; (2) the modification of pre-existing responses to S1 and/or S2. In all instances these modifications consisted in the decrease or disappearance of the "afferent inhibition" and/or the appearance of long-latency excitatory components. These effects appeared after some 30-100 trials and persisted in some cases up to 20 min after interruption of pairing. Our observations provide the first physiological data on the plasticity of the vibrissa projections in the chronic adult rodent. Though the underlying plastic neural elements and mechanisms remain to be specified, these phenomena suggest that "learned" changes in unit activity may occur in sensory systems and not only in "non-specific" ones.


[Problems in the use of radioactively labelled bacteria in experiments. 2. Quantitative method for the evaluation of pathogens in the calf lung by means of labelled bacteria after aerosol or intratracheal administration].
By means of two aerosol apparatures radioactive labelled Pasteurella-multocida-germs were given to calves via a respiratory mask. Labelling of Pasteurellae was done internal by using special nutritive media with Fe-59 or P-32. In a period of 10-25 minutes 5 X 10(9)-10(10) labelled bacteria were given to the animals for inhalation. Another animal group was injected intratrachealy with the same quantity of labelled germs. Immediately after termination of germ application the animals were killed and dissected. After solution or homogenization, respectively of the total lung tissue radioactivity was determined by liquid-scintillation-counting (Fe-59) or Cerenkov-measurement (P-32), respectively. The activities recovered from lung homogenates rendered is possible to calculate the received amount of bacteria. 40-80% of germs would be recovered in the lung after application by intratracheal injection while only 1-7% could be recovered after individual aerosol application lasting for 15-25 minutes.


Identifying the patient harms to include in an in silico clinical trial.
Clinical trials represent a crucial step in the development and approval of medical devices. These trials involve evaluating the safety and efficacy of the device in a controlled setting with human subjects. However, traditional clinical trials can be expensive, time-consuming, and ethically challenging. Augmenting clinical trials with data from computer simulations, so called in silico clinical trials (ISCT), has the potential to address these challenges while satisfying regulatory requirements. However, determination of the patient harms in scope of an ISCT is necessary to ensure all harms are sufficiently addressed while maximizing the utility of the ISCT. This topic is currently lacking guidance. The objective of this work is to propose a general method to determine which patient harms should be included in an ISCT for a regulatory submission. The proposed method considers the risk associated with the harm, the impact of the device on the likelihood of occurrence of the harm and the technical feasibility of evaluating the harm via ISCT. Consideration of the risk associated with the harm provides maximum clinical impact of the ISCT, in terms of focusing on those failure modes which are most relevant to the patient population. Consideration of the impact of the device on a particular harm, and the technical feasibility of modeling a particular harm supports that the technical effort is devoted to a problem that (1) is relevant to the device in question, and (2) can be solved with contemporary modeling techniques. As a case study, the proposed method is applied to a total shoulder replacement humeral system. With this framework, it is hoped that a consistent approach to scoping an ISCT can be adopted, supporting investment in ISCT by the industry, enabling consistent review of the ISCT approach across device disciplines by regulators, and providing maximum impact of modeling technologies in support of devices to improve patient outcomes.


In situ remediation of 2,4-dicholrophenoxyacetic acid herbicide using amine-functionalized imidazole coordination complexes.
Demand of clean water is always a major concern due to continuous use of toxic pesticides and herbicides to overcome food scarcity. In Asian countries, wide use of ionizable 2,4-D herbicide has worsen problem due to its less binding ability with soil and can easily contaminate drinking water that causes potential risks to humans and environment. The present research focused on synthesis of amino-factionalized coordination complexes using imidazole-based amino benzoic acid ligands for remediation of acidic 2,4-D herbicide. Coordination complexes characterized with FTIR, 1H-NMR, elemental analysis, thermogravimetric analysis, powder XRD, and BET revealed successful incorporation of functionalized groups with high thermal stability and surface area that make them suitable for adsorption experiments. Batch adsorption experiments conducted at different temperature conditions depicted the spontaneous physisorption process (- ∆G) having endothermic nature (∆H, ∆S). The removal efficiency of the amino-functionalized coordination complex is found to be higher (73%) compared to non-functionalized (35%) and acetic anhydride-functionalized coordination complex (42%). Kinetic studies supported pseudo 2nd-order kinetics with three phases of adsorption depicted by intra-particle diffusion model. Amino-functionalized complexes favored Langmuir isotherm while Freundlich isotherm is best fitted for non-functionalized complexes. The synthesized adsorbents were also proven to be effective for removal of herbicide from irrigated wastewater with average percent removal of 56% for amino functionalized, acetic anhydride functionalized (23%), and non-functionalized (20%).


Validation of core medical knowledge by postgraduates and specialists.
Curriculum constructors and teachers must decide on the content and level of objectives and materials included in the medical curriculum. At University Medical Centre Utrecht it was decided to test relatively detailed knowledge at a regular level in study blocks and to design a progress test aimed at the medical core knowledge that every graduating doctor should possess. This study was conducted to validate the level of knowledge tested in this progress test. We designed a questionnaire to investigate whether postgraduate trainees and experienced specialists agree with item writers on what is required core knowledge. Postgraduates and specialists received a questionnaire with 80 items designed to test core knowledge. Respondents were asked to indicate to what extent the items actually represented the core knowledge required of a recently graduated medical student. Of the clinical questions, 82.4% were judged to reflect core knowledge, whereas only 42.4% of the basic science questions were judged to reflect core knowledge. There was a strikingly high correlation on the mean judgements per item of postgraduate trainees versus medical specialists (r = 0.975). Many items, written to reflect core knowledge, appear to be judged by postgraduates and clinicians as pertaining to non-core knowledge. Postgraduate trainees appear to be as capable as experienced specialists of making judgements regarding core knowledge. Fewer basic science items are regarded as core knowledge than clinical items. This may suggest that, specifically, basic science teachers do not agree with physicians on what is to be considered medical core knowledge for graduating doctors.


Therapy of mixed anaerobic-aerobic infections. Lessons from studies of intra-abdominal sepsis.
Mixed anaerobic-aerobic infections may occur in a variety of anatomical locations and are usually related to the spread of bacteria from a proximal mucosal surface. Much has been learned about the pathophysiology and treatment of mixed anaerobic-aerobic infections from the study of intra-abdominal sepsis related to spillage of colonic contents. There is an average of five microorganisms at the infected site: three anaerobic and two aerobic pathogens. Appendicitis and diverticulosis are the most common conditions which predispose to fecal contamination of the intra-abdominal cavity. Initially, peritonitis develops which, if untreated, progresses to an abscess. The abscess is a unique pathologic entity which may form a protective environment for the microorganisms and present a barrier to the action of certain antimicrobial agents. Treatment usually involves two modalities: surgical drainage or debridement and appropriate antimicrobial agents to cover both components of the mixed infection. On the basis of in vitro susceptibility there are six groups of antimicrobial agents that are useful in treating intra-abdominal infections: clindamycin; metronidazole; chloramphenicol; broad-spectrum penicillins (carbenicillin/ticarcillin/piperacillin); cephalosporins (cefoxitin/moxalactam); and imipenem. Randomized prospective studies have shown that the first five of these groups are effective in the therapy of intra-abdominal mixed infections. Preliminary data indicate that imipenem/cilastatin is very effective in the therapy of this serious infection; however its place in the therapeutic armamentarium awaits the completion of randomized prospective studies against established drugs.


Education Liaison improves implementation of school accommodations for students with sickle cell disease.
Children with sickle cell disease (SCD) have lower academic attainment than healthy peers. Many benefit from neuropsychological testing (NPT) and educational accommodations, including Individualized Education Programs (IEPs) and Section 504 plans (504s). Despite medical barriers to academic attainment, many children with SCD do not receive indicated NPT or accommodations. We hypothesize that a dedicated Education Liaison (EL) embedded in the SCD team increases implementation of NPT and accommodations. This retrospective study included children aged 5-20 years with SCD receiving care at a single center from 2017 through 2020. Univariate analysis and multiple logistic regression were performed. Total 316 children with SCD were included. At baseline, 52.8% had accommodations (IEP: 24.4%, 504: 38.0%). The EL interacted with 62.0% of children. Children with EL contact were more likely to undergo NPT (odds ratio [OR]: 5.385), have an IEP (OR: 4.580), and have a 504 (OR: 2.038) (p < .001 for all). At the end of the study period, 64.6% had accommodations (IEP: 33.5%, 504: 54.4%), which increased from baseline (p < .001 for all). EL interaction was associated with overt or silent stroke history (OR: 1.911), acute chest syndrome history (OR: 2.257), hospitalizations since age 5 (OR: 3.216), and hospitalization for vaso-occlusive pain since age 5 (OR: 2.226) (p < .001 for all). EL interaction improves access to NPT and educational accommodations among children with SCD. SCD centers should incorporate ELs in comprehensive care teams to improve access to appropriate educational accommodations.


Detecting the exponential relaxation spectrum in glasses by high-precision nanocalorimetry.
Nonexponential relaxations are universal characteristics for glassy materials. There is a well-known hypothesis that nonexponential relaxation peaks are composed of a series of exponential events, which have not been verified. In this Letter, we discover the exponential relaxation events during the recovery process using a high-precision nanocalorimetry, which are universal for metallic glasses and organic glasses. The relaxation peaks can be well fitted by the exponential Debye function with a single activation energy. The activation energy covers a broad range from α relaxation to β relaxation and even the fast γ/β' relaxation. We obtain the complete spectrum of the exponential relaxation peaks over a wide temperature range from 0.63Tg to 1.03Tg, which provides solid evidence that nonexponential relaxation peaks can be decomposed into exponential relaxation units. Furthermore, the contribution of different relaxation modes in the nonequilibrium enthalpy space is measured. These results open a door for developing the thermodynamics of nonequilibrium physics and for precisely modulating the properties of glasses by controlling the relaxation modes.


Lessons from the field on COVID-19: a public health point of view.
The COVID-19 pandemic in world affected all strata of population. It started on 28 January 2020 in Wuhan province of China and since then it has been spreading all over the globe rapidly. Today there are nearly 6 million cases of COVID-19 all over the globe. India with its second largest population in the world, with approximately 1.2 billion, has 22% of its population below poverty line and illiteracy at large. Kashmir, a Union Territory of India with a population of 7 million, has been equally hit by the Severe Acute Respiratory Syndrome-Corona Virus-(SARS-CoV) pandemic. In such a limited-resource setting, working under constraints leads to generation of innovations which are the support system of community medicine/public health management.


Morphological evaluation of melanocytic lesions with three-dimensional line-field confocal optical coherence tomography: correlation with histopathology and reflectance confocal microscopy. A pilot study.
Line-field confocal optical coherence tomography (LC-OCT) is a new in vivo emerging technique that provides cellular resolution, allows deep imaging (400 μm) and produces real-time images in both the horizontal and vertical plane and in three dimensions. No previous description of different subtypes of melanocytic lesions and their correlation with histopathology and reflectance confocal microscopy has been reported. To describe the features of melanocytic lesions by LC-OCT and their correlation with histopathology and reflectance confocal microscopy (RCM) findings. Selected melanocytic benign lesions and melanomas were imaged in vivo with RCM and LC-OCT at the Fundación Hospital Clinic (Barcelona, Spain). A minimum area of 4 × 4 mm (block image) at four depths (stratum granulosum, suprabasal, layer dermoepidermal junction and upper dermis) were acquired with RCM and a minimum of three cubes with LC-OCT. Horizontal, vertical sections and three-dimensional (3D) cubes of LC-OCT were matched with RCM (Vivablock two-dimensional composite mosaic) and histopathology, with ~5 μm lateral resolution accuracy (the same cell nuclei were measured in X, Y and Z) and evaluated by three observers experienced in using RCM and histopathology. In total, 12 melanocytic tumours (2 in situ melanomas, 2 invasive melanomas, 4 atypical naevi, 2 intradermal naevi, 1 compound naevus and 1 junctional naevus) were included. High correlation with 5 μm accuracy between RCM and LC-OCT was observed for each tumour. The 3D images of melanocytic lesions were obtained with cellular resolution and correlated with both RCM and histopathology, allowing an understanding of the architecture and precise correlation at the cellular level with RCM. Similarities between LC-OCT and RCM for the described diagnostic features and architecture (nests of melanocytic cells, ringed and meshwork pattern, and cellular details of tumour cells as dendritic and pagetoid cells) were confirmed. The main advantage of diagnosis by RCM fixed probe was the ability to produce larger scans of the lesion using mosaicing compared with an LC-OCT handheld probe. LC-OCT allows the architectural and cellular description of different types of melanocytic lesions. LC-OCT showed high correlation with histopathology (vertical sections) and RCM (horizontal sections) in melanocytic lesions. Diagnostic criteria for RCM were similar to those for LC-OCT.


Approaches towards the stabilization of hemiaminal function at ornithine unit of mulundocandin.
Semisynthetic modifications at position-12 (ornithine-5-position, hemiaminal function) of mulundocandin were carried out to improve its chemical stability. New carbon-carbon (C-C) and carbon-hydrogen (C-H) linkage at hemiaminal function -12 has been achieved. Lewis acid catalyzed introduction of electron rich aryl group at position-12 of mulundocandin is developed. Synthesized mulundocandin analogues were evaluated for their chemical stability and antifungal activity against C. albicans and A. fumigatus.


Triterpenoid saponins from Ilex latifolia.
Three new triterpenoid saponins, latifolosides F, G, H were isolated from the leaves of Ilex latifolia. Their structures were elucidated on the basis of chemical and spectral evidence. Latifoloside F was determined to be 3-O-[alpha-L-rhamnopyranosyl(1-2)]-[beta-D-glucopyranosyl(1-3)-]- alpha-L-arabinopyranosyl ilexgenin B 28-O-[alpha-L-rhamnopyranosyl(1-2)]-beta-D-glucopyranoside. Latifoloside G was 3-O-[alpha-L-rhamnopyranosyl(1-2)]-[beta-D-glucopyranosyl(1-3)-]- alpha-L-arabinopyranosyl pomolic acid 28-O-[alpha-L-rhamnopyranosyl(1-2)]-beta-D-glucopyranoside. Latifolioside H(3) was 3-O-[alpha-L-rhamnopyranosyl(1-2)]-[beta-D-glucopyranosyl(1-3)-]- alpha-L-arabinopyranosyl siaresinolic acid 28-O-[alpha-L-rhamnopyranosyl(1-2)]-beta-D-glucopyranoside.


A novel ballooned-tip percutaneous endoscopic gastrojejunostomy tube: a pilot study.
The tip of currently available percutaneous endoscopic gastrojejunostomy (PEGJ) tubes frequently migrates back into the stomach. To study the safety of a novel, ballooned-tip, PEGJ tube and assess the risk of retrograde migration into the stomach within 3 weeks of placement. Prospective clinical study (NCT01551095). Tertiary-care center. Seven patients who required post-pyloric feeding were included. Placement of PEGJ feeding tubes. Position of the PEGJ, abdominal radiograph findings, adverse events. Seven patients underwent placement of self-propelled PEGJ tubes during the study period. Technical success was achieved in all patients (100%). All procedures were rated as technically simple, and jejunostomy tubes were placed in <5 minutes during all procedures. Abdominal radiographs showed that the jejunostomy tubes were in the jejunum in all 7 patients at both 1 and 3 weeks after tube placement. Small number of patients and short follow-up. Ballooned-tip PEGJ feeding tubes were safe and easy to place. The presence of the balloon prevented migration into the stomach. Ballooned-tip PEGJ tubes have the potential to eliminate the need for hospital readmission and repeat endoscopies for retrograde tube migration, and this may result in large systemic cost savings.


Maternal alcohol ingestion and neural tube defects: observation of four brothers in a family.
The authors report the observation of four brothers with myelomeningoceles, sons of an alcoholic mother. The typical signs of the alcohol fetal syndrome was seen in only one of them. The chronic alcoholism of the mother was the only known teratogenic factor during the four pregnancies.


Mismatched base-pair simulations for ASFV Pol X/DNA complexes help interpret frequent G*G misincorporation.
DNA polymerase X (pol X) from the African swine fever virus is a 174-amino-acid repair polymerase that likely participates in a viral base excision repair mechanism, characterized by low fidelity. Surprisingly, pol X's insertion rate of the G*G mispair is comparable to that of the four Watson-Crick base pairs. This behavior is in contrast with another X-family polymerase, DNA polymerase beta (pol beta), which inserts G*G mismatches poorly, and has higher DNA repair fidelity. Using molecular dynamics simulations, we previously provided support for an induced-fit mechanism for pol X in the presence of the correct incoming nucleotide. Here, we perform molecular dynamics simulations of pol X/DNA complexes with different incoming incorrect nucleotides in various orientations [C*C, A*G, and G*G (anti) and A*G and G*G (syn)] and compare the results to available kinetic data and prior modeling. Intriguingly, the simulations reveal that the G*G mispair with the incoming nucleotide in the syn configuration undergoes large-scale conformational changes similar to that observed in the presence of correct base pair (G*C). The base pairing in the G*G mispair is achieved via Hoogsteen hydrogen bonding with an overall geometry that is well poised for catalysis. Simulations for other mismatched base pairs show that an intermediate closed state is achieved for the A*G and G*G mispair with the incoming dGTP in anti conformation, while the protein remains near the open conformation for the C*C and the A*G syn mismatches. In addition, catalytic site geometry and base pairing at the nascent template-incoming nucleotide interaction reveal distortions and misalignments that range from moderate for A*G anti to worst for the C*C complex. These results agree well with kinetic data for pol X and provide a structural/dynamic basis to explain, at atomic level, the fidelity of this polymerase compared with other members of the X family. In particular, the more open and pliant active site of pol X, compared to pol beta, allows pol X to accommodate bulkier mismatches such as guanine opposite guanine, while the more structured and organized pol beta active site imposes higher discrimination, which results in higher fidelity. The possibility of syn conformers resonates with other low-fidelity enzymes such as Dpo4 (from the Y family), which readily accommodate oxidative lesions.


The Evaluation of a Borderline Long QT Interval in an Asymptomatic Patient.
QT prolongation on resting electrocardiography (ECG) is common, and the clinician is often challenged by the dilemma of excluding acquired causes and recognizing potential congenital long QT syndrome (LQTS). The hallmark of LQTS is an abnormally long QT interval. However, a normal or borderline long QT interval may be observed in up to 50% of patients with LQTS because of the intermittent nature of QT prolongation. This review presents an approach to evaluating the asymptomatic patient with a borderline long QT interval, which incorporates a comprehensive clinical assessment, rest and provocative ECG testing, and genetic testing when appropriate.


Digital subtraction venography for assessment of deep venous thrombosis in the arms following pacemaker implantation.
We recently performed digital subtraction venography and detected axillary venous thrombosis in a 56-year-old female with nonspecific symptoms related to the right arm following a permanent transvenous endocardial pacemaker implantation two years ago. In view of its cost-effectiveness and less invasive approach, digital venography appears ideally suited for evaluation of the frequently occurring subclinical deep venous thrombosis in these patients.


Chronic mitochondria antioxidant treatment in older adults alters the circulating milieu to improve endothelial cell function and mitochondrial oxidative stress.
Excessive reactive oxygen species production by mitochondria (mtROS) is a key contributor to age-related vascular endothelial dysfunction. We recently showed in a crossover design, placebo-controlled clinical trial in older adults that 6 wk of treatment with the mitochondria-targeted antioxidant (MitoQ) improved endothelial function, as measured by nitric oxide (NO)-mediated endothelium-dependent dilation (EDD), by lowering mtROS and was associated with reduced circulating levels of oxidized low-density lipoprotein (oxLDL). Here, we conducted an ancillary analysis using plasma samples from our clinical trial to determine if MitoQ treatment-mediated changes in the "circulating milieu" (plasma) contribute to improvements in endothelial function and the mechanisms involved. With the use of an ex vivo model of endothelial function, acetylcholine-stimulated NO production was quantified in human aortic endothelial cells (HAECs) exposed to plasma collected after chronic MitoQ and placebo supplementation in 19 older adults (67 ± 1 yr; 11 females). We also assessed the influence of plasma on endothelial cell (EC) mtROS bioactivity and the role of lower circulating oxLDL in plasma-mediated changes. NO production was ∼25% higher (P = 0.0002) and mtROS bioactivity was ∼25% lower (P = 0.003) in HAECs exposed to plasma collected from subjects after MitoQ treatment versus placebo. Improvements in NO production ex vivo and NO-mediated EDD in vivo with MitoQ were correlated (r = 0.4683; P = 0.0431). Increasing oxLDL in plasma collected after MitoQ to placebo levels abolished MitoQ treatment effects on NO production and mtROS bioactivity, whereas inhibition of endogenous oxLDL binding to its lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) prevented these effects. These findings provide novel insight into the mechanisms by which MitoQ treatment improves endothelial function in older adults.NEW & NOTEWORTHY Chronic supplementation with a mitochondria-targeted antioxidant (MitoQ) improves vascular endothelial function in older adults, but the mechanisms of action are incompletely understood. Here, we show that MitoQ supplementation leads to changes in the circulating milieu (plasma), including reductions in oxidized low-density lipoprotein that enhance nitric oxide production and reduce mitochondrial oxidative stress in endothelial cells. These findings provide new information regarding the mechanisms by which MitoQ improves age-related endothelial dysfunction.


A Journey in the Brain's Clock: In Vivo Veritas?
The suprachiasmatic nuclei (SCN) of the hypothalamus contain the circadian pacemaker that coordinates mammalian rhythms in tune with the day-night cycle. Understanding the determinants of the intrinsic rhythmicity of this biological clock, its outputs, and resetting by environmental cues, has been a longstanding goal of the field. Integrated techniques of neurophysiology, including lesion studies and in vivo multi-unit electrophysiology, have been key to characterizing the rhythmic nature and outputs of the SCN in animal models. In parallel, reduced ex vivo and in vitro approaches have permitted us to unravel molecular, cellular, and multicellular mechanisms underlying the pacemaker properties of the SCN. New questions have emerged in recent years that will require combining investigation at a cell resolution within the physiological context of the living animal: What is the role of specific cell subpopulations in the SCN neural network? How do they integrate various external and internal inputs? What are the circuits involved in controlling other body rhythms? Here, we review what we have already learned about the SCN from in vivo studies, and how the recent development of new genetically encoded tools and cutting-edge imaging technology in neuroscience offers chronobiologists the opportunity to meet these challenges.


Pre-culture with transferrin-Fe3+ before in vitro maturation improves the developmental competence of porcine oocytes matured in vitro.
Since the developmental competence of oocytes cultured after in vitro maturation (IVM) is low, it is necessary to improve the IVM method for efficient offspring production. In this study, we revealed that transferrin (TF)-Fe3+ was accumulated in follicular fluid with increasing the follicular diameter, and that TF receptor (TFR1) was localized in granulosa cells of pig. Thus, we hypothesized that TF-Fe3+ would be a factor in the induction of developmental competence of porcine oocytes. To mimic the follicular development environment, cumulus-oocyte complexes (COCs) were cultured in pre-IVM medium (low dose of FSH) without or with Holo-TF (monoferric or diferric TF) or Apo-TF (non-iron bond TF). After pre-IVM without or with Holo-TF, COCs were cultured in IVM medium (high dose of FSH and EGF) without or with Holo-TF. Cultivation with Holo-TF increased the expression of follicular development maker (Cyp19a1 and Ccnd2), E2 production, and proliferative activity of cumulus cells, whereas cultivation with Apo-TF did not show these positive effects. The treatment with Holo-TF during pre-IVM, but not during IVM, dramatically induced oocyte maturation with increasing the blastocyst rate. We succeeded in showing for the first time that the cultivation with Holo-TF in pre-IVM can produce embryos in pig with high efficiency.


Repeated testing to improve skills in a pharmacy practice laboratory course.
To evaluate the impact of repeated simulations and testing on the pharmacy practice skills development of third-year doctor of pharmacy (PharmD) students. A pharmacy practice skills laboratory was redesigned to reinforce skills development and enhance retention. Timed, repeated learning experiences that increased in complexity throughout the semester were used to test student knowledge, skills, and abilities. Over a 5-year period, scores from skills-based activities deemed essential to professional practice and repeated 4 or more times in the course were analyzed. There was a significant improvement in scores on drug utilization reviews and patient counseling simulations despite the increasing difficulty and complexity of the medication problems presented (p <0.001). Students' scores on prescription verification and sterile product verification also improved significantly over 3 assessments (p <0.001), but then plateaued, with less improvement seen in performance on subsequent assessments. Providing multiple opportunities for students to conduct or simulate pharmacy practice activities and then test their knowledge and skills improves students' learning and performance.


Role of neurotrophic and growth factors in the rapid and sustained antidepressant actions of ketamine.
The neurotrophic hypothesis of depression proposes that reduced levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) contribute to neuronal atrophy or loss in the prefrontal cortex (PFC) and hippocampus and impaired hippocampal adult neurogenesis, which are associated with depressive symptoms. Chronic, but acute, treatment with typical monoaminergic antidepressants can at least partially reverse these deficits, in part via induction of BDNF and/or VEGF expression, consistent with their delayed onset of action. Ketamine, an N-methyl-d-aspartate receptor antagonist, exerts rapid and sustained antidepressant effects. Rodent studies have revealed that ketamine rapidly increases BDNF and VEGF release and/or expression in the PFC and hippocampus, which in turn increases the number and function of spine synapses in the PFC and hippocampal neurogenesis. Ketamine also induces the persistent release of insulin-like growth factor 1 (IGF-1) in the PFC of male mice. These neurotrophic effects of ketamine are associated with its rapid and sustained antidepressant effects. In this review, we first provide an overview of the neurotrophic hypothesis of depression and then discuss the role of BDNF, VEGF, IGF-1, and other growth factors (IGF-2 and transforming growth factor-β1) in the antidepressant effects of ketamine and its enantiomers. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Prevalence of neuropathic pain in knee or hip osteoarthritis: A systematic review and meta-analysis.
Discordance between radiographic and pain severity in osteoarthritis (OA) has led researchers to investigate other pain mechanisms, including neuropathic pain. Accurate identification of any neuropathic pain in hip or knee OA is important for appropriate management, but neuropathic pain prevalence is unknown. We aimed to obtain an overall prevalence estimate by systematically reviewing and meta-analysing the prevalence of neuropathic pain in people with hip or knee OA. Observational studies which measured neuropathic pain in people aged 18 years and older with hip or knee OA were considered for inclusion. Electronic databases were searched up to February 2016. Two reviewers independently identified eligible studies and assessed methodological quality. Prevalence estimates and 95% confidence intervals were calculated using random effects meta-analytic techniques. Nine studies met the inclusion criteria. Study samples were from general population, hospital and community settings and all used self-report questionnaires to determine neuropathic pain. The overall prevalence estimate was 23% (95% CI: 10-39%), with considerable heterogeneity (I2 = 97.9%, p < 0.001). This estimate was largely unchanged with subgroup analyses based on index joint, questionnaire type, setting and consideration of other potential causes of neuropathic pain. However, the estimate for two studies that excluded other potential causes of neuropathic pain was substantially higher (32%, 95% CI: 29-35%). Neuropathic pain prevalence in people with knee or hip OA is considerable at 23%, and may be higher after other potential causes of neuropathic pain are excluded. Concerns regarding the validity of neuropathic pain questionnaires, selection bias, methodological quality and study heterogeneity suggest caution with interpretation of these findings. Prevalence studies using standardised criteria for neuropathic pain are required.


White matter lesions and intra-arterial thrombolysis.
The aim of the study was to assess the influence of white matter lesions in patients with acute ischemic stroke treated with intra-arterial thrombolysis (IAT). From September 2003 to January 2010, we treated 400 patients with IAT at our institution. Of these patients, 292 were evaluated with MRI scans and included in this observational study. Clinical data were collected prospectively. Outcome after 3 months was measured with the modified Rankin Scale (mRS); mRS 0-1 was considered as favorable outcome. White matter lesions were scored visually by two observers using the semiquantitative Scheltens and Fazekas scores. Logistic regression analysis was used to identify the association of white matter lesions and clinical outcome, recanalization, and cerebral hemorrhage. The severity of white matter lesions was inversely correlated with favorable outcome, survival and successful recanalization. White matter lesions were an independent predictor of outcome (OR 0.569, p = 0.007) and survival (OR 0.550, p = 0.018) and a weak but independent predictor for recanalization (OR 0.949, p = 0.038). Asymptomatic intracerebral bleeding after IAT was associated with white matter lesions in the basal ganglia in the univariate analysis (p = 0.036), but not after multivariable analysis. The severity of white matter lesions independently predicts clinical outcome and survival in patients treated with IAT. White matter lesions are also a weak but independent predictor for recanalization. Symptomatic intracranial bleeding after IAT are not associated with white matter lesions. Therefore, white matter lesions should not be considered as a contraindication against IAT.


Nucleoside reverse transcriptase inhibitors, mitochondrial DNA and AIDS therapy.
NRTIs are cornerstones of antiretroviral therapy and perhaps the most important drugs developed for AIDS treatment. Judicious use of NRTIs in the fight against HIV infection has afforded significant clinical advances in AIDS treatment. Nonetheless, it is axiomatic to expect side effects from NRTIs as well. A principal toxicity of NRTIs relates to chronic and cumulative MT in various tissues. The long-term impact of this toxicity on affected patients is not clear except in extreme cases where morbidity was severe and mortality occurred. Because of chronicity and potential for severity, NRTI MT remains an important clinical problem. Further studies will help us unravel mechanisms of NRTI MT and the natural history of mitochondrial biogenesis in humans and other mammalian systems.


Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages.
Innate lymphoid cells (ILCs) are a recently recognized group of lymphocytes that have important functions in protecting epithelial barriers against infections and in maintaining organ homeostasis. ILCs have been categorized into three distinct groups, transcriptional circuitry and effector functions of which strikingly resemble the various T helper cell subsets. Here, we identify a common, Id2-expressing progenitor to all interleukin 7 receptor-expressing, "helper-like" ILC lineages, the CHILP. Interestingly, the CHILP differentiated into ILC2 and ILC3 lineages, but not into conventional natural killer (cNK) cells that have been considered an ILC1 subset. Instead, the CHILP gave rise to a peculiar NKp46(+) IL-7Rα(+) ILC lineage that required T-bet for specification and was distinct of cNK cells or other ILC lineages. Such ILC1s coproduced high levels of IFN-γ and TNF and protected against infections with the intracellular parasite Toxoplasma gondii. Our data significantly advance our understanding of ILC differentiation and presents evidence for a new ILC lineage that protects barrier surfaces against intracellular infections.


Cyclin B1 overexpression in conventional oral squamous cell carcinoma and verrucous carcinoma- A correlation with clinicopathological features.
Nuclear localization of cyclin B1 is an indicator for cells undergoing mitotic division, and the overexpression has shown promising results as a good prognostic predictor for patients of squamous cell carcinoma (SCC). Cyclin B1 overexpression among histological grades of conventional oral squamous cell carcinoma (COSCC), as well as comparison with verrucous carcinoma (VC) has been less investigated. Immunohistochemical expression of cyclin B1 was compared with various clinicopathological features in 30 primary COSCC and 31 primary VC cases. Cyclin B1 showed significant overexpression for some clinical features for both the variants of oral squamous cell carcinoma. In histopathological variants, statistical significance was observed among grades of COSCC, as well as COSCC and its grades with VC. The concomitant increase in cyclin B1 overexpression from VC to grades COSCC was observed. Our study findings draw attention to cyclin B1 overexpression is involved in early carcinogenesis, cell differentiation and tumor proliferation.


Perinatal changes in amylase and serum corticosterone levels in rats.
In rats amylase activity in the pancreas increased greatly from day 15 of gestation to a maximum on day 21. Then it decreased to less than one-tenth of this maximum value on about day 5 after birth. It increased again about 15 days after birth and reached the adult level about 30 days after birth. No amylase activity was in the parotid gland before birth: it appeared about 12 days after birth and reached the adult level, which was higher than that in the pancreas, about 30 days after birth. The serum corticosterone level was as high as the adult level before birth. Then it decreased to less than one-tenth of the adult level 5 days after birth and increased again from 15 to 25 days after birth to the adult level. The developmental change in the serum corticosterone level seemed to influence amylase activity in the pancreas both before and after birth, and that in the parotid gland only after birth. The serum contained both pancreatic and parotid type isozymes of amylase until 1 day after birth but only the parotid type from 3 days after birth.


Age- and sex-specific association of circulating osteocalcin with dynamic measures of glucose homeostasis.
Our study showed that serum osteocalcin levels are closely related to glucose metabolism in men of all ages and younger women. This association disappeared in postmenopausal women in which increases bone turnover rates. The association between serum osteocalcin levels and glucose homeostasis should be interpreted according to age and sex. Osteocalcin, a marker of bone formation, appears to be associated with glucose homeostasis. We investigated the age- and sex-specific association of serum osteocalcin level with variables related to glucose metabolism. This study was based on cross-sectional analysis from 719 participants aged 20-85 years after excluding patients taking antidiabetic or antiosteoporotic drugs. The subjects were divided into four groups according to age and sex as follows: men <50 years (n = 131), men ≥50 years (n = 191), women <50 years (n = 108), and women ≥50 years (n = 279). Anthropometric and biochemical variables including insulin resistance (HOMA-IR) and β cell function (HOMA-β) from a 75-g oral glucose tolerance test, and serum 25-OH-vitamin D and parathyroid hormone levels were measured. The serum osteocalcin level was significantly higher in women aged ≥50 years compared with women <50 years (20.4 ± 7.8 vs. 17.9 ± 6.8 ng/ml, p < 0.001), but there was no difference between men aged ≥50 years and men <50 years (16.4 ± 5.9 vs. 16.8 ± 6.0 ng/ml, p = 0.905). The participants diagnosed with diabetes had lower serum osteocalcin levels than normal or prediabetic participants. Multivariable regression analyses including HOMA-IR and HOMA-β indicated that serum osteocalcin levels had a negative and independent association with HbA1c levels in men and women aged <50 years, but not in women ≥50 years. Low osteocalcin levels are associated with impaired glucose metabolism in men and premenopausal women. The osteocalcin levels may be determined by factors related to bone metabolism in postmenopausal women. Our data suggest that the serum levels of osteocalcin associated with glucose homeostasis should be interpreted according to age and sex.


Interleukin-17 receptor C is essential for the pro-inflammatory pathogenicity of granulocyte-macrophage-colony-stimulating factor-producing T helper cells in experimental autoimmune uveitis.
Autoimmune uveitis is an inflammatory disorder of the eye triggered by the responses of autoreactive T cells to ocular autoantigens. This study aims to understand the role of granulocyte-macrophage-colony-stimulating factor (GM-CSF)-producing T helper (ThGM) cells in the pathophysiology of mouse experimental autoimmune uveitis (EAU). We established an EAU model by immunizing mice with interphotoreceptor retinoid-binding protein (IRBP) 651-670. Splenic or eye-infiltrating ThGM cells were analyzed and enriched by flow cytometry according to the levels of an array of surface markers, transcription factors, and cytokines. Lentiviral transduction was conducted to silence or overexpress the target gene in differentiated ThGM cells. The adoptive transfer was applied to determine the pathogenicity of ThGM cells in vivo. We found that ThGM cells were present in the spleen and the eye after EAU induction. Both splenic and eye-infiltrating ThGM cells were phenotypically CD4+CCR7-CXCR3-CCR6-CCR10hi. Eye-infiltrating ThGM cells up-regulated interleukin-1β (IL-1β), interleukin-6 (IL-6), and IL-17 receptor C (IL-17RC) relative to splenic ThGM cells. IL-17RC overexpression enabled interleukin-17A (IL-17A)-induced up-regulation of IL-1β and IL-6 production in ThGM cells. Adoptive transfer of IL-17RC overexpressing ThGM cells exacerbated EAU severity, as evidenced by a higher histology score as well as increased pro-inflammatory cytokines and inflammatory cells in the eye. However, IL-17RC-silenced ThGM cells did not impact EAU. Therefore, for the first time, this study unveils the essential pro-inflammatory role of IL-17RC-expressing ThGM cells in EAU pathophysiology. We discovered a novel mechanism underlying the pathophysiology of autoimmune uveitis.