Pediatric aphakic glaucoma: a study of 65 patients.
The anterior segment findings of children with glaucoma following pediatric cataract extraction were studied to determine the mechanism of this complication. The clinical records of 65 children with glaucoma cared for by the author were studied. Patients with bilateral lensectomy followed by bilateral glaucoma, bilateral lensectomy followed by unilateral glaucoma, and unilateral lens surgery followed by glaucoma were identified and studied. It was determined that vitreous cutting instruments were used for 80% of the lensectomy procedures, with 77% of the lens procedures done in the first year. Eighty-seven percent of the patients were recognized to have glaucoma two or more years after their lensectomy. Preoperative gonioscopy revealed no consistent angle defect, while postoperative gonioscopy revealed a near constant (96%) but variable angle defect characterized by blockage of the trabecular meshwork by an acquired repositioning of the iris against the posterior trabecular meshwork, associated with abnormal pigmentation and synechia formation. The results reported document the development of a characteristic acquired filtration angle deformity in children with glaucoma following early lensectomy frequently associated with significant residual lens tissue and unassociated with evidence of chronic anterior segment inflammation.


[Roles and mechanisms of m6A modification regulating RP11-426A6.5 in laryngeal squamous cell carcinoma].
Objective: To investigate the roles of N6-methyladenosine (m6A) modification in regulating RP11-426A6.5 in the development of laryngeal squamous cell carcinoma (LSCC). Methods: The methylation and expression levels of lncRNAs were identified and important lncRNAs were screened utilizing long non-coding RNA (lncRNA) m6A methylation microarray. Cancer and para cancer tissue samples were taken from 48 LSCC patients hospitalized to the Department of Otolaryngology-Head and Neck Surgery of the Second Affiliated Hospital of Harbin Medical University between January and September 2017. Expression profiling microarray was performed in 3 of 48 LSCC samples, and methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR) and quantitative real-time fluorescent PCR (qRT-PCR) were performed in the remaining 45 LSCC samples to verify the m6A modification and expression levels of RP11-426A6.5. Correlations between RP11-426A6.5 and clinical factors were anlysed. Laryngeal cancer cell line with low expression of RP11-426A6.5 was created in vitro using RNA interference (RNAi) technology. The 5-Ethynyl-2'-deoxyuridine (EdU) cell proliferation experiment, wound healing experiment, and transwell invasion experiment were used respectively to measure the proliferation, migration, and invasion of LSCC cells. The effect of RP11-426A6.5 down-regulation on the growth of transplanted tumors in vivo was verified by nude mice tumorigenesis assay. The Cancer Genome Atlas (TCGA) database and sequence-based RNA adenosine methylation site predictor (SRAMP) website were used to predict the enzymes and corresponding methylation sites. MazF digestion was chosen to validate the binding sites. RNAi technology was used to observe the changes in cell function after interfering with the expression of the corresponding genes of the modified enzymes. MeRIP-qPCR was used to detect the level of RP11-426A6.5 m6A cell line treated with actinomycin D was used to observe the stability of RP11-426A6.5. Results: RP11-426A6.5 methylation and expression levels were significantly higher in LSCC tissues than those in paracancerous tissues (methylation levels: 23.828±4.975 vs 20.280±3.607; expression levels: 1.197±0.314 vs 1.015±0.170, all P values<0.05). RP11-426A6.5 expression levels were closely correlated with T stage (T1-2: 1.081±0.298 vs T3-4: 1.306±0.292, χ2=5.35, P<0.05). The postoperative survival of patients with high RP11-426A6.5 expressions was significantly lower than that of patients with low RP11-426A6.5 expression (P=0.046). Assays in vitro and in vivo showed that the downregulation of RP11-426A6.5 significantly decreased the proliferation, migration, and invasion abilities of LSCC cells and the growth of transplanted tumors. The binding of methyltransferase-like 3 (METTL3), an m6A-modified enzyme, to the corresponding methylation site of RP11-426A6.5 enhanced its stability and mediated its regulation of malignant behaviors of LSCC cells. Conclusions: RP11-426A6.5 can regulate the malignant behaviors of LSCC cells, which is mediated by the m6A modification process involving in the methyltransferase METTL3.


A cluster randomised trial of a school-based intervention to prevent decline in adolescent physical activity levels: study protocol for the 'Physical Activity 4 Everyone' trial.
Adolescence is an established period of physical activity decline. Multi-component school-based interventions have the potential to slow the decline in adolescents' physical activity; however, few interventions have been conducted in schools located in low-income or disadvantaged communities. This study aims to assess the effectiveness of a multi-component school-based intervention in reducing the decline in physical activity among students attending secondary schools located in disadvantaged communities. The cluster randomised trial will be conducted with 10 secondary schools located in selected regions of New South Wales, Australia. The schools will be selected from areas that have a level of socio-economic status that is below the state average. Five schools will be allocated to receive an intervention based on the Health Promoting Schools framework, and will be supported by a part-time physical activity consultant placed in intervention schools who will implement a range of intervention adoption strategies. Study measures will be taken at baseline when students are in Year 7 (12-13 years) and again after 12- and 24-months. The primary outcome, minutes of moderate- to-vigorous- intensity physical activity per day and percentage of time in moderate- to vigorous-intensity physical activity (MVPA), will be objectively assessed using accelerometers (Actigraph GT3x+). Group allocation and intervention delivery will commence after baseline data collection. The intervention will continue during school terms through to 24-month follow-up. The study will provide evidence regarding the effectiveness of a multi-component school-based intervention that includes an in-school physical activity consultant targeting the physical activity levels of adolescents in disadvantaged Australian secondary schools. Australian New Zealand Clinical Trials Registry ACTRN12612000382875.


The reaction of Fe(III) myoglobin fluoride with reducing agents.
The reaction of reducing agents with Fe(III) myoglobin fluoride from sperm whale was studied at alkaline pH values. The rate of reduction by dithionite was indistinguishable from the rate of ligand dissociation even when the values of the rate constants for both were only 1.0 X 10(-3)S-1 (at pH 10.6). Reduction by the reduced Methyl Viologen radical ion and reduced Safranine was faster than the rate of dissociation, providing evidence that these reductants can donate electrons to the iron centre via a pathway involving an (undetectable) liganded Fe(II) intermediate.


Retinal hemorrhages. Its significance in 100 patients with acute encephalopathy of unknown cause.
A total of 94 patients had subarachnoid hemorrhage and it was strongly suspected in the remaining six patients. Acute encephalopathy associated with independent ocular hemorrhage due to hypoxia, multiple emboli, or bleeding tendencies was not a diagnostic problem during this study. Aneurysms occurred in 64 patients (combined with vascular malformations in four), isolated vascular malformations in four; "spontaneous" hematomas in 13, evidence of cryptic head trauma in six, hemorrhage from a glioblastoma in one, and no cause was identified in six patients. Retinal hemorrhages were more prominent ipsilateral to the site of intracranial bleeding. No single aneurysm location predominated and multiple aneurysms were common. The high mortality of 56% supports previous conclusions that retinal hemorrhages tend to accompany severe intracranial bleeding.


The use of bispectral index monitoring in education - a tool to improve nurse-anaesthetists practice.
This paper is a report of a study to investigate whether monitoring depth of anaesthesia by bispectral index would reduce recovery time and consumption of anaesthetic drugs in anaesthetics performed by student nurse-anaesthetists. It is difficult to assess the depth of anaesthesia clinically. Studies have shown that experienced anaesthetists can titrate anaesthetics more accurately when using bispectral index monitors. It is not known if student nurse-anaesthetists can benefit from their use in a similar way. A multicentre study involving four hospitals was carried out during a 13-month period in 2003 and 2004. In total 25 nurses participated, each contributing with two procedures: one with monitoring and one without. The nurses had at least 10 months of experience in conducting anaesthesia and all had a theoretical introduction and a test session to become familiar with the equipment. The sequence was randomized and the observer was blinded to whether a monitor was used. Fifty patients were anaesthetized with propofol and fentanyl. Recovery time, consumption of anaesthetic drugs, and patient satisfaction were measured in both groups. Recovery time was 11 minutes in the monitor group (range: 2-53 minutes) and 15 minutes in the control group, (range: 3-60 minutes). P = 0.26. There were no statistically significant differences in consumption of anaesthetic drugs or patient satisfaction in the two groups. It was not possible to demonstrate a statistically significant reduction in recovery time or consumption of anaesthetic drugs when using bispectral index monitoring during training of student nurse-anaesthetists.


Health knowledge, attitudes and practices of family planning service providers and clients in Akwapim North District of Ghana.
Family planning services help save lives by reducing women's exposure to risks of child birth and abortion. While family planning services provide measures to prevent unintended pregnancies and time the formation of families, the acceptability and coverage is still very low worldwide. Some of the reasons for this include poor quality of service, unavailability of range of methods, fear of opposition from partners, side effects and health concerns among others.About 40 % of the world's 215,000 annual deaths in childbirth occur in the Sub-Saharan region. In Ghana, urban-rural fertility differences range from two to three children. The acceptability and coverage of family planning are still low and in the study area in particular. We sought to examine factors that contribute to low acceptability and coverage of family planning services in a sub-urban community with a design of quantitative cross-sectional. Ethical approval was given by the Ghana Health Service. Midwives and community health nurses who provide family planning services were interviewed. Exit-interview was also conducted with women receiving a variety of outpatient services. Most of the women in this study (48.7 %) were in the 25-34 age range and were either married (42.8 %) or cohabiting (40.5 %). Majority of these women (67.7 %) have middle/Junior high level of formal education with a modal parity of two. Sixty eight (68) clients were identified as current family planning users. About 6.0 % and 4.5 % were dissatisfied about auditory and visual privacy during counselling respectively. This was confirmed by providers who attributed it to inappropriate facility layout. Most of the clients (79.1 %) were not given educational materials although 88.8 % were talked to about family planning and this could be due to unavailability of these hand-outs.Though clients show satisfaction of services received, providers did not follow standard protocols with as much as 73.7 % faced with challenges in provision of services which were attributed to improper facility layout and lack of furniture. About 77.2 % were willing to provide short term methods, while 91.2 % wanted to provide long term methods. As much as 93.3 % of the women said they would have liked providers give more detailed information on family planning. While most of the women (88.3 %) used injectables, only 6.1 % and 0.9 % used Implants and IUD respectively. Finding ways to improve client privacy through good facility layout will ensure visual and auditory privacy to enhance family planning service provision and uptake. Continuous competency training will assist providers design innovative action plans and meet client satisfaction needs.


Taurodontism, Root Dilaceration, and Tooth Transposition: A Radiographic Study of a Population With Nonsyndromic Cleft Lip and/or Palate.
In an effort to contribute to proper dental planning and define possible dental phenotypes of nonsyndromic cleft lip and/or palate (CL/P), this study aimed to investigate the occurrence of taurodontism, root dilaceration, and tooth transposition in persons with nonsyndromic CL/P, specifically analyzing the differences among gender, cleft types, and the most affected teeth. This retrospective study analyzed 974 panoramic x-rays from nonsyndromic Brazilians older than 16 years and categorized into the following four groups: group 1, 250 persons with unilateral cleft lip and palate; group 2, 250 persons with unilateral cleft lip; group 3, 224 persons with cleft palate; and a control group of 250 persons without clefts. Radiographs were digitalized with a scanner and analyzed. In the Brazilian population studied, the prevalence of taurodontism was 60.4% in group 1, 62.4% in group 2, 67.0% in group 3, and 42.8% in the control group. Root dilacerations had a prevalence of 31.2% in group 1, 29.6% in group 2, 26.3% in group 3, and 27.2% in the control group. The teeth most affected by taurodontism were 17 and 27; whereas root dilacerations were most common in teeth 38 and 48. No tooth transpositions were found in any radiograph analyzed. Taurodontism is significantly more prevalent in Brazilians with nonsyndromic CL/P than in persons without clefts; whereas the prevalence of root dilaceration no different from that in the control group. However, root dilacerations in anterior teeth were increased in groups 1 and 2 when compared to the control group.


Potential cross-species correlations in social hierarchy and memory between mice and young children.
Social hierarchy is associated with various phenotypes. Although memory is known to be important for hierarchy formation, the difference in memory abilities between dominant and subordinate individuals remains unclear. In this study, we examined memory performance in mice with different social ranks and found better memory abilities in dominant mice, along with greater long-term potentiation and higher memory-related gene expression in the hippocampus. Daily injection of memory-improving drugs could also enhance dominance. To validate this correlation across species, through inventory, behavioral and event-related potential studies, we identified better memory abilities in preschool children with higher social dominance. Better memory potentially helped children process dominance facial cues and learn social strategies to acquire higher positions. Our study shows a remarkable similarity between humans and mice in the association between memory and social hierarchy and provides valuable insight into social interactions in young animals, with potential implications for preschool education.


Cardiopulmonary Exercise Testing With Echocardiography to Assess Recovery in Patients With Ventricular Assist Devices.
The left ventricular assist device (LVAD) is an established treatment for select patients with end-stage heart failure. Some patients recovered and are considered for explantation. Assessing recovery involves exercise testing and echo ramping on full and minimal LVAD support. Combined cardiopulmonary exercise testing with simultaneous echo ramping (CPET-R) has not been well studied. Patients were included if they had CPET within the previous 6 months, were clinically stable, and had an INR >2.0 on the day of examination. Patients had CPET-R on two occasions within 14 days: (a) with LVAD at therapeutic speed and (b) with LVAD at the lowest speed possible. Six patients were between 29 and 75 years (two female). One patient did not complete a turn-down test due to evidence of ischemia on initial CPET-R subsequently confirmed as a significant coronary artery stenosis on angiography. There were no significant differences in CPET or echo metrics between LVAD speeds. Two patients were explanted due to presumed LV recovery and remained event free for 30 and 47 months, respectively. Serial CPET-R seems safe and feasible for the evaluation of LV and global function and may result in improved clinical decision making for LVAD explantation.


The diagnostic and prognostic significance of small nuclear ribonucleoprotein Sm D1 aberrantly high expression in hepatocellular carcinoma.
Small nuclear ribonucleoprotein Sm D1 (SNRPD1), one of the crucial genes encoding core spliceosome components, was abnormally highly expressed in multiple types of tumors. In this study, we investigated the diagnostic and prognostic significance of SNRPD1 in hepatocellular carcinoma (HCC). The investigation of datasets from GEO and TCGA databases revealed that SNRPD1 expression in HCC was significantly higher than adjacent normal liver tissues, which was validated by immunohistochemistry (IHC). Both GO, KEGG analysis showed that the SNRPD1 co-expressed genes mainly enriched in Cell division, Nuclear import, mRNA splicing via spliceosome, Ribosome, Cell cycle, etc. Survival analysis from the GSE14520 dataset and 154 HCC cohorts exhibited a significant association of high SNRPD1 expression with poor overall survival and recurrence-free survival. ROC analysis showed that the abnormally high SNRPD1 mRNA expression has diagnostic significance in distinguishing between HCC and normal liver tissue (AUC = 0.819). Gene set enrichment analysis (GSEA) demonstrated that the high expression of SNRPD1 might regulate HCC tumorigenesis and progression by affecting the cell cycle, mismatch repair, DNA replication, and RNA degradation, etc. The luciferase report assay revealed that SNRPD1 was the direct target gene of miR-100 manifested by decreased SNRPD1 expression and luciferase activity in the HCC cells upon miR-100 overexpression. Finally, SNRPD1 may as an oncogene affecting the progression of HCC through regulates the mTOR pathway and autophagy.


Wogonin attenuates the deleterious effects of traumatic brain injury in anesthetized Wistar rats.
Wogonin, a flavonoid (5,7-dihydroxy-8-methoxyflavone) with reported neuroprotective properties, is widely used in treating inflammatory diseases. The main goal of this study was to explore the role of wogonin in preventing deleterious cardiovascular effects of traumatic brain injury (TBI). Experiments were carried out in adult male urethane-anesthetized, artificially ventilated, Wistar rats, weighing 300-350 gm. TBI was produced by fluid percussion injury (FPI). A significant decrease in blood pressure (BP), heart rate (HR) and greater splanchnic nerve activity (GSNA), which lasted for up to 4 h, was observed after the application of moderate FPI. Intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of wogonin before and after the moderate FPI significantly attenuated the decreases in BP, HR, and GSNA elicited by FPI. Administration of wogonin also prevented the attenuation of baroreflex-induced bradycardia elicited by FPI. Based on these results, it was concluded that administration of wogonin attenuates the deleterious effects of moderate FPI.


Performance optimization in elastography: multicompression with temporal stretching.
A general theoretical framework known as the strain filter has been previously used to evaluate the performance in elastography. The strain filter describes the relationship among the resolution, dynamic range, sensitivity and elastographic SNR (SNRe), and may be plotted as a graph of the upper bound of the SNRe vs. the strain experienced by the tissue, for a desired elastographic axial resolution as determined by the data window length. The ideal strain filter has an infinitely high, flat all-pass characteristic shape in the strain domain, which means that all local tissue strains are displayed in the elastogram with infinite SNRe; it also means that the strain dynamic range in the elastogram is infinite as well. Practical strain filters obtained using a single tissue compression have a bandpass characteristic shape in the strain domain, where the -3 dB width of this bandpass characteristic may be defined as the elastographic dynamic range. In this paper, we present an optimal technique for stretching multicompression elastography, practiced by selecting the optimum incremental applied strain using the strain filter. Two techniques, temporal stretching and multicompression elastography, are combined in this paper to improve elastogram quality. Stretching multicompression elastography using the optimal applied strain increment alters the shape of the strain filter from its bandpass characteristic to a more desirable high-emphasis filter. The dynamic range of optimal stretching multicompress on elastography is limited only by tissue nonlinearities. This optimal applied strain increment minimizes signal decorrelation and achieves the maximum achievable elastographic SNRe.


Responsiveness of the Japanese Osteoporosis Quality of Life questionnaire in women with postmenopausal osteoporosis.
The Japanese Osteoporosis Quality of Life (JOQOL) questionnaire measures quality of life in Japanese patients with osteoporosis. However, several important aspects of the psychometric properties of individual domains, including responsiveness, have not been addressed to enable valid clinical application. This analysis examined the internal and external responsiveness of the JOQOL questionnaire. This was a post hoc analysis of a 24-week prospective postmarketing study of raloxifene (60 mg/day) administered to postmenopausal Japanese women with osteoporosis (JapicCTI-070465). Internal responsiveness was assessed using Standardized Response Mean (SRM) statistics and changes in JOQOL domain scores. Patients were also stratified into those who did or did not achieve a minimal clinically important change (MCIC) in pain, assessed by a visual analogue scale for pain (VAS pain): comparisons were made between treated patients who achieved VAS pain reduction ≥ 20 mm versus VAS pain reduction < 20 mm. External responsiveness was assessed using Pearson's correlation coefficient (r) for changes in JOQOL domain scores with Short Form-8 Health Survey and European Quality of Life Instrument scores. Of 506 patients analyzed, 421 had a baseline value for VAS pain; of these, 152 patients (36.1%) had a MCIC, whereas 264 patients (62.7%) did not. The JOQOL domains pain, overall health, and falls/psychological factors had small to moderate SRM values (0.3-0.5) in all patients, but consistently showed significantly larger changes in patients whose pain score changes exceeded the MCIC. Together, these findings suggest some degree of internal responsiveness for these domains. However, activities of daily living domain had a SRM value as low as 0.2, and recreation/social activities and posture/physique domains had SRM values close to 0. Moderate correlation (defined as r ≥ 0.4 to < 0.6) was noted between the domains pain, activities of daily living, and overall health and some Short Form-8 Health Survey subscales and the European Quality of Life total score, suggesting external responsiveness of these domains. The inconsistent responsiveness among individual JOQOL domains in treated patients suggests the need for improving several JOQOL domains, especially the activities of daily living, recreation/social activities and posture/physique domains, before application to clinical research.


Neither Eastern nor Western: Patterns of independence and interdependence in Mediterranean societies.
Social science research has highlighted "honor" as a central value driving social behavior in Mediterranean societies, which requires individuals to develop and protect a sense of their personal self-worth and their social reputation, through assertiveness, competitiveness, and retaliation in the face of threats. We predicted that members of Mediterranean societies may exhibit a distinctive combination of independent and interdependent social orientation, self-construal, and cognitive style, compared to more commonly studied East Asian and Anglo-Western cultural groups. We compared participants from eight Mediterranean societies (Spain, Italy, Greece, Turkey, Cyprus [Turkish Cypriot and Greek Cypriot communities], Lebanon, Egypt) to participants from East Asian (Korea, Japan) and Anglo-Western (the United Kingdom, the United States) societies, using six implicit social orientation indicators, an eight-dimensional self-construal scale, and four cognitive style indicators. Compared with both East Asian and Anglo-Western samples, samples from Mediterranean societies distinctively emphasized several forms of independence (relative intensity of disengaging [vs. engaging] emotions, happiness based on disengaging [vs. engaging] emotions, dispositional [vs. situational] attribution style, self-construal as different from others, self-directed, self-reliant, self-expressive, and consistent) and interdependence (closeness to in-group [vs. out-group] members, self-construal as connected and committed to close others). Our findings extend previous insights into patterns of cultural orientation beyond commonly examined East-West comparisons to an understudied world region. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Characterization of the specific pyruvate transport system in Escherichia coli K-12.
A mutant of Escherichia coli K-12 lacking pyruvate dehydrogenase and phosphoenolpyruvate synthase was used to study the transport of pyruvate by whole cells. Uptake of pyruvate was maximal in mid-log phase cells, with a Michaelis constant for transport of 20 microM. Pretreatment of the cells with respiratory chain poisons or uncouplers, except for arsenate, inhibited transport up to 95%. Lactate and alanine were competitive inhibitors, but at nonphysiological concentrations. The synthetic analogs 3-bromopyruvate and pyruvic acid methyl ester inhibited competitively. The uptake of pyruvate was also characterized in membrane vesicles from wild-type E. coli K-12. Transport required an artificial electron donor system, phenazine methosulfate and sodium ascorbate. Pyruvate was concentrated in vesicles 7- to 10-fold over the external concentration, with a Michaelis constant of 15 microM. Energy poisons, except arsenate, inhibited the transport of pyruvate. Synthetic analogs such as 3-bromopyruvate were competitive inhibitors of transport. Lactate initially appeared to be a competitive inhibitor of pyruvate transport in vesicles, but this was a result of oxidation of lactate to pyruvate. The results indicate that uptake of pyruvate in E. coli is via a specific active transport system.


Avian color expression and perception: is there a carotenoid link?
Carotenoids color many of the red, orange and yellow ornaments of birds and also shape avian vision. The carotenoid-pigmented oil droplets in cone photoreceptors filter incoming light and are predicted to aid in color discrimination. Carotenoid use in both avian coloration and color vision raises an intriguing question: is the evolution of visual signals and signal perception linked through these pigments? Here, we explore the genetic, physiological and functional connections between these traits. Carotenoid color and droplet pigmentation share common mechanisms of metabolic conversion and are both affected by diet and immune system challenges. Yet, the time scale and magnitude of these effects differ greatly between plumage and the visual system. Recent observations suggest a link between retinal carotenoid levels and color discrimination performance, but the mechanisms underlying these associations remain unclear. Therefore, we performed a modeling exercise to ask whether and how changes in droplet carotenoid content could alter the perception of carotenoid-based plumage. This exercise revealed that changing oil droplet carotenoid concentration does not substantially affect the discrimination of carotenoid-based colors, but might change how reliably a receiver can predict the carotenoid content of an ornament. These findings suggest that, if present, a carotenoid link between signal and perception is subtle. Deconstructing this relationship will require a deeper understanding of avian visual perception and the mechanisms of color production. We highlight several areas where we see opportunities to gain new insights, including comparative genomic studies of shared mechanisms of carotenoid processing and alternative approaches to investigating color vision.


Continuous Glucose Monitoring Diving and Diabetes: An Update of the Swedish Recommendations.
Divers travel to different countries to explore various diving sites worldwide. In 2005, the Divers Alert Network (DAN) published their guidelines for recreational diving and diabetes mellitus. However, although years have passed, there is still no consensus in the form of international guidelines on diabetes and diving. Large differences are noted with regard to the regulations in different countries. Furthermore, the diabetes technology has evolved rapidly and is not reflected in current international guidelines. This is potentially both a medical and an insurance problem for a diver with diabetes. We present a short summary of the recently updated Swedish recommendations for recreational divers with type 1 diabetes mellitus, focusing on the use of continuous glucose monitoring and continuous subcutaneous insulin infusion during such circumstances.


Charge Carrier Trapping Processes in RE2O2S (RE = La, Gd, Y, and Lu).
Two different charge carrier trapping processes have been investigated in RE2O2S:Ln3+ (RE = La, Gd, Y, and Lu; Ln = Ce, Pr, and Tb) and RE2O2S:M (M = Ti4+ and Eu3+). Cerium, praseodymium and terbium act as recombination centers and hole trapping centers while host intrinsic defects provide the electron trap. The captured electrons released from the intrinsic defects recombine at Ce4+, Pr4+, or Tb4+ via the conduction band. On the other hand, Ti4+ and Eu3+ act as recombination centers and electron trapping centers while host intrinsic defects act as hole trapping centers. For these codopants we find evidence that recombination is by means of hole release instead of electron release. The released holes recombine with the trapped electrons on Ti3+ or Eu2+ and yield broad Ti4+ yellow-red charge transfer (CT) emission or characteristic Eu3+ 4f-4f emission. We will conclude that the afterglow in Y2O2S:Ti4+, Eu3+ is due to hole release instead of more common electron release.


Expression of stanniocalcin-1 in culprit coronary plaques of patients with acute myocardial infarction or stable angina.
Stanniocalcin-1 (STC1) is involved in fundamental biological processes such as angiogenesis, inflammation and wound healing, but little is known about its expression in human coronary atherosclerotic plaques or its relationship to plaque instability. STC1 expression was examined in the culprit coronary plaques of 70 patients with acute myocardial infarction (AMI; n=49) or stable angina (n=21) who underwent directional coronary atherectomy. The specimens were stained with H&E, STC1-specific antibodies, and endothelial cells, macrophages and smooth muscle cell markers. The baseline characteristics of the two groups of patients were largely similar. CD31-immunopositive and CD68-immunopositive areas, indicative of the presence of endothelial cells and macrophages, respectively, were proportionately larger while areas immunopositive for α-actin, as a smooth muscle cell marker, were proportionately smaller in the AMI group than in the stable angina group. The proportion of STC1-immunopositive areas was significantly greater in the AMI group than in the stable angina group (20.0% (8.2-29.0%) vs 8.8% (3.9-19.4%), p=0.022). Areas positive for STC1 were independently correlated with those immunopositive for CD31 (r=0.42, p<0.001) and CD68 (r=0.40, p<0.001). STC1 immunoreactivity co-localised with CD31-immunopositive and CD68-immunopositive cells. STC1 is differentially expressed in the culprit coronary plaques of patients with AMI versus those with stable angina. STC1 may play a role in plaque instability.


Contemporary Management of ST-Elevation Myocardial Infarction.
Recent advances have caused a major shift in the way ST-elevation myocardial infarctions are managed. This review explores the pharmacological and interventional techniques that have evidence for improving outcomes and the landmark trials that have sparked change. The new P2Y12 inhibitors, ticagrelor and prasugrel, have been shown to be superior to clopidogrel in STEMI patients undergoing primary percutaneous coronary intervention. Concurrently, many technical aspects of percutaneous coronary intervention have been further clarified by trial data, with bare-metal stents, routine thrombus aspiration and femoral access showing evidence of inferiority. Ongoing trials will provide more information on the role of non-culprit lesion PCI, bioresorbable vascular scaffolds, mechanical devices in persistent ischaemia and early automatic implantable cardioverter-defibrillators for inducible ventricular tachycardia.


Therapeutic vaccination in chronic hepatitis B: preclinical studies in the woodchuck.
Recommended treatment of chronic hepatitis B with interferon-α and/or nucleos(t)ide analogues does not lead to a satisfactory result. Induction of HBV-specific T cells by therapeutic vaccination or immunotherapies may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients did not result in effective control of HBV infection, suggesting that new formulations of therapeutic vaccines are needed. The woodchuck (Marmota monax) is a useful preclinical model for developing the new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments with nucleos(t)ide analogues, DNA vaccines, and protein vaccines were tested in the woodchuck model. In this paper we summarize the available data concerning therapeutic immunization and gene therapy using recombinant viral vectors approaches in woodchucks, which show encouraging results. In addition, we present potential innovations in immunomodulatory strategies to be evaluated in this animal model.


As depressing as it was predictable? Lung cancer, clinical trials, and the Medical Research Council in postwar Britain.
In recent years lung cancer specialists have complained that due to stigma resulting from the association of the disease with smoking, theirs is a neglected field. This paper demonstrates that in the 1950s and 1960s, when the British Medical Research Council (MRC) started to organize clinical trials for various forms of cancer, this was not the case. Rather, the organizers of these trials saw lung cancer as a particularly promising object of research, for much was known about the disease. The cancer trials were part of a strategy to use the Randomized Controlled Trial (RCT) technology to cement the role of the MRC as the dominant body overseeing medical research in Britain. The organization of the trials, however, turned out to be very difficult, due to ethical problems and the dominance of one form of therapy, surgery. The trial results were deeply disappointing. I argue that these frustrating results contributed to the notion of hopelessness that has come to surround lung cancer, and to the shift of focus from cure to prevention that was triggered by epidemiologic studies identifying tobacco smoke as the main cause of the disease. The paper deals with an important episode in the history of clinical cancer research in postwar Britain, illustrating the ethical and practical problems faced by the organizers.


T cell-intrinsic factors contribute to the differential ability of CD8+ T cells to rapidly secrete IFN-γ in the absence of antigen.
A subset of CD44(hi)CD8(+) T cells isolated from C57BL/6/J (B6) mice, but not BALB/c/By/J (BALB/c) mice, rapidly secrete IFN-γ within 16 h of infection with Listeria monocytogenes. This Ag-independent response requires the presence of both IL-12 and IL-18. Previous studies showed that dendritic cells from B6 mice produced more Th1-type cytokines such as IL-12 than did those from BALB/c mice in response to L. monocytogenes infection. In this report, we demonstrate that the microenvironment in L. monocytogenes-infected BALB/c mice is sufficient to induce responsive B6 CD8(+) T cells to rapidly secrete IFN-γ. Furthermore, BALB/c CD8(+) T cells did not rapidly secrete IFN-γ even when they were exposed to high concentrations of IL-12 plus IL-18 in vitro. In the presence of IL-12 and IL-18, B6 CD44(hi)CD8(+) T cells upregulated expression of the receptor subunits for these cytokines more rapidly than did BALB/c T cells. In comparing particular subsets of memory phenotype CD8(+) T cells, we found that virtual memory cells, rather than true Ag-experienced cells, had the greatest level of impairment in BALB/c mice. These data suggest that the degree of cytokine-driven bystander activation of CD8(+) T cells that occurs during infection depends on both APCs and T cell-intrinsic properties that can vary among mouse strains.


Tau-related grey matter network breakdown across the Alzheimer's disease continuum.
Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-β (Aβ) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum. We included 533 individuals (178 Aβ-negative cognitively unimpaired (CU) subjects, 105 Aβ-positive CU subjects, 122 Aβ-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions. Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aβ-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology. Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.


Metyrapone-responsive ectopic ACTH-secreting pheochromocytoma with a vicious cycle via a glucocorticoid-driven positive-feedback mechanism.
In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor. 18F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while 123I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing's syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained.


Vascular dysfunction and heart failure: epiphenomenon or etiologic agent?
Endothelial function plays a key role in the local regulation of vascular tone. Alterations in endothelial function may result in impaired release of endothelium-derived relaxing factors or increased release of endothelium-derived contracting factors. Heart failure may impair endothelial function by means of reduced synthesis and release of nitric oxide (NO) or by increased degradation of NO and increased production of endothelin-1. Endothelial dysfunction may worsen heart function by means of peripheral effects, causing increased afterload and central effects such as myocardial ischemia and inducible nitric oxide synthase (iNOS)-induced detrimental effects. Evidence from clinical studies has suggested that there is a correlation between decreased endothelial function and increasing severity of congestive heart failure (CHF). Treatments that improve heart function may also improve endothelial dysfunction. The relationship between endothelial dysfunction and heart failure may be masked by the stage of endothelial dysfunction, the location of vessels being tested, and the state of endothelial-dependent vasodilatation response.


The effect of capsular repair, bone block healing, and position on the results of the Bristow-Latarjet procedure (study III): long-term follow-up in 319 shoulders.
We evaluated the results of the May modification of the Bristow-Latarjet procedure ("coracoid in standing position") in 319 shoulders with respect to (1) coracoid healing and position and (2) surgical treatment of the joint capsule. From 1980 until 2004, all shoulders with a Bristow-Latarjet repair were registered at our hospital. This study consists of 3 different cohorts with respect to follow-up. Series 1, 118 shoulders operated on during 1980 through 1985, had 15 years' radiographic and clinical follow-up. Series 2, 167 shoulders that had surgery during 1986 through 1999, underwent retrospective follow-up by a questionnaire and scores--Western Ontario Shoulder Instability Index; Disabilities of the Arm, Shoulder and Hand; and Subjective Shoulder Value--after 10 to 23 years. Series 3, 34 shoulders treated during 2000 through 2004, with an added modified Bankart repair ("capsulopexy") in 33 shoulders, were prospectively followed up for 5 to 8 years with the same questionnaire and scores as series 2. Of 319 shoulders, 16 (5%) had 1 or more redislocations and 3 of these (1%) had revision surgery because of remaining instability. One or more subluxations were reported in 41 shoulders (13%). The worst scores were found in 16 shoulders with 2 or more subluxations (P < .001). Radiographs showed bony healing in 246 of 297 shoulders (83%), fibrous union in 34 (13%), migration by 0.5 cm or more in 14 (5%), and no visualization in 3 (1%). Five of six shoulders that had the transplant positioned 1 cm or more medial to the glenoid rim had redislocations (83%, P = .001). Shoulders with migrated transplants did not differ from those with bony or fibrous healing with respect to redislocations and subluxations. When just a horizontal capsular shift was added to the transfer, the recurrence rate (redislocations or subluxations) decreased, with 2 of 53 (4%)compared with 37 of 208 (18%) with just anatomic closure of the capsule (P = .005), and the Western Ontario Shoulder Instability Index score improved (92 vs 85.6, P = .048). In total, for 307 of 319 shoulders (96%), patients were satisfied or very satisfied at final follow-up. The open Bristow-Latarjet procedure yields good and consistent results, with bony fusion of the coracoid in 83%. A position of the coracoid 1 cm or more medial to the rim meant significantly more recurrences. The rate of recurrences decreased and subjective results improved when a horizontal capsular shift was added to the coracoid transfer.


Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury.
The nuclear enzyme poly (ADP-ribose) synthetase (PARS) has been shown to play an important role in the pathogenesis of ischemia/reperfusion injury and circulatory shock. The aim of this study was to investigate whether PARS activity may modulate endothelial-neutrophil interaction. We present evidence that genetic disruption of PARS provides protection against myocardial ischemia and reperfusion injury by inhibiting the expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) and, consequently, by inhibiting the recruitment of neutrophils into the jeopardized tissue. Furthermore, using in vitro studies, we demonstrate that in fibroblasts lacking a functional gene for PARS, cytokine-stimulated expression of ICAM-1 is significantly reduced compared with fibroblasts from animals with a normal genotype. Similarly, in cultured human endothelial cells, oxidative- or cytokine-dependent expression of P-selectin and ICAM-1 is reduced by pharmacological inhibition of PARS by 3-aminobenzamide. These findings provide the first direct evidence that PARS activation participates in neutrophil-mediated myocardial damage by regulating the expression of P-selectin and ICAM-1 in ischemic and reperfused myocardium, and they also provide the basis for a novel therapeutic approach for the treatment of reperfusion injury.


Restriction fragment length polymorphism of flagellin genes of Campylobacter jejuni and/or C. coli isolates from Egypt.
The conservation of flagellin genes from thermophilic Campylobacter spp. strains isolated in Egypt was evaluated by a restriction fragment length polymorphism (RFLP) assay. The flaA and flaB genes were amplified from 59 independent clinical isolates and digested with EcoRI and PstI, and the resulting patterns were compared with each other and with previously described RFLP groups. The results indicate that the isolates fell into 14 groups for flaA and 11 groups for flaB, 9 of which have been described, and that considerable genetic variability exists among isolates belonging to the same LIO serogroup. In most cases, the flaB gene displayed the same RFLP pattern as that of the flaA gene of the same strain, although some variability was observed. The data suggest that more variability of flagellin genes exists within the LIO serogroups common to Campylobacter field isolates from Egypt than has previously been reported for North American isolates.


Heat shock protein 90 and its co-chaperone protein phosphatase 5 interact with distinct regions of the tomato I-2 disease resistance protein.
Recent data suggest that plant disease resistance (R) proteins are present in multi-protein complexes. Tomato R protein I-2 confers resistance against the fungal pathogen Fusarium oxysporum. To identify components of the I-2 complex, we performed yeast two-hybrid screens using the I-2 leucine-rich repeat (LRR) domain as bait, and identified protein phosphatase 5 (PP5) as an I-2 interactor. Subsequent screens revealed two members of the cytosolic heat shock protein 90 (HSP90) family as interactors of PP5. By performing in vitro protein-protein interaction analysis using recombinant proteins, we were able to show a direct interaction between I-2 and PP5, and between I-2 and HSP90. The N-terminal part of the LRR domain was found to interact with HSP90, whereas the C-terminal part bound to PP5. The specific binding of HSP90 to the N-terminal region of the I-2 LRR domain was confirmed by co-purifying HSP90 from tomato lysate using recombinant proteins. Similarly, the interaction between PP5 and HSP90 was established. To investigate the role of PP5 and HSP90 for I-2 function, virus-induced gene silencing was performed in Nicotiana benthamiana. Silencing of HSP90 but not of PP5 completely blocked cell death triggered by I-2, showing that HSP90 is required for I-2 function. Together these data suggest that R proteins require, like steroid hormone receptors in animal systems, an HSP90/PP5 complex for their folding and functioning.


Positive effects of indoor environmental conditions on students and their performance in higher education classrooms: A between-groups experiment.
This study explores if multiple alterations of the classrooms' indoor environmental conditions, which lead to environmental conditions meeting quality class A of Dutch guidelines, result in a positive effect on students' perceptions and performance. A field study, with a between-group experimental design, was conducted during the academic course in 2020-2021. First, the reverberation time (RT) was lowered in the intervention condition to 0.4 s (control condition 0.6 s). Next, the horizontal illuminance (HI) level was raised in the intervention condition to 750 lx (control condition 500 lx). Finally, the indoor air quality (IAQ) in both conditions was improved by increasing the ventilation rate, resulting in a reduction of carbon dioxide concentrations, as a proxy for IAQ, from ~1100 to <800 ppm. During seven campaigns, students' perceptions of indoor environmental quality, health, emotional status, cognitive performance, and quality of learning were measured at the end of each lecture using questionnaires. Furthermore, students' objective cognitive responses were measured with psychometric tests of neurobehavioural functions. Students' short-term academic performance was evaluated with a content-related test. From 201 students, 527 responses were collected. The results showed that the reduction of the RT positively influenced students' perceived cognitive performance. A reduced RT in combination with raised HI improved students' perceptions of the lighting environment, internal responses, and quality of learning. However, this experimental condition negatively influenced students' ability to solve problems, while students' content-related test scores were not influenced. This shows that although quality class A conditions for RT and HI improved students' perceptions, it did not influence their short-term academic performance. Furthermore, the benefits of reduced RT in combination with raised HI were not observed in improved IAQ conditions. Whether the sequential order of the experimental conditions is relevant in inducing these effects and/or whether improving two parameters is already beneficial, is unknown.


[(2S,3aR,6aR)-5-Oxohexa-hydro-furo[3,2-b]furan-2-yl]methyl acetate.
The title compound, C9H12O5, is a bicyclic lactone, presenting a 2,6-dioxabi-cyclo-[3.3.0]octan-3-one skeleton, which was obtained through an intra-molecular lactonization. The bicyclic lactone presents a cis ring-junction and a 1,5-trans-substituted tetra-hydro-furan. Both five-membered rings are in twisted envelope conformations with one of the fused C atoms as the flap. The dihedral angle between the mean planes of the bicyclic lactone residue, defined by the di-hydro-furan-2(3H)-one and the tetra-hydro-furan rings, is 69.5 (2)°. The atoms of the ester chain are coplanar [maximum deviation = 0.013 (2) Å]. The absolute structure was not determined.


Bone marrow transplantation. What you need to known.
Bone marrow transplantation can cure otherwise lethal diseases, improve quality of life, and prolong survival for many patients. More than one half of acute nonlymphocytic leukemia and chronic myelogenous leukemia patients and one third of acute lymphocytic leukemia patients in early remission who have matched sibling donors clearly benefit from such therapy. Advances in transplantation technology may extend benefits to patients lacking sibling donors. Continued investigation into fundamental immunology and tumor biology, as well as careful attention to the development of improved supportive-care techniques to reduce both the risks and the costs of marrow grafting, are still required. The complexities of such therapy are enormous, but equally impressive are the clinical successes already achieved. Continuing advances in this exciting field are sure to come.


Lamotrigine and lithium in primary care psychiatric consultation: adoption and adverse effects.
The Collaborative Care Model of psychiatric consultation in primary care has improved outcomes for unipolar depression, but bipolar depressions are challenging for providers and consultants. Although lamotrigine and lithium are both first line medications for bipolar depression, their use in primary care has been declining over the last decade. Our project aimed to quantify the frequency of and adoption of recommendations for lamotrigine and lithium, and their adverse effects, in a Collaborative Care program. Chart review. For 620 depressed adult patients (Public Health Questionnaire, 9-item ≥10), lamotrigine and lithium were recommended by psychiatric consultant for 35% and 26% of patients, respectively; and when recommended, were prescribed by primary care providers 50% and 32% of the time, respectively. Eighty-four percent of lithium dosages were 600 mg or less; average serum level 0.32 mEq/l. In follow-up up to 6 months, lithium was associated with no more weight gain than lamotrigine; but 12% of patients receiving lithium had thyroid stimulating hormone increases exceeding the upper limit of normal, occurring in an average of 32 days after the initial prescription. (i) In a Collaborative Care program of psychiatric consultation, recommendations for lamotrigine and lithium were very frequent. (ii) Adoption of these recommendations is variable, warranting further investigation. (iii) Like higher doses, low doses of lithium induced hypothyroidism (rapidly)-but not weight gain.


Religious life of individuals with affective disorders.
We inquired into aspects of the family history, the marital status, and the religious practices of groups of normal subjects and patients with affective disorders. Consistent with past findings in the literature, individuals with affective disorders came from homes where one parent was frequently missing. The affective disorders group did not differ significantly from control subjects in their adult religious behavior, but had shown significantly diminished religious interest during adolescence. We suggest that this sample of patients with affective disorders returned to religious commitment after adolescence. A possibly related finding is a higher rate of intact marriage and lower rates of separation and divorce among these patients, as well as upward social mobility.


Spatial prediction of risk areas for vector transmission of Trypanosoma cruzi in the State of Paraná, southern Brazil.
After obtaining certification of the absence of transmission of the Trypanosoma cruzi by Triatoma infestans in 2006, other native species of protozoan vectors have been found in human dwellings within municipalities of the State of Paraná, Southern Brazil. However, the spatial distribution of T. cruzi vectors and how climatic and landscape combined variables explain the distribution are still poorly understood. The goal of this study was to predict the potential distribution of T. cruzi vectors as a proxy for Chagas disease transmission risk using Ecological Niche Models (ENMs) based on climatic and landscape variables. We hypothesize that ENM based on both climate and landscape variables are more powerful than climate-only or landscape-only models, and that this will be true independent of vector species. A total of 2,662 records of triatomines of five species were obtained by community-based entomological surveillance from 2007 to 2013. The species with the highest number of specimens was Panstrongylus megistus (73%; n = 1,943), followed by Panstrongylus geniculatus (15.4%; 411), Rhodnius neglectus (6.0%; 159), Triatoma sordida (4.5%; 119) and Rhodnius prolixus (1.1%; 30). Of the total, 71.9% were captured at the intradomicile. T. cruzi infection was observed in 19.7% of the 2,472 examined insects. ENMs were generated based on selected climate and landscape variables with 1 km2 spatial resolution. Zonal statistics were used for classifying the municipalities as to the risk of occurrence of synanthropic triatomines. The integrated analysis of the climate and landscape suitability on triatomines geographical distribution was powerful on generating good predictive models. Moreover, this showed that some municipalities in the northwest, north and northeast of the Paraná state have a higher risk of T. cruzi vector transmission. This occurs because those regions present high climatic and landscape suitability values for occurrence of their vectors. The frequent invasion of houses by infected triatomines clearly indicates a greater risk of transmission of T. cruzi to the inhabitants. More public health attention should be given in the northern areas of the State of Paraná, which presents high climate and landscape suitabilities for the disease vectors. In conclusion, our results-through spatial analysis and predictive maps-showed to be effective in identifying areas of potential distribution and, consequently, in the definition of strategic areas and actions to prevent new cases of Chagas' disease, reinforcing the need for continuous and robust surveillance in these areas.


[Occupational selection in industrial medicine].
The article deals with contemporary state of occupational selection (educational, social and psychologic, medical) in Russia, its importance in industrial medicine and connection with ethic problems. The author defined topical directions in research of occupational selection and occupational fitness examination.


Astrocytic GABA transporter controls sleep by modulating GABAergic signaling in Drosophila circadian neurons.
A precise balance between sleep and wakefulness is essential to sustain a good quality of life and optimal brain function. GABA is known to play a key and conserved role in sleep control, and GABAergic tone should, therefore, be tightly controlled in sleep circuits. Here, we examined the role of the astrocytic GABA transporter (GAT) in sleep regulation using Drosophila melanogaster. We found that a hypomorphic gat mutation (gat33-1) increased sleep amount, decreased sleep latency, and increased sleep consolidation at night. Interestingly, sleep defects were suppressed when gat33-1 was combined with a mutation disrupting wide-awake (wake), a gene that regulates the cell-surface levels of the GABAA receptor resistance to dieldrin (RDL) in the wake-promoting large ventral lateral neurons (l-LNvs). Moreover, RNAi knockdown of rdl and its modulators dnlg4 and wake in these circadian neurons also suppressed gat33-1 sleep phenotypes. Brain immunohistochemistry showed that GAT-expressing astrocytes were located near RDL-positive l-LNv cell bodies and dendritic processes. We concluded that astrocytic GAT decreases GABAergic tone and RDL activation in arousal-promoting LNvs, thus determining proper sleep amount and quality in Drosophila.


Synthesis and characterization of DNA duplexes containing an N(4)C-ethyl-N(4)C interstrand cross-link.
Short DNA duplexes containing an N(4)C-ethyl-N(4)C interstrand cross-link, C-C, were synthesized on controlled pore glass supports. Duplexes having two, three, or four A/T base pairs on either side of the C-C cross-link and terminating with a C(4) overhang at their 5'-ends were prepared. The cross-link was introduced using a convertible nucleoside approach. Thus, an oligonucleotide terminating at its 5'-end with O(4)-triazoyl-2'-deoxyuridine was first prepared on the support. The triazole group of support-bound oligomer was displaced by the aminoethyl group of 5'-dimethoxytrityl-3'-O-tert-butyldimethylsilyl-N(4)-(2-aminoethyl)deoxycytidine to give the cross-link. The dimethoxytrityl group was removed, and the upper and lower strands of the duplex were extended from two 5'-hydroxyl groups of the cross-link using protected nucleoside 3'-phosphoramidites. The tert-butyldimethylsilyl group of the resulting partial duplex was then removed, and the chain was extended in the 3'-direction from the resulting 3'-hydroxyl of the cross-link using protected nucleoside 5'-phosphoramidites. The cross-linked duplexes were purified by HPLC and characterized by enzymatic digestion and MALDI-TOF mass spectrometry. Duplexes with three or four A/T base pairs on either side of the C-C cross-link gave sigmoidal shaped A(260) profiles when heated, a behavior consistent with cooperative denaturation of the A/T base pairs. Each cross-linked duplex could be ligated to an acceptor duplex using T4 DNA ligase, a result that suggests that the C-C cross-link does not interfere with the ligation reaction, even when it is located only two base pairs from the site of ligation. The ability to synthesize duplexes with a defined interstrand cross-link and to incorporate these duplexes into longer pieces of DNA should enable preparation of substrates that can be used for a variety of biophysical and biochemical experiments, including studies of DNA repair.


Isolation and characterization of beta- and gamma-caseins from horse milk.
Three groups of casein components were isolated from horse milk. Group I is almost insoluble at acid and neutral pH, and is rather heterogeneous on alkaline gels with or without sodium dodecyl sulphate. Group II shows strong similarity to beta-casein from other species, as concluded from its amino acid composition and its N- and C-terminal sequences. This group consists of five electrophoretically distinguishable forms, all containing ester phosphate groups but no carbohydrate. Group III is composed of C-terminal fragments of the beta-like (group II) fraction and probably arises from the action of a plasmin-like enzyme present in horse milk. It does not contain phosphate or carbohydrate. Homology of this group with bovine gamma-caseins is demonstrated. Both beta- and gamma-like caseins are more soluble at 4 degrees C than at room temperature.


Impaired proprioception and osteoarthritis.
The increase in the prevalence of osteoarthritis (OA) with age may be due in part to increased joint load resulting from age-related declines in neuromechanical factors, including joint position sense or proprioception. Several studies have demonstrated that knee proprioception is worse in knee OA patients versus age-matched control subjects. Functional consequences of impaired proprioception may include lower gait velocity, shorter stride length, and slower stair walking time. Some studies have shown that proprioception can be enhanced by wearing an elastic bandage or similar orthoses and by muscle training. A variety of other interventions have been proposed as well. To date studies of proprioception in OA patients have been cross-sectional. Theoretically, impaired proprioception might contribute toward or result from OA. A paradigm depicting directions in the relationship between proprioception impairment and OA is offered. Longitudinal data are badly needed to elucidate cause and effect and to determine the relative importance of impaired proprioception in disease progression. The relationship between sensory input and protective or damaging muscle activity has been minimally evaluated in the setting of OA. In studies of clinical conditions related to OA, experimental effusions had no effect on proprioception. Proprioception was worse in hypermobility syndrome patients versus age-matched controls. Anterior cruciate ligament insufficiency is associated with a decline in proprioception.


Management of chronic (post-viral) fatigue syndrome.
Simple rehabilitative strategies are proposed to help patients with the chronic fatigue syndrome. A model is outlined of an acute illness giving way to a chronic fatigue state in which symptoms are perpetuated by a cycle of inactivity, deterioration in exercise tolerance and further symptoms. This is compounded by the depressive illness that is often part of the syndrome. The result is a self-perpetuating cycle of exercise avoidance. Effective treatment depends upon an understanding of the interaction between physical and psychological factors. Cognitive behavioural therapy is suggested. Cognitive therapy helps the patient understand how genuine symptoms arise from the frequent combination of physical inactivity and depression, rather than continuing infection, while a behavioural approach enables the treatment of avoidance behaviour and a gradual return to normal physical activity.


School-Age Hearing Screening Based on Speech-in-Noise Perception Using the Digit Triplet Test.
This study aims to investigate the large-scale applicability of the Digit Triplet test (DTT) for school-age hearing screening in fifth grade elementary (5E) (9 to 12 years old) and third grade secondary (3S) (13 to 16 years old) school children. The reliability of the test is investigated as well as whether pass/fail criteria need to be corrected for training and/or age, and whether these criteria have to be refined with respect to referral rates and pure-tone audiometry results. Eleven school health service centers participated in the region of Flanders (the Northern part of Belgium). Pure-tone screening tests, which are commonly used for hearing screening in school children, were replaced by the DTT. Initial pass/fail criteria were determined. Children with speech reception thresholds (SRT) of -7.2 dB signal to noise ratio (SNR) (5E) and -8.3 dB SNR (3S) or worse were referred for an audiogram and follow-up. In total, n = 3412 (5E) and n = 3617 (3S) children participated. Population SRTs (±2 SD) were -9.8 (±1.8) dB SNR (5E) and -10.5 (±1.6) dB SNR (3S), and do not need correction for training and/or age. Whereas grade-specific pass/fail criteria are more appropriate, a linear regression analysis showed an improvement of 0.2 dB per year of the SRT until late adolescence. SRTs could be estimated with a within-measurement reliability of 0.6 dB. Test duration was also grade-dependent, and was 6 min 50 sec (SD = 61 sec) (5E) and 5 min 45 sec (SD = 49 sec) (3S) on average for both ears. The SRT, test reliability, and test duration were comparable across centers. With initial cut-off values, 2.9% (5E) and 3.5% (3S) of children were referred. Based on audiograms of n = 39 (5E) and n = 59 (3S) children, the diagnostic accuracy of the DTT was assessed. A peripheral hearing loss was detected in 31% (5E) and 53% (3S) of the referred children. Hearing losses found were mild. Less strict pass/fail criteria increased the diagnostic accuracy. Optimal pass/fail criteria were determined at -6.5 dB SNR (5E) and -8.1 dB SNR (3S). With these criteria, referral rates dropped to 1.3% (5E) and 2.4% (3S). The DTT has been implemented as the new hearing screening methodology in the Flemish school-age hearing screening program. Based on the results of this study, pass/fail criteria were determined and optimized to be used for systematic hearing screening of 5E and 3S school children. Furthermore, this study provides reference values for the DTT in children 9 to 16 years of age. Reliable SRTs can be obtained with the test, allowing accurate monitoring of hearing over time. This is important in the context of a screening guideline, which aims to identify children with noise-induced hearing loss. Validation of the screening result should go beyond taking an audiogram, as a peripheral hearing impairment cannot always be found in children with a failed test.


Non-scarring alopecia of lupus erythematosus: A comprehensive review.
Although non-scarring alopecia (NSA) is a frequent clinical finding in patients with systemic lupus erythematosus (SLE), it has been poorly described in the literature. It is considered a nonspecific sign in the current classification of skin lesions of LE. The aim of this study was to give an updated overview of the spectrum of NSA in LE patients, with emphasis on the clinical significance thereof. We conducted a review of the English literature using the PubMed-Medline database using the keywords "Alopecia" + "Lupus erythematosus". Publications describing LE patients with NSA were included. Data for 237 patients from 27 publications were analyzed. Ninety-one patients had diffuse NSA, 43 had patchy NSA, 83 had lupus hair, 3 had alopecia of dermal cutaneous LE, and 17 had alopecia of linear and annular lupus panniculitis of the scalp. Patients with diffuse/patchy NSA and lupus hair shared the following features: strong association with systemic activity of LE, subtle clinical/trichoscopic signs of inflammation, histological aspect consistent with lesions specific to cutaneous LE, high likelihood of response to SLE therapy, and absence of progression to scarring alopecia. Association with SLE was rare in patients with dermal cutaneous LE or linear and annular lupus panniculitis of the scalp, and skin-directed therapies were most often effective. One patient of each subtype progressed to scarring alopecia. Diffuse/patchy NSA and lupus hair may represent a topographic variation of a single entity specific for LE. Prospective studies are warranted to further document the clinical significance of this manifestation.


A structure model and growth mechanism for multishell carbon nanotubes.
A model that postulates a mixture of scroll-shaped and concentric, cylindrical graphene sheets is proposed to explain the microstructure of graphite multishell nanotubes grown by arc discharge. The model is consistent with the observed occurrence of a relatively small number of different chiral angles within the same tubule. The model explains clustering in a natural way and is consistent with the observation of asymmetric (0002) lattice fringe patterns and with the occurrence of singular fringe spacings larger than c/2 (c is the c parameter of graphite) in such patterns. Anisotropic thermal contraction accounts for the 2 to 3 percent increase in the c parameter of nanotubes, compared with bulk graphite, but is too small to explain the singular fringe spacings. The model also explains the formation of multishell closure domes. Nucleation is attributed to the initial formation of a fullerene "dome."


Stereoselective synthesis of bishomo-inositols as glycosidase inhibitors.
For the synthesis of various bishomo-inositol derivatives, 1,3,3a,7a-tetrahydro-2-benzofuran was used as the key compound. For further functionalization of the diene unit, the diene was subjected to photooxygenation, epoxidation, and cis-hydroxylation reactions. The endoperoxide linkage was cleaved by thiourea. The remaining double bond was subjected to epoxidation and cis-hydroxylation reactions. The epoxide rings and tetrahydrofuran rings formed were opened by acid-catalyzed reaction with sulfamic acid. The combination of these reactions resulted in the formation of various new inositol derivatives such as bishomo-chiro-inositol, bishomo-myo-inositol, and two isomeric bishomo-allo-inositols.


Template-based prediction of vigilance fluctuations in resting-state fMRI.
Changes in vigilance or alertness during a typical resting state fMRI scan are inevitable and have been found to affect measures of functional brain connectivity. Since it is not often feasible to monitor vigilance with EEG during fMRI scans, it would be of great value to have methods for estimating vigilance levels from fMRI data alone. A recent study, conducted in macaque monkeys, proposed a template-based approach for fMRI-based estimation of vigilance fluctuations. Here, we use simultaneously acquired EEG/fMRI data to investigate whether the same template-based approach can be employed to estimate vigilance fluctuations of awake humans across different resting-state conditions. We first demonstrate that the spatial pattern of correlations between EEG-defined vigilance and fMRI in our data is consistent with the previous literature. Notably, however, we observed a significant difference between the eyes-closed (EC) and eyes-open (EO) conditions, finding stronger negative correlations with vigilance in regions forming the default mode network and higher positive correlations in thalamus and insula in the EC condition when compared to the EO condition. Taking these correlation maps as "templates" for vigilance estimation, we found that the template-based approach produced fMRI-based vigilance estimates that were significantly correlated with EEG-based vigilance measures, indicating its generalizability from macaques to humans. We also demonstrate that the performance of this method was related to the overall amount of variability in a subject's vigilance state, and that the template-based approach outperformed the use of the global signal as a vigilance estimator. In addition, we show that the template-based approach can be used to estimate the variability across scans in the amplitude of the vigilance fluctuations. We discuss the benefits and tradeoffs of using the template-based approach in future fMRI studies.


Hormone replacement therapy and colorectal adenoma recurrence among women in the Polyp Prevention Trial.
Epidemiologic studies have suggested that estrogen may protect against the development of colorectal cancers and adenomatous polyps. We conducted a prospective study to evaluate the association between hormone replacement therapy (HRT) and adenoma recurrence among perimenopausal and postmenopausal women participating in the Polyp Prevention Trial, a randomized dietary intervention study of individuals with colorectal adenomas. We used a questionnaire and interviews to collect detailed information, at baseline and at each of four annual study visits, from 620 women regarding hormone use, menopausal status, diet, alcohol consumption, and other risk factors. Adenoma recurrence was ascertained by complete colonoscopy at baseline and after 1 and 4 years. Logistic regression models were used to evaluate the association between hormone use and adenoma recurrence after adjusting for intervention group and for age and body mass index at baseline. All statistical tests were two-sided. Adenomas recurred in 200 women. There was no overall association between adenoma recurrence and either overall hormone use (odds ratio [OR] = 1.01; 95% confidence interval [CI] = 0.70 to 1.45), combined estrogen and progestin use (OR = 0.94; 95% CI = 0.57 to 1.56), or unopposed estrogen use (OR = 1.04; 95% CI = 0.68 to 1.59). HRT use was associated with a reduction in risk for recurrence of distal adenomas (OR = 0.56; 95% CI = 0.32 to 1.00) and a statistically nonsignificant increase in risk for recurrence of proximal adenomas (OR = 1.39; 95% CI = 0.85 to 2.26). We observed a statistically significant interaction between the HRT-adenoma recurrence association and age (P =.02). HRT was associated with a 40% reduced risk of adenoma recurrence among women older than 62 years (OR = 0.58; 95% CI = 0.35 to 0.97) but with an increased risk among women younger than 62 years (OR = 1.99; 95% CI = 1.11 to 3.55). HRT was not associated with a reduced risk for overall adenoma recurrence in this trial cohort, although there was a suggestion of an age interaction. The effect of age on the association needs to be confirmed in other adenoma recurrence trials.


The capacity ratio as a measure of solvency in experiential education.
To determine the utility of the capacity ratio to measure and compare solvency in experiential education in 6 colleges and schools of pharmacy in the Northwestern United States. The 6 colleges and schools of pharmacy combined data on student placements needed, site availability, and changes made to placements during the 2009-2010 and 2010-2011 academic years and calculated capacity ratios for the advanced and introductory experience programs in the region. Comparisons also were made to previously published capacity results to determine whether the capacity ratio was useful in identifying trends and guiding preceptor and site development. Capacity ratio calculations were successful in facilitating comparison of capacity within and across regions. Experiential education is solvent in the Northwest overall, but specific parts of experiential programs were found to have more capacity than others. Trends in the Northwest were consistent with capacity in other regions. The capacity ratio can determine and facilitate comparison of solvency within and across colleges and schools of pharmacy and thereby inform decisions about resource management in experiential education.


[Hamman-Rich syndrome].
An observation of Hamman-Rich syndrome in a man of 47 with an acute, rapidly progressive course due to an immunoconflict situation in the lungs is presented. This situation is characterized by marked changes of the microcirculatory bed of interalveolar septae, with increased permeability, productive-desquamative alveolitis and formation of hyalin membranes, lymphoid-macrophage cell reaction of diffuse fibrosis. The peculiar features of this case include not only the involvement of the lungs but also the occurrence of generalized productive vasculitis with the involvement of the myocardium and the kidneys which, alongside with considerable immune alterations in the spleen and lymph nodes, confirm the hypothesis of the systemic autoaggression nature of this disease.


Amblyopia.
Amblyopia is commonly associated with squint (strabismus) or refractive errors resulting in different visual inputs to each eye during the sensitive period of visual development (<7-8 years of age). The cumulative incidence is estimated at 2% to 4% in children aged up to 15 years. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to detect amblyopia early? What are the effects of medical treatments for amblyopia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations, such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review, we present information relating to the effectiveness and safety of the following interventions: active vision therapy; glasses alone or with occlusion; or penalisation to treat amblyopia; and screening to detect amblyopia early.


Cognitive-affective neuroscience of somatization disorder and functional somatic syndromes: reconceptualizing the triad of depression-anxiety-somatic symptoms.
Somatization disorder is a somatoform disorder that overlaps with a number of functional somatic syndromes and has high comorbidity with major depression and anxiety disorders. Proposals have been made for revising the category of somatoform disorders, for simplifying the criteria for somatization disorder, and for emphasizing the unitary nature of the functional somatic syndromes in future classifications. A review of the cognitive-affective neuroscience of somatization disorder and related conditions suggests that overlapping psychobiological mechanisms mediate depression, anxiety, and somatization symptoms. Particular genes and environments may contribute to determining whether symptoms are predominantly depressive, anxious, or somatic, and there are perhaps also overlaps and distinctions in the distal evolutionary mechanisms that produce these symptoms.


Development and evaluation of a bio-ion measurement system on acupoints for meridian diagnosis.
The aim of this study was to develop a new method of measuring the meridian energy potential (MEP) at an acupoint with bioelectrical impedance in order to establish an objective meridian diagnosis. To confirm the reflection of the changes in body composition at acupoints, the changes in the MEP on the bladder meridian before, during and after cupping were observed. Additionally, to evaluate the usefulness of diagnosis, the MEP on the stomach meridian before and after a meal was measured. Significant increases were found at every acupoint during cupping and after eating a meal. It was confirmed that the MEP data reflected changes in body composition at every acupoint and that these changes were associated with functioning of the associated internal organs. In conclusion, we propose the usefulness of this method, which can indicate the state of acupoints.


Rates and probabilities in economic modelling: transformation, translation and appropriate application.
Economic modelling is increasingly being used to evaluate the cost effectiveness of health technologies. One of the requirements for good practice in modelling is appropriate application of rates and probabilities. In spite of previous descriptions of appropriate use of rates and probabilities, confusions persist beyond a simple understanding of their definitions. The objective of this article is to provide a concise guide to understanding the issues surrounding the use of rates and probabilities reported in the literature in economic models, and an understanding of when and how to transform them appropriately. The article begins by defining rates and probabilities and shows the essential difference between the two measures. Appropriate conversions between rates and probabilities are discussed, and simple examples are provided to illustrate the techniques and pitfalls. How the transformed rates and probabilities may be used in economic models is then described and some recommendations are suggested.


Entrepreneurial Strategies to Seek Venture Capital Funding.
Innovation is vital for progress in any industry. Evolving technology, paired with human ingenuity, brings ideas for prototypes and business models. Many physicians conceptualize platforms to serve their patients; however, many struggle and ultimately fail to bring their product or service to market. Financing is often the limiting factor. Studies have proven venture capital (VC) funding to be a pivotal source for helping a business survive in its early stages. Plastic surgeons can benefit from learning how to seek out VC funding. In this presentation, common terminology and key players will be defined, from seed capital to angel investors. Doing recommended "homework" will help the plastic surgeon identify a financier tailored to their specific needs-ideally one with a focus in the medical space. A clear-cut approach to assembling a "pitch deck" presentation will be outlined to prepare the plastic surgeon for their first meeting. Insider pearls will be presented from the VC perspective. The plastic surgeon should be prepared to answer fundamental questions expected at different stages of the process. Nevertheless, each meeting also serves as an opportunity for the plastic surgeon to probe the VC firm and their intentions. The role of background checks, social media, and electronic profiles will be discussed. Transparency from both parties at all times can help establish a successful relationship, even if it ends in a referral to a better suited VC firm. Between January and September of 2017, $12.1 billion of seed and VC was invested into life science companies in the United States. Growth is exponential. The surgeon is at the frontier of developing ideas and cutting-edge products that help us serve our patients with enhanced care and improved outcomes. In seeking out the proper financier, your product or service can become a reality in the market, contributing to the betterment of medicine and plastic surgery.


Subgroups of children with Kawasaki disease: a data-driven cluster analysis.
Although Kawasaki disease is commonly regarded as a single disease entity, variability in clinical manifestations and disease outcome has been recognised. We aimed to use a data-driven approach to identify clinical subgroups. We analysed clinical data from patients with Kawasaki disease diagnosed at Rady Children's Hospital (San Diego, CA, USA) between Jan 1, 2002, and June 30, 2022. Patients were grouped by hierarchical clustering on principal components with k-means parcellation based on 14 variables, including age at onset, ten laboratory test results, day of illness at the first intravenous immunoglobulin infusion, and normalised echocardiographic measures of coronary artery diameters at diagnosis. We also analysed the seasonality and Kawasaki disease incidence from 2002 to 2019 by subgroup. To explore the biological underpinnings of identified subgroups, we did differential abundance analysis on proteomic data of 6481 proteins from 32 patients with Kawasaki disease and 24 healthy children, using linear regression models that controlled for age and sex. Among 1016 patients with complete data in the final analysis, four subgroups were identified with distinct clinical features: (1) hepatobiliary involvement with elevated alanine transaminase, gamma-glutamyl transferase, and total bilirubin levels, lowest coronary artery aneurysm but highest intravenous immunoglobulin resistance rates (n=157); (2) highest band neutrophil count and Kawasaki disease shock rate (n=231); (3) cervical lymphadenopathy with high markers of inflammation (erythrocyte sedimentation rate, C-reactive protein, white blood cell, and platelet counts) and lowest age-adjusted haemoglobin Z scores (n=315); and (4) young age at onset with highest coronary artery aneurysm but lowest intravenous immunoglobulin resistance rates (n=313). The subgroups had distinct seasonal and incidence trajectories. In addition, the subgroups shared 211 differential abundance proteins while many proteins were unique to a subgroup. Our data-driven analysis provides insight into the heterogeneity of Kawasaki disease, and supports the existence of distinct subgroups with important implications for clinical management and research design and interpretation. US National Institutes of Health and the Irving and Francine Suknow Foundation.


Cybertherapy--new applications for discomfort reductions. Surgical care unit of heart, neonatology care unit, transplant kidney care unit, delivery room-cesarean surgery and ambulatory surgery, 27 case reports.
We demonstrate the feasibility of virtual reality scenarios to reduce discomfort in patients during ambulatory and obstetric surgeries and patients hospitalized in postoperative care units from Cardiac, nephrology, and neonatology unirs. 27 patients have been participated in this preliminary reports from 3 public hospitals from Mexico city in 2006. The VR scenarios were developed in the Virtual Reality Medical Center of San Diego CA, USA, and the HMD is from the Southern University of los Angeles, CA, USA. The majority of patients demonstrated comfort with virtual scenarios during surgical procedures or hospitalization. In ambulatory surgeries the reduction of medication dosage was real. We present the first applications in surgery, obstetrics and care units. The preliminary results must be supported in the future with more number of cases and statistical results; however we can predict the usefulness because we have found reduction of medication in ambulatory surgeries. Explore new applications in different areas in medicine is a challenge of Virtual Reality.


Molecular analysis of a constitutional X-autosome translocation in a female with muscular dystrophy.
The gene responsible for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) maps to the X chromosome short arm, band Xp21. In a few females with DMD or BMD, the Xp21 region is disrupted by an X-autosome translocation. Accumulating evidence suggests that the exchange has physically disrupted the DMD/BMD locus to cause the disease. One affected female with a t(X;21)(p21;p12) translocation was studied in detail. The exchange points from both translocation chromosomes were cloned, restriction-mapped, and sequenced. The translocation is reciprocal, but not conservative. A small amount of DNA is missing from the translocated chromosomes; 71 to 72 base pairs from the X chromosome and 16 to 23 base pairs from the 28S ribosomal gene on chromosome 21.


Structure, regulation, and (patho-)physiological functions of the stress-induced protein kinase CK1 delta (CSNK1D).
Members of the highly conserved pleiotropic CK1 family of serine/threonine-specific kinases are tightly regulated in the cell and play crucial regulatory roles in multiple cellular processes from protozoa to human. Since their dysregulation as well as mutations within their coding regions contribute to the development of various different pathologies, including cancer and neurodegenerative diseases, they have become interesting new drug targets within the last decade. However, to develop optimized CK1 isoform-specific therapeutics in personalized therapy concepts, a detailed knowledge of the regulation and functions of the different CK1 isoforms, their various splice variants and orthologs is mandatory. In this review we will focus on the stress-induced CK1 isoform delta (CK1δ), thereby addressing its regulation, physiological functions, the consequences of its deregulation for the development and progression of diseases, and its potential as therapeutic drug target.


Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation.
We present a general method called atom-wise free energy perturbation (AFEP), which extends a conventional molecular dynamics free energy perturbation (FEP) simulation to give the contribution to a free energy change from each atom. AFEP is derived from an expansion of the Zwanzig equation used in the exponential averaging method by defining that the system total energy can be partitioned into contributions from each atom. A partitioning method is assumed and used to group terms in the expansion to correspond to individual atoms. AFEP is applied to six example free energy changes to demonstrate the method. Firstly, the hydration free energies of methane, methanol, methylamine, methanethiol, and caffeine in water. AFEP highlights the atoms in the molecules that interact favorably or unfavorably with water. Finally AFEP is applied to the binding free energy of human immunodeficiency virus type 1 protease to lopinavir, and AFEP reveals the contribution of each atom to the binding free energy, indicating candidate areas of the molecule to improve to produce a more strongly binding inhibitor. FEP gives a single value for the free energy change and is already a very useful method. AFEP gives a free energy change for each "part" of the system being simulated, where part can mean individual atoms, chemical groups, amino acids, or larger partitions depending on what the user is trying to measure. This method should have various applications in molecular dynamics studies of physical, chemical, or biochemical phenomena, specifically in the field of computational drug discovery.


Oxygenation Responses While Wearing the Elevation Training Mask During an Incremental Cycling Test.
Romero-Arenas, S, López-Pérez, E, Colomer-Poveda, D, and Márquez, G. Oxygenation responses while wearing the elevation training mask during an incremental cycling test. J Strength Cond Res 35(7): 1897-1904, 2021-The Elevation Training Mask 2.0 (ETM) is a commercial training mask that purportedly simulates altitude training, although their effects have not been conclusively demonstrated. Therefore, the purpose of this study was to evaluate the influence of wearing the ETM on muscle and brain oxygenation responses during a maximal incremental cycling test, as well as the influence of this device on the heart rate (HR) response, perception of effort (rating of perceived exertion [RPE]), arterial oxygen saturation (SaO2), blood lactate (La+), and performance (POpeak). Fourteen active males completed an incremental cycling test to volitional exhaustion in 2 separate and counterbalanced conditions, wearing the mask set at 9,000 feet (i.e., 2743 m) and a control condition (CTR, without ETM). During the trial, muscle and cerebral oxygenation were monitored continuously using near-infrared spectroscopy. Heart rate, RPE, and SaO2 were also recorded from the beginning of the test until the volitional exhaustion. La+ was measured at the end of each test. Wearing the ETM significantly reduced the POpeak by -6.9 ± 6.6% (p = 0.002) and this was accompanied by lower La+ values (-12.8 ± 21.6%; p = 0.027). SaO2 was also significantly lower at maximal intensity in comparison with the CTR condition (-1.5 ± 0.3%; p = 0.028). However, both HR and RPE showed a similar trend during both sessions, as well as muscle oxygenation. Nevertheless, the mask caused an increase in brain oxygenation compared with the CTR condition (p < 0.05). In conclusion, our findings suggest that wearing the ETM causes a pronounced increase in O2Hb and tHb in the frontoparietal cortex without any change in the muscle oxygenation.


Spectral statistics of permutation matrices.
We compute the mean two-point spectral form factor and the spectral number variance for permutation matrices of large order. The two-point correlation function is expressed in terms of generalized divisor functions, which are frequently discussed in number theory. Using classical results from number theory and casting them in a convenient form, we derive expressions which include the leading and next to leading terms in the asymptotic expansion, thus providing a new point of view on the subject, and improving some known results.


Parenting × Brain Development interactions as predictors of adolescent depressive symptoms and well-being: Differential susceptibility or diathesis-stress?
It is unclear how individual differences in parenting and brain development interact to influence adolescent mental health outcomes. This study examined interactions between structural brain development and observed maternal parenting behavior in the prediction of adolescent depressive symptoms and psychological well-being. Whether findings supported diathesis-stress or differential susceptibility frameworks was tested. Participants completed observed interactions with their mothers during early adolescence (age 13), and the frequency of positive and aggressive maternal behavior were coded. Adolescents also completed structural magnetic resonance imaging scans at three time points: mean ages 13, 17, and 19. Regression models analyzed interactions between maternal behavior and longitudinal brain development in the prediction of late adolescent (age 19) outcomes. Indices designed to distinguish between diathesis-stress and differential susceptibility effects were employed. Results supported differential susceptibility: less thinning of frontal regions was associated with higher well-being in the context of low levels of aggressive maternal behavior, and lower well-being in the context of high levels of aggressive maternal behavior. Findings suggest that reduced frontal cortical thinning during adolescence may underlie increased sensitivity to maternal aggressive behavior for better and worse and highlight the importance of investigating biological vulnerability versus susceptibility.


Anti-nucleocapsid antibodies enhance the production of IL-6 induced by SARS-CoV-2 N protein.
A cytokine storm induces acute respiratory distress syndrome, the main cause of death in coronavirus disease 2019 (COVID-19) patients. However, the detailed mechanisms of cytokine induction due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. To examine the cytokine production in COVID-19, we mimicked the disease in SARS-CoV-2-infected alveoli by adding the lysate of SARS-CoV-2-infected cells to cultured macrophages or induced pluripotent stem cell-derived myeloid cells. The cells secreted interleukin (IL)-6 after the addition of SARS-CoV-2-infected cell lysate. Screening of 25 SARS-CoV-2 protein-expressing plasmids revealed that the N protein-coding plasmid alone induced IL-6 production. The addition of anti-N antibody further enhanced IL-6 production, but the F(ab')2 fragment did not. Sera from COVID-19 patients also enhanced IL-6 production, and sera from patients with severer disease induced higher levels of IL-6. These results suggest that anti-N antibody promotes IL-6 production in SARS-CoV-2-infected alveoli, leading to the cytokine storm of COVID-19.