TNFRSF1A-pR92Q variant identifies a subset of patients more similar to systemic undifferentiated recurrent fever than TNF receptor-associated periodic syndrome.
To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF). Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients. In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients. Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.


Considering built environment and spatial correlation in modeling pedestrian injury severity.
This study looks at mitigating and aggravating factors that are associated with the injury severity of pedestrians when they have crashes with another road user and overcomes existing limitations in the literature by focusing attention on the built environment and considering spatial correlation across crashes. Reports for 6,539 pedestrian crashes occurred in Denmark between 2006 and 2015 were merged with geographic information system resources containing detailed information about the built environment and exposure at the crash locations. A linearized spatial logit model estimated the probability of pedestrians sustaining a severe or fatal injury conditional on the occurrence of a crash with another road user. This study confirms previous findings about older pedestrians and intoxicated pedestrians being the most vulnerable road users and crashes with heavy vehicles and in roads with higher speed limits being related to the most severe outcomes. This study provides novel perspectives by showing positive spatial correlations of crashes with the same severity outcomes and emphasizing the role of the built environment in the proximity of the crash. This study emphasizes the need for thinking about traffic calming measures, illumination solutions, road maintenance programs, and speed limit reductions. Moreover, this study emphasizes the role of the built environment, because shopping areas, residential areas, and walking traffic density are positively related to a reduction in pedestrian injury severity. Often, these areas have in common a larger pedestrian mass that is more likely to make other road users more aware and attentive, whereas the same does not seem to apply to areas with lower pedestrian density.


Scientific and Regulatory Considerations for Generic Complex Drug Products Containing Nanomaterials.
In the past few decades, the development of medicine at the nanoscale has been applied to oral and parenteral dosage forms in a wide range of therapeutic areas to enhance drug delivery and reduce toxicity. An obvious response to these benefits is reflected in higher market shares of complex drug products containing nanomaterials than that of conventional formulations containing the same active ingredient. The surging market interest has encouraged the pharmaceutical industry to develop cost-effective generic versions of complex drug products based on nanotechnology when the associated patent and exclusivity on the reference products have expired. Due to their complex nature, nanotechnology-based drugs present unique challenges in determining equivalence standards between generic and innovator products. This manuscript attempts to provide the scientific rationales and regulatory considerations of key equivalence standards (e.g., in vivo studies and in vitro physicochemical characterization) for oral drugs containing nanomaterials, iron-carbohydrate complexes, liposomes, protein-bound drugs, nanotube-forming drugs, and nano emulsions. It also presents active research studies in bridging regulatory and scientific gaps for establishing equivalence of complex products containing nanomaterials. We hope that open communication among industry, academia, and regulatory agencies will accelerate the development and approval processes of generic complex products based on nanotechnology.


Analysis of LncRNA43234-Associated ceRNA Network Reveals Oil Metabolism in Soybean.
Soybean [Glycine max (Linn.) Merr.] is an important oil crop. Long noncoding RNAs (lncRNAs) play a variety of functions in plants. However, their function in the soybean oil synthesis pathway is yet to be uncovered. Here, the lncRNA43234 gene related to soybean oil synthesis was screened, and the full-length cDNA sequence of the lncRNA was obtained using rapid amplification of cDNA ends. Overexpression of lncRNA43234 increased the content of crude protein in seeds, decreased the content of oleic acid, and affected the content of alanine and arginine in free amino acids. RNA interference of the lncRNA43234 gene decreased the crude protein content in seeds. Quantitative real-time polymerase chain reaction analysis revealed that lncRNA43234 influenced the expression of XM_014775786.1 associated with phosphatidylinositol metabolism by acting as a decoy for miRNA10420, thereby affecting the content of soybean oil. Our results provide insights into how lncRNA-mediated competing endogenous RNA regulatory networks are involved in soybean oil synthesis.


Transcriptome analysis of PPARγ target genes reveals the involvement of lysyl oxidase in human placental cytotrophoblast invasion.
Human placental development is characterized by invasion of extravillous cytotrophoblasts (EVCTs) into the uterine wall during the first trimester of pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) plays a major role in placental development, and activation of PPARγ by its agonists results in inhibition of EVCT invasion in vitro. To identify PPARγ target genes, microarray analysis was performed using GeneChip technology on EVCT primary cultures obtained from first-trimester human placentas. Gene expression was compared in EVCTs treated with the PPARγ agonist rosiglitazone versus control. A total of 139 differentially regulated genes were identified, and changes in the expression of the following 8 genes were confirmed by reverse transcription-quantitative polymerase chain reaction: a disintegrin and metalloproteinase domain12 (ADAM12), connexin 43 (CX43), deleted in liver cancer 1 (DLC1), dipeptidyl peptidase 4 (DPP4), heme oxygenase 1 (HMOX-1), lysyl oxidase (LOX), plasminogen activator inhibitor 1 (PAI-1) and PPARγ. Among the upregulated genes, lysyl oxidase (LOX) was further analyzed. In the LOX family, only LOX, LOXL1 and LOXL2 mRNA expression was significantly upregulated in rosiglitazone-treated EVCTs. RNA and protein expression of the subfamily members LOX, LOXL1 and LOXL2 were analyzed by absolute RT-qPCR and western blotting, and localized by immunohistochemistry and immunofluorescence-confocal microscopy. LOX protein was immunodetected in the EVCT cytoplasm, while LOXL1 was found in the nucleus and nucleolus. No signal was detected for LOXL2 protein. Specific inhibition of LOX activity by β-aminopropionitrile in cell invasion assays led to an increase in EVCT invasiveness. These results suggest that LOX, LOXL1 and LOXL2 are downstream PPARγ targets and that LOX activity is a negative regulator of trophoblastic cell invasion.


Rapid glucocorticoid mediation of suppressed testosterone biosynthesis in male mice subjected to immobilization stress.
Physical and psychosocial stress challenge homeostasis, increasing glucocorticoid secretion (in rodents, corticosterone [CORT]) while decreasing testosterone (T) levels. The dynamics of stress-induced changes in T, CORT, and luteinizing hormone (LH) concentrations in mice have not been investigated previously. In particular, it remains to be established whether there is a rapid effect of CORT that is directly mediated by glucocorticoid receptors (GRs) in the testis. Therefore, serum and intratesticular T, serum CORT, and LH levels were measured during acute immobilization (IMO) stress, using the C57BL/6 strain of mice. The effects of testicular GR blockade were investigated by administration of the GR antagonist, RU486, via intratesticular (IT) or intraperitoneal (IP) injection. CORT levels increased in stressed males starting at 15 minutes, reaching a fivefold higher plateau by 1 hour compared with controls (P < .01). Conversely, starting from 30 minutes on, both serum and intratesticular T levels decreased in stressed males to 30% and 8% of control values, respectively, by 6 hours (P < .01). In contrast, LH was unchanged by IMO stress for up to 6 hours. Intratesticular treatment with RU486 partially prevented the IMO-induced decline in T levels. CORT treatment reduced intracellular cyclic adenosine monophosphate (cAMP) content in Leydig cells by 15 minutes and T production by 30 minutes in vitro. We conclude that 1) the rapid changes in T suggest a suppression of T biosynthesis by glucocorticoid through a nongenomic mechanism, lowering the production of cytoplasmic cAMP; 2) changes in gonadotropic stimulation of Leydig cells are unlikely to explain the suppression of T levels during acute stress; and 3) the results are consistent with a direct inhibitory action of CORT on Leydig cells.


Persistence Paths and Signature Features in Topological Data Analysis.
We introduce a new feature map for barcodes as they arise in persistent homology computation. The main idea is to first realize each barcode as a path in a convenient vector space, and to then compute its path signature which takes values in the tensor algebra of that vector space. The composition of these two operations-barcode to path, path to tensor series-results in a feature map that has several desirable properties for statistical learning, such as universality and characteristicness, and achieves state-of-the-art results on common classification benchmarks.


Evidence for carrier-mediated transport of monosaccharides in the Ehrlich ascites tumor cell.
Evidence for carrier-mediated transport of monosaccharides in the Ehrlich ascites tumor cells was provided through kinetic analysis of data obtained by: (a) studying sugar uptake by dilute cell suspensions with an optical densimetric apparatus, (b) studying sugar uptake by thicker cell suspensions by means of direct chemical analytical methods using packed cell plugs, (c) observing the effects of a competitive inhibitor upon sugar uptake with the chemical analytical method, and (d) measurement of tracer uptake of a high affinity sugar in thick cell suspensions in the absence of net movement. Quantitative application of the data obtained with the above experimental procedures to theoretical model systems derived for both carrier-mediated transport and simple passive diffusion indicated that the results were consonant with predictions for the carrier-mediated transport model, but could not be explained on the basis of uncomplicated diffusion.


Hyperparameter Tuning with High Performance Computing Machine Learning for Imbalanced Alzheimer's Disease Data.
Accurate detection is still a challenge in machine learning (ML) for Alzheimer's disease (AD). Class imbalance in imbalanced AD data is another big challenge for machine-learning algorithms working under the assumption that the data are evenly distributed within classes. Here, we present a hyperparameter tuning workflow with high-performance computing (HPC) for imbalanced data related to prevalent mild cognitive impairment (MCI) and AD in the Health and Aging Brain Study-Health Disparities (HABS-HD) project. We applied a single-node multicore parallel mode to hyperparameter tuning of gamma, cost, and class weight using a support vector machine (SVM) model with 10 times repeated fivefold cross-validation. We executed the hyperparameter tuning workflow with R's bigmemory, foreach, and doParallel packages on Texas Advanced Computing Center (TACC)'s Lonestar6 system. The computational time was dramatically reduced by up to 98.2% for the high-performance SVM hyperparameter tuning model, and the performance of cross-validation was also improved (the positive predictive value and the negative predictive value at base rate 12% were, respectively, 16.42% and 92.72%). Our results show that a single-node multicore parallel structure and high-performance SVM hyperparameter tuning model can deliver efficient and fast computation and achieve outstanding agility, simplicity, and productivity for imbalanced data in AD applications.


Brown adipose tissue in genetically obese (fa/fa) rats: response to cold and diet.
Young genetically obese (fatty, fa/fa) rats (7-8 wk old) maintained on a chow diet at 28 degrees C have a relatively normal amount of brown adipose tissue (BAT) (normal protein content, normal noradrenaline content, normal or slightly reduced cytochrome oxidase content, 30% reduction in DNA content) with cells grossly hypertrophied by accumulation of lipid. The binding of purine nucleotides by BAT mitochondria is lower in fa/fa rats than in lean rats, suggesting a lesser thermogenic activation of this tissue. Acute exposure to cold (24 h at 4 degrees C) activates BAT thermogenesis (visible hyperemia, marked increase in mitochondrial binding of purine nucleotides, depletion of noradrenaline content) in fa/fa rats as in lean rats. In contrast, feeding a cafeteria diet to young fa/fa rats fails to activate BAT (no increase in mitochondrial binding of purine nucleotides) as it does in lean rats, and these rats accumulate more extra fat (increase in weight of gonadal white adipose tissue) than do cafeteria diet-fed lean rats. It is concluded that the young fa/fa rat has normal cold-induced nonshivering thermogenesis in BAT but defective diet-induced thermogenesis in BAT and that the consequent reduction in energy expenditure, coupled with hyperphagia, contributes to the development of its obesity. The most probable location for the defect is suggested to be associated with the hypothalamus.


Stereopsis in idiopathic macular hole with special reference to the size of the hole and its effect on stereoacuity.
To identify the characteristics of binocular vision in unilateral idiopathic macular hole (MH) regarding the size of the hole and its effect on stereopsis. Twelve patients with idiopathic MH were tested using the Amsler Grid, Bagolini Striated Glasses, Starlight Test, Titmus Stereotest (the Titmus) and Lang Stereotest (the Lang). The results were analyzed with reference to two parameters: visual acuity and the size of the MH. The size of the MH in 12 subjects ranged from 0.67 degrees to 2.13 degrees (mean, 1.29 degrees). The MHs caused distorted central vision under binocular conditions. Visual acuities ranged from 0.3 to 0.06. Nine out of the 12 patients (75%) failed the 800 seconds of arc (") with the Titmus, but all 12 patients (100%) demonstrated stereoacuity of 550" to 600" with the Lang. The discrepancy of measured stereoacuity between the Titmus and the Lang was hypothesized to be due to the different size of the test charts and their targets and the pattern of the visual deficit. The pass rate of 92% (550") with the Lang is better than rates for other patients with higher visual acuities, such as children with amblyopia (62-70%) or adults undergoing visual screening (67%). In cases of MH, intact overlapped visual field beyond the central 0-2 degrees played an important role in maintaining stereoscopic vision.


The role of tyrosine phosphorylation in signal transduction through surface Ig in human B cells. Inhibition of tyrosine phosphorylation prevents intracellular calcium release.
Cross-linking surface Ig on human B cells, or the TCR complex on T cells leads to the rapid appearance of newly tyrosine phosphorylated proteins. This is associated with inositol phospholipid turnover and a rise in intracellular calcium. Incubation of human B or T lymphocytes with the tyrosine kinase inhibitors, herbimycin and genistein, inhibits new tyrosine phosphorylation after receptor-linked activation. This is associated with complete abrogation of the increase in intracellular calcium in these lymphocytes and inhibition of inositol phospholipid turnover. Herbimycin- and genistein-treated lymphocytes are nevertheless still capable of responding to aluminum fluoride with a rise in intracellular calcium. These data support the contention that a B cell-associated protein tyrosine kinase regulates signal transduction via phospholipase C. CD45, the membrane associated protein tyrosine phosphatase, and PMA that activates protein kinase C, both inhibit the calcium response in B lymphocytes induced by receptor cross-linking. PMA and cross-linking CD45 both induced the appearance of tyrosine phosphorylated proteins in human B cells, although the pattern is quite distinct from that seen when surface lg is cross-linked. However, the induction of new tyrosine phosphorylation by anti-mu does not appear to be affected by these reagents. Although this may reflect an insensitivity of the tyrosine phosphorylation assay, it could indicate that regulation of the calcium response and regulation of the tyrosine kinase can be independent processes.


[Coxsackie B virus in children with acute myocarditis].
To study etiopathogenic and follow-up aspects of patients with myocarditis. Among 44 cases of acute myocarditis in children studied from clinical and virological point of view, it was selected 16 which were positive to coxsackie B virus. The clinical investigation included blood test to enzyme dosage, chest X-ray, electro and echocardiogram. The virological work up to coxsackie B1, B3, B4, B5 and B6 included culture neutralization test and IgM (indirect immunofluorescence). The positive results were: B4 in 9 (57%); B5 in 4 (25%), B1 in 2 (12%) and B3 in 1 (6%). It was not used immunosuppressive treatment. The follow-up (at least one year it was: 7 patients became free of symptoms (43%); 4 (25%) turned to be chronic dilated myocardiopathy 1 (6%) died and 4 (25%) were discharged from hospital but did not return to out-patient clinic. One of patients of chronic group during 4 years of follow-up had ventricular extrasystoles, second degree heart block and now is asymptomatic. We did not observe significative differences among the several types of coxsackie B related to clinical course.


Effectiveness of resistance training on muscle strength and physical function in people with Parkinson's disease: a systematic review and meta-analysis.
To systematically review the evidence investigating the effectiveness of resistance training on strength and physical function in people with Parkinson's disease. Seven electronic databases (COCHRANE, CINAHL, Medline ISI, Psycinfo, Scopus, Web of Science ISI and Embase) were systematically searched for full-text articles published in English between 1946 and November 2014 using relevant search terms. Only randomized controlled trials investigating the effects of resistance training on muscle strength and physical function in people with Parkinson's disease were considered. The PEDro scale was used to assess study quality. Studies with similar outcomes were pooled by calculating standardized mean differences (SMD) using fixed or random effects model, depending on study heterogeneity. Seven studies, comprising of 401 participants with early to advanced disease (Hoehn & Yahr stage 1 to 4), were included. The median quality score was 6/10. The meta-analyses demonstrated significant SMD in favour of resistance training compared to non-resistance training or no intervention controls for muscle strength (0.61; 95% CI, 0.35 to 0.87; P <0.001), balance (0.36; 95% CI, 0.08 to 0.64; P = 0.01) and parkinsonian motor symptoms (0.48; 95% CI, 0.21 to 0.75; P < 0.001) but not for gait, balance confidence and quality of life. This review demonstrates that moderate intensity progressive resistance training, 2-3 times per week over 8-10 weeks can result in significant strength, balance and motor symptoms gains in people with early to moderate Parkinson's disease.


Epidemiology of insect-venom anaphylaxis.
Knowledge of the epidemiology, natural history and risk factors of insect-venom allergy is crucial for improving the clinical management of allergic patients. This review focuses on the recent research on these aspects of Hymenoptera-sting anaphylactic reactions. The latest data from population-based studies of anaphylactic reactions due to Hymenoptera stings, as well as those extrapolated from studies of epidemiology of anaphylaxis due to any cause are reviewed. The topic of biphasic anaphylactic reactions due to insect stings is also examined. Although no parameter has been identified that can predict which sensitized individuals will have a future anaphylactic reaction, several factors associated with the severity of a systemic resting reaction are known and emphasized here. As half of individuals with fatal sting reactions had no documented history of previous systemic reaction, we need to further improve the knowledge of the natural history and risk factors, especially in asymptomatic-sensitized individuals. Moreover, and no less important, the epidemiological studies on sting anaphylaxis conducted in the 2000s continue to reveal the poor management of allergic patients and the startling lack of awareness of the efficacy of venom immunotherapy. These findings indicate the urgent need to educate the general population and doctors on the management of venom-allergic patients.


Correlation between serum pro inflammatory cytokines and clinical scores of knee osteoarthritic patients using resveratrol as a supplementary therapy with meloxicam.
The objective of this study was to analyze the associations between the pro-inflammatory markers with the clinical outcomes of knee osteoarthritis (OA) in patients using resveratrol as an add-on treatment with meloxicam. This was a double-blind controlled clinical investigation, with 110 eligible patients with OA assigned randomly to receive 15 mg a day meloxicam with either resveratrol 500 mg a day or placebo for 90 days. The standard tools for assessment of pain severity and physical functions were utilized. The tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in the blood were evaluated. Spearman's correlation coefficient test was used to determine the significance of correlations. The regression analysis to determine the correlation between reductions of the inflammatory biomarkers with the amelioration of the clinical scores showed a nonsignificant weak correlation between these variables. Total clinical scores of each assessment tool that was used "Knee Injury and OA Outcome Score (KOOS) and WOMAC" displayed a weak and nonsignificant correlation with TNF-α, IL-1β blood level. The Spearman's correlation shows a relatively nonsignificant association between IL-6 levels and KOOS, WOMAC, and Visual Analog Scale scores after incorporating resveratrol as an adjuvant with meloxicam for 90 days. A weak and nonsignificant correlation between serum biomarkers and the clinical outcomes has been suggested in patients with painful knee OA treated with meloxicam and resveratrol.


Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes.
High-level expression of the telomerase reverse transcriptase (hTERT) in >85% of human cancers, in contrast with its restricted expression in normal adult tissues, points to hTERT as a broadly applicable molecular target for anticancer immunotherapy. CTLs recognize peptides derived from hTERT and kill hTERT+ tumor cells of multiple histologies in vitro. Moreover, because survival of hTERT+ tumor cells requires functionally active telomerase, hTERT mutation or loss as a means of escape may be incompatible with sustained tumor growth. A Phase I clinical trial was performed to evaluate the clinical and immunological impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTERT I540 peptide presented with keyhole limpet hemocyanin by ex vivo generated autologous dendritic cells. As measured by peptide/MHC tetramer, enzyme-linked immunospot, and cytotoxicity assays, hTERT-specific T lymphocytes were induced in 4 of 7 patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTERT peptide. Tetramer-guided high-speed sorting and polyclonal expansion achieved highly enriched populations of hTERT-specific cells that killed tumor cells in an MHC- restricted fashion. Despite concerns of telomerase activity in rare normal cells, no significant toxicity was observed. Partial tumor regression in 1 patient was associated with the induction of CD8+ tumor infiltrating lymphocytes. These results demonstrate the immunological feasibility of vaccinating patients against telomerase and provide rationale for targeting self-antigens with critical roles in oncogenesis.


Prolonged grief disorder prevalence in adults 65 years and over: a systematic review.
Prolonged grief disorder (PGD) is a recently recognised mental health disorder with an estimated prevalence of 10% in the bereaved adult population. This review aims to appraise and summarise evidence relating to PGD in older adults (≥65 years), a growing population group, most likely to experience bereavement and often assumed to cope well. Literature from Medline, PsycINFO, CINAHL, Cochrane Library and Web of Science was searched. Epidemiological and non-epidemiological studies including data on frequency of PGD in older adults bereaved by mainly natural causes were included and a descriptive analysis undertaken. From 2059 records, three epidemiological and six non-epidemiological studies were included. Most studies had good internal but not external validity. Conditional prevalence for PGD ranged between 3.2% and 48.8%. Heterogeneity in sample characteristics and study methodology contributed to this variability resulting in a descriptive analysis. The prevalence rate of 9.1% by Kersting et al was the best available estimate for PGD in older adults for western countries. The small number of epidemiological studies and the use of varying PGD-constructs which did not match International Classification of Diseases 11th Revision and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria were the main limiting factors. This first review on PGD prevalence in older adults suggests that, despite studies' methodological short comings, a similar proportion of older adults experience PGD as the general bereaved adult population (1:10). With older adults forming the largest subgroup among the bereaved, health and social care systems need to adapt their provision of care to address the specific needs of older adults.


Prevalence of aspects of distress, coping, support and care among adolescents and young adults undergoing and being off cancer treatment.
The overall aim is to describe the prevalence of physical and psychosocial distress, coping, support and care among adolescents and young adults who are both undergoing and off cancer treatment, and who find life satisfying or less satisfying. Prevalence of distress, coping, support and care were investigated using the Life Situation Scale for Adolescents (LSS-A) answered by 15 adolescents and young adults undergoing cancer treatment and 39 adolescents and young adults off cancer treatment. More adolescents and young adults receiving treatment reported problems with fatigue, eating, hair loss, taking medications/tablets and having to plan everything according to hospital visits than those adolescents and young adults off treatment. Fewer adolescents and young adults who reported finding life satisfying reported problems with fatigue, eating, not having any influence on their own life, often being sad and problems with school/work than those finding life less satisfying. Whether adolescents and young adults find life satisfying or not is not related to whether they are undergoing or off cancer treatment. The findings indicate the importance for those working with adolescent cancer victims to be alert of the fact that the treatment period is connected with more problems related to physical distress than the period after treatment, whereas aspects of psychosocial distress are as prevalent during the treatment period as they are after.


Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial.
To assess pregabalin monotherapy for partial-onset seizures using a historical-controlled conversion-to-monotherapy design. Adults with inadequately controlled partial-onset seizures while receiving 1 or 2 antiepileptic drugs during an 8-week prospective baseline were randomized to double-blind monotherapy with pregabalin 600 or 150 mg/d (4:1) for 20 weeks (8-week conversion and 12-week monotherapy period). The primary endpoint was the seizure-related exit rate for pregabalin 600 mg/d, based on discontinuations due to predefined criteria. Efficacy was declared if the upper limit of the 95% confidence interval for the exit rate was below a historical-control threshold of 74%, with stepwise evaluation using a threshold of 68%. The trial was stopped early for positive efficacy after an interim analysis in 125 patients. The full study population included 161 patients, with 148 evaluable for efficacy. The mean time since epilepsy diagnosis was 14 years. Overall, 54.3% (600 mg/d) and 46.9% (150 mg/d) of patients completed 20 weeks of double-blind treatment. Seizure-related exit rate in the 600 mg/d group (27.5%; 95% confidence interval, 17.8%-37.2%) was significantly below the 74% and 68% thresholds (p < 0.001 for both). Eight patients on 600 mg/d and 2 on 150 mg/d were seizure-free throughout pregabalin monotherapy. Pregabalin's overall safety profile was consistent with prior trials. Pregabalin monotherapy was safe and efficacious for patients with inadequately controlled partial-onset seizures. This study provides Class III evidence that patients with inadequately controlled partial-onset seizures switched to pregabalin monotherapy have fewer seizure-related exit events compared with historical controls switched to pseudo-placebo monotherapy.


[The long-term evaluation of artificial myoplastic anus and artificial classical anus based on manometric and radiological examinations].
The aim of this study was comparative evaluation of the pressure profile in the artificial myoplastic anus and the one created by the use of classical method. Radiological examinations of the colon by the use of the contrasting agent were performed in all patients in each group. In the group of patients with artificial myoplastic anus radiological examinations showed the narrowing of the lumen 4-7 cm in length in all patients. Above the narrowing the widening of the lumen was present. Reflexive flow of the contrasting agent from the colon was not present. In the group of patients with the artificial classical anus the narrowing of the terminal part of the colon was not noticed in the radiological examination. In all patients the reverse flow of the contrasting agent through the artificial anus was observed. Patients with the artificial myoplastic anus created by the use of pedunculated fold of the muscular coat of the colon have much higher average pressures around the myoplastic sphincter than in the presphincteric area, while the patients with the artificial classical anus did not present the area with the increased pressure in the terminal part of the colon. The possibility of preventing uncontrolled defecation and flatulence by the patients with the artificial myoplastic anus is related to the repeatedly higher pressures around the sphincter than in the presphincteric area, which do not decrease as the time passes by after the surgery.


Estrogen decreases chemokine levels in murine mammary tissue: implications for the regulatory role of MIP-1 alpha and MCP-1/JE in mammary tumor formation.
Estrogen contributes to the development of breast cancer through mechanisms that are not completely understood. Estrogen influences the function of immune effector cells, primarily through alterations in cytokine expression. Chemokines are proinflammatory cytokines that attract various immune cells to the site of tissue injury or inflammation, and activate many cell types, including T lymphocytes and monocytes. As an initial step toward ultimately determining whether regulation of chemokine expression and/or biological activity by estrogen could potentially be a contributing factor to the development and progression of mammary tumors, we evaluated the effect of estrogen on the expression of specific chemokines in murine mammary tissue. We also evaluated whether exposure of female mice to various chemokines could alter the growth of mammary tumors in the presence of estrogen. We report here that estrogen significantly decreases levels of the chemokines MIP-1alpha and MCP-1/JE in murine mammary tissue. Co-treatment with 4-hydroxytamoxifen partially reverses the suppressive effect of estrogen on MIP-1alpha levels. Estrogen increases the growth of CCL- 51 cell-based tumors in the mammary glands of female mice. Co-treatment with the chemokine MIP-1alpha or MCP- 1/JE substantially decreases the ability of estrogen to stimulate the formation of CCL-51 cell-based tumors. Our results show that estrogen might influence the bioactivity of specific chemokines through alteration of chemokine expression in mammary tissue, and further suggest that decreases in murine chemokines evoked by estrogen exposure could contribute to the promotion of mammary tumor growth.


The hematopoietic stem cell transplant comorbidity index can predict for 30-day readmission following autologous stem cell transplant for lymphoma and multiple myeloma.
Patients who undergo autologous stem cell transplant (ASCT) for hematologic malignancies frequently have multiple comorbidities. The hematopoietic cell transplantation comorbidity index (HCT-CI), a transplant-specific modification of the Charlson comorbidity index, can predict risk of readmission following allogeneic stem cell transplant. Its utility in the autologous setting is unknown. We evaluated 620 patients who underwent ASCT at the Ohio State University from 2007 to 2012 for lymphoma or multiple myeloma (MM) to identify factors associated with readmission. Univariable and multivariable logistic regression were used to estimate the odds of readmission within 30 days of discharge following ASCT. A Cox proportional hazards model was used to evaluate OS. Sixty-four patients were readmitted within 30 days; the most common indications were fever and prolonged gastrointestinal toxicity. MM compared with lymphoma (odds ratio (OR) 1.89, 95% confidence interval (95% CI): 1.06-3.38, P=0.03), HCT-CI⩾3 (OR 1.74, 95% CI: 1.03-2.96, P=0.04) and length of hospitalization ⩾28 days (OR 3.14, 95% CI: 1.26-7.83, P=0.01) remained significantly associated with 30-day readmission in a multivariable model. While the model had excellent fit (P>0.75), its ability to predict individual patients who would be readmitted was less than acceptable (receiver-operator curve=0.64, 95% CI: 0.57-0.71). In a multivariable proportional hazards model, 30-day readmission (hazards ratio (HR) 1.81, 95% CI: 1.04-3.18, P=0.04), length of hospitalization ⩾28 days (HR 4.93, 95% CI: 2.65-9.18, P<0.001) and chemorefractory disease (HR 3.08, 95% CI: 1.74-5.43, P<0.001) were independently associated with inferior OS, but HCT-CI was not. Evaluation of other assessment tools may allow better prediction of outcomes following ASCT.


Risk of Pancreatitis With Incretin Therapies Versus Thiazolidinediones in the Veterans Health Administration.
Incretin therapies, comprised of the dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have been increasingly utilized for the treatment of type 2 diabetes (T2DM). Previous studies have conflicting results regarding risk of pancreatitis associated with these agents-some suggest an increased risk and others find no correlation. Adverse event reporting systems indicate that incretin therapies are some of the most common drugs associated with reports of pancreatitis. This study aimed to compare the odds of developing pancreatitis in veterans with T2DM prescribed an incretin therapy versus thiazolidinediones (TZDs: pioglitazone and rosiglitazone) within the Veterans Health Administration (VHA). This was a retrospective cohort study analyzing veterans with T2DM first prescribed an incretin therapy or a TZD between January 1, 2011, and December 31, 2021. A diagnosis of pancreatitis within 365 days of being prescribed either therapy was counted as a positive case. Data was collected and analyzed utilizing VA's Informatics and Computing Infrastructure (VINCI) and an adjusted odds ratio was calculated. The TZD cohort consisted of 42 912 patients compared with the incretin cohort of 304 811 patients. The TZD cohort had a pancreatitis incidence rate of 1.94 cases per 1000 patients. The incretin cohort had a incidence rate of 2.06 cases per 1000 patients. An adjusted odds ratio found no statistical difference of pancreatitis cases between the TZD and incretin cohorts (adjusted odds ratio [AOR] = 0.94, 95% CI [0.75, 1.18]). This retrospective cohort study of national VHA data found a relatively low incidence of pancreatitis in both cohorts, and an adjusted odds ratio found no statistical difference of pancreatitis in patients prescribed an incretin therapy compared with a control group. This data adds to growing evidence that incretin therapies do not seem to be associated with an increased risk of developing pancreatitis.


A rare cause of acute ST-elevation myocardial infarction: case report of native aortic valve thrombosis.
One to 13% of all patients with the clinical diagnosis of an acute coronary syndrome (ACS) show no evidence of significant obstructive coronary artery disease on angiography. Less common causes should be considered in those situations. A very rare cause of ACS is native aortic valve thrombosis. A 69-year-old previously healthy woman presented with acute chest pain. The electrocardiogram showed an anterolateral ST-elevation myocardial infarction (STEMI). She was immediately transferred for primary percutaneous coronary intervention. Shortly after arriving in hospital her condition deteriorated, with development of cardiogenic shock necessitating cardiopulmonary resuscitation. A coronary angiogram was performed during resuscitation that did not reveal any obstructive coronary artery disease. Echocardiography showed no pericardial effusion, no significant left-sided valve pathology, no signs of an aortic dissection or pulmonary embolism. She died of cardiogenic shock of unknown cause. Permission for autopsy was obtained. Pathologic examination revealed a large anterolateral myocardial infarction caused by a mass attached to the bottom of the left coronary cusp of the native aortic valve, which was large enough to occlude the ostium of the left main coronary artery. Microscopic analysis showed a thrombus of unknown origin. The aortic valve itself showed no signs of pathology. An ST-elevation myocardial infarction due to native aortic valve thrombosis is a rare condition, especially when there are no significant valvular abnormalities. This case demonstrates that thrombosis can develop in an apparently healthy middle-aged woman without any history of thrombotic disease.


Does postdural puncture headache left untreated lead to subdural hematoma? Case report and review of the literature.
The patient was a 39-year-old pregnant woman who was scheduled for cesarean section. Spinal anesthesia was induced using a 26-gauge needle with an atraumatic bevel. Postoperatively, the patient developed cranial subdural hematoma manifesting as severe non-postural headache, associated with right eye tearing, fifth cranial nerve palsy and left hemiparesis. The diagnosis was confirmed by computed tomography scan. The patient was managed by careful neurological follow-up associated with conservative treatment and recovered fully after 12 weeks. Our report reviews the literature on 46 patients who developed a postdural puncture headache complicated by subdural hematoma following spinal or epidural anesthesia. It is possible that postdural puncture headache left untreated may be complicated by the development of subdural hematoma. Patients developing a postdural puncture headache unrelieved by conservative measures, as well as the change from postural to non-postural, require careful follow-up for early diagnosis and management of possible subdural hematoma.


Comparative Evaluation of Corneal Storage Medias Used as Tooth Avulsion Medias in Maintaining the Viability of Periodontal Ligament Cells Using the Cell Counting Kit-8 Assay.
The prime factor in determining the success of reimplantation of an avulsed tooth is the maintenance of the viability of periodontal ligament fibroblast cells (PDFC). This study aims to evaluate and compare Mc Carey Kaufman media (MK), Cornisol, Dulbecco's Modified Eagles Medium (DMEM), Hanks Balanced Salt Solution (HBSS) and distilled water in preserving the viability of the PDFC using the Cell Counting Kit-8 assay (CCK-8). Cryopreserved PDFC were suspended in DMEM and incubated in CO2 incubator at 370C with 95% humidity and 5% CO2 for attachment. Once cells attained 80% confluence, they were trypsinised and passed into T-25 culture flasks to expand the culture population. Cells from passage 5 were pooled for experimentation. Trypan blue exclusion test was performed before each experiment to measure cell viability and batches showing more than 95% viability were used in the experiment. The viable PDFC with 1×105 were seeded in 96 well plates and incubated in CO2 incubator at 370C, 95% humidity and 5% CO2 for 24 hours to allow cell attachment. A 100µL of the experimental media were added in the wells and the cells were exposed for 1, 24 and 48 hours respectively. The viability was determined using the CCK-8. Experiment was performed in triplicates and data was subjected to statistical analysis. Statistical analysis was performed using repeated measure ANOVA, ANOVA, and post-hoc Bonferroni test with the significance level p<0.05. The values are as follows: MK (1.3146 ±0.0588, 1.9012±0.0511, 2.0723±0.1211) > Cornisol (1.2399±0.0548, 1.9596±0.0652, 1.9592±0.1361) >DMEM (1.1914±0.0691, 1.8479±0.0116, 2.0718±0.0795) > HBSS (0.3665±0.0814, 0.0184±0.0010, 0.0248±0.0042) >distilled water (0.0122±0.0033, 0.0225±0.0085, 0.0104±0.0008) at 1 hour, 24 hours and 48 hours respectively. MK >Cornisol>DMEM>HBSS>distilled water. It can be concluded that the corneal preservation solutions showed promising results in preserving periodontal ligament cell viability for extended time periods.


Targeted epigenetic silencing of UCHL1 expression suppresses collagen-1 production in human lung epithelial cells.
Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is highly expressed in smokers, but little is known about the molecular mechanism of UCHL1 in airway epithelium and its possible role in affecting extracellular matrix (ECM) remodelling in the underlying submucosa. Since cigarette smoking is a major cause of lung diseases, we studied its effect on UCHL1 expression and DNA methylation patterns in human bronchial epithelial cells, obtained after laser capture micro-dissection (LCM) or isolated from residual tracheal/main stem bronchial tissue. Targeted regulation of UCHL1 expression via CRISPR/dCas9 based-epigenetic editing was used to explore the function of UCHL1 in lung epithelium. Our results show that cigarette smoke extract (CSE) stimulated the expression of UCHL1 in vitro. The methylation status of the UCHL1 gene was negatively associated with UCHL1 transcription in LCM-obtained airway epithelium at specific sites. Treatment with a UCHL1 inhibitor showed that the TGF-β1-induced upregulation of the ECM gene COL1A1 can be prevented by the inhibition of UCHL1 activity in cell lines. Furthermore, upon downregulation of UCHL1 by epigenetic editing using CRISPR/dCas-EZH2, mRNA expression of COL1A1 and fibronectin was reduced. In conclusion, we confirmed higher UCHL1 expression in current smokers compared to non- and ex-smokers, and induced downregulation of UCHL1 by epigenetic editing. The subsequent repression of genes encoding ECM proteins suggest a role for UCHL1 as a therapeutic target in fibrosis-related disease.


Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study.
Current definitions for the preclinical phase of dementia focus predominantly on cognitive measures, with particular emphasis on memory and the prediction of Alzheimer's disease. Incorporation of non-cognitive, clinical markers into preclinical definitions may improve their predictive power. The Sydney Older Persons Study examined 6-year outcomes of 630 community-dwelling participants aged 75 or over at recruitment. At baseline, participants were defined as demented, cognitively intact or having a syndrome possibly representing the preclinical phase of Alzheimer's disease, vascular dementia, an extrapyramidal dementia or various combinations of the three. Those with cognitive impairment in combination with gait and motor slowing were the most likely to dement over the 6-year period (OR 5.6; 95% CI 2.5-12.6). This group was also the most likely to die (OR 3.3; 95% CI 1.6-6.9). White matter indices on MRI scanning were not consistently correlated with gait abnormalities. Simple measures of gait may provide useful clinical tools, assisting in the prediction of dementia. However, the underlying nature of these deficits is not yet known.


Hepatitis C virus JFH-1 strain infection in chimpanzees is associated with low pathogenicity and emergence of an adaptive mutation.
The identification of the hepatitis C virus (HCV) strain JFH-1 enabled the successful development of infectious cell culture systems. Although this strain replicates efficiently and produces infectious virus in cell culture, the replication capacity and pathogenesis in vivo are still undefined. To assess the in vivo phenotype of the JFH-1 virus, cell culture-generated JFH-1 virus (JFH-1cc) and patient serum from which JFH-1 was isolated were inoculated into chimpanzees. Both animals became HCV RNA-positive 3 days after inoculation but showed low-level viremia and no evidence of hepatitis. HCV viremia persisted 8 and 34 weeks in JFH-1cc and patient serum-infected chimpanzees, respectively. Immunological analysis revealed that HCV-specific immune responses were similarly induced in both animals. Sequencing of HCV at various times of infection indicated more substitutions in the patient serum-inoculated chimpanzee, and the higher level of sequence variations seemed to be associated with a prolonged infection in this animal. A common mutation G838R in the NS2 region emerged early in both chimpanzees. This mutation enhances viral assembly, leading to an increase in viral production in transfected or infected cells. Our study shows that the HCV JFH-1 strain causes attenuated infection and low pathogenicity in chimpanzees and is capable of adapting in vivo with a unique mutation conferring an enhanced replicative phenotype.


Passive Tick Surveillance: Exploring Spatiotemporal Associations of Borrelia burgdorferi (Spirochaetales: Spirochaetaceae), Babesia microti (Piroplasmida: Babesiidae), and Anaplasma phagocytophilum (Rickettsiales: Anaplasmataceae) Infection in Ixodes scapularis (Acari: Ixodidae).
Ixodes scapularis transmits a group of pathogens, including Borrelia burgdorferi, Babesia microti, and Anaplasma phagocytophilum, the causative agents for Lyme disease, babesiosis, and anaplasmosis, respectively. I. scapularis ticks submitted by state residents to the Connecticut Agricultural Experiment Station-Tick Testing Laboratory between 2015 and 2018 were screened using standard PCR and pathogen-specific primers. Infection and coinfection prevalence in I. scapularis was estimated to assess differences in infection status by life stage (nymph or adult female), county, and year, as well as whether infection with B. burgdorferi changes the likelihood of infection with either B. microti or A. phagocytophilum. Of the 11,254 I. scapularis acquired in Connecticut, 40.7% tested positive for at least one pathogen and the remaining 59.3% were negative. Most I. scapularis ticks tested positive for a single pathogen (33.6%), and only 7.2% were infected with more than one pathogen, of which 93.2% were identified with dual infection and 6.8% tested positive for all three pathogens. Adults were more likely than nymphs to be infected or coinfected with these pathogens. Furthermore, we found that ticks were 74% more likely to be infected with B. microti and 98% more likely to be infected with A. phagocytophilum if infected with B. burgdorferi compared with those not infected. We did not find spatial differences in infection or coinfection prevalence, but between 2015 and 2018, the likelihood that a tick was coinfected increased with time. These results from Connecticut, an endemic state for Lyme disease with long-established populations of I. scapularis, suggest that the increased likelihood of coinfection prevalence over time may have significant implications for clinical diagnosis, course, severity, and treatment of human disease cases.


Molecular genetic alterations in superficial and locally advanced human bladder cancer.
We attempted to define the role of tumor suppressor genes in the pathogenesis of human bladder cancer through a combined molecular genetic and immunohistochemical approach. Thirty-four bladder tumors (1 Pis, 6 Pa, 5 P1, 3 P3a, 18 P3b, 1 P4; 8 low grade and 26 high grade tumors) have been analyzed. Restriction fragment length polymorphism analysis directed at 5 suspected or established tumor suppressor gene regions (3p21-25, 11p15, 13q14, 17p11-13, and 18q21) was combined with immunohistochemical using Rb-PMG3-245 monoclonal antibody directed at the retinoblastoma (Rb) gene product. Tumor grade correlated with deletions of 3p (P = 0.004) and 17p (P = 0.063). Tumor stage correlated with deletions of 3p (P = 0.010), 17p (P = 0.015) and altered Rb expression (P = 0.054). Vascular invasion correlated only with deletions of 17p (P = 0.038). No marker correlated with positive lymph nodes. Our results suggest that altered Rb expression occurs in all grades and stages of bladder cancer but is more commonly associated with invasive tumors. Genetic alterations of 3p, 11p, 17p, and 18q are rare events in low grade, superficial tumors, whereas they are more common in high grade and invasive bladder cancer. The role of these genetic alterations in the prognosis of bladder cancer will require additional follow-up and further studies.


Adaptation of the schupmann medial telescope to a large scale astronomical optical system.
The classical Schupmann medial telescope is free of the secondary-spectrum residual associated with large refractors. The difficulties in obtaining large glass disks of the necessary optical quality and the problem associated with their mounting preclude the use of this unconventional lens in large scale astronomical systems. However, to circumvent these limitations, the Schupmann lens was modified by replacing the refractive objective with a spherical mirror producing a new catadioptric lens configuration adaptable to large-scale astronomy. The design parameters and performance data are given for an f/5.4, 5.5-m focal length design covering a 2 degrees full field.


Significant reduction of patellar height affected lower clinical outcomes and knee flexion over five-year follow-up after total knee arthroplasty.
This study aimed to investigate the relationship between changes in patellar height and clinical outcomes at a mean follow-up of 7.7 years (5 to 10) after fixed-bearing posterior-stabilized total knee arthroplasty (PS-TKA). We retrospectively evaluated knee radiographs of 165 knees, which underwent fixed-bearing PS-TKA with patella resurfacing. The incidence of patella baja and changes in patellar height over a minimum of five years of follow-up were determined using Insall-Salvati ratio (ISR) measurement. We examined whether patella baja (ISR < 0.8) at final follow-up affected clinical outcomes, knee joint range of motion (ROM), and Knee Society Score (KSS). We also assessed inter- and intrarater reliability of ISR measurements and focused on the relationship between patellar height reduction beyond measurement error and clinical outcomes. The ISR gradually decreased over five years after TKA, and finally 33 patients (20.0%) had patella baja. Patella baja at the final follow-up was not related to passive knee ROM or KSS. Interestingly, when we divided into two groups - patella baja and patella normal-alta (ISR ≥ 0.8) - the patella baja group already had a lower patellar height before surgery, compared with the patella normal-alta group. The ISR measurement error in this study was 0.17. Both passive knee flexion and KSS were significantly decreased in the group with a decrease in ISR of ≥ 0.17 at final follow-up. Patellar height gradually decreased over five years of follow-up after TKA. The reduction in patellar height beyond measurement error following TKA was associated with lower clinical outcomes. Cite this article: Bone Jt Open 2021;2(12):1075-1081.


Physical activity in long-term breast cancer survivors - A mixed-methods approach.
Traditional methods measuring physical activity (PA) may misrepresent breast cancer survivors (BCSs) and low-socioeconomic status (SES) groups. This study identifies PA-levels, routines and experiences among BCSs, in general and by SES, and explores whether a mixed-methods approach might unveil diversities of PA in BCS across SES. 250 BCSs referred to postoperative radiation therapy in 2007-2008 participated in a longitudinal follow-up study examining health-related quality-of-life and late-effects. Subsample-data on SES and PA were collected by questionnaires (n = 52), activity-logs (n = 52) and interviews (n = 37). Parallel mixed analyses were conducted, in combination with sequential, full-sample analyses of questionnaires and contrasting case analyses of logs and interviews. Dependent on which measurement used, 23%, 35%, 54% and 63% of BCSs met PA guidelines. Questionnaire-data revealed no significant differences in PA levels between SES groups. Log-data showed more PA bouts in high-SES BCSs, but no difference in min/week across SES. Neighbourhood walking was preferred, while scheduled exercise was rare. Interview-data added that PA was medicating, normatively described and accompanied by unfulfilled ambitions, particularly in low-SES BCSs. Balancing duties and activities was demanding. PA constraints were similar across groups. Domestic PA was important in low-SES, while high-SES BCSs described more energy. Although PA levels among BCSs were similar across SES and equal to PA in the general population, SES differences became evident when measured by activity-logs and as stated in interviews. Future follow-up programs for BCSs could benefit from expanding the PA perspectives, thus better meet the needs of different SES groups.


[Prognostic values of oestradiol/oocyte rate in ICSI patients].
To analyze the pregnancy rate in women who underwent Intracytoplasmic Sperm Injection (ICSI) program depending of the oestradiol/oocyte index. Retrospective, comparative. 332 patients were included. There were divided in three groups depending on the oestradiol/oocyte index: Group A:(100 pg/mL, group B: 101-250 pg/mL and group C: > 250 pg/mL). Therapeutic protocol. Down regulation with leuprolide acetate in late luteal phase protocol, COH with rec-FSH and / or HMG, ultrasonographic and estradiol blood levels were monitored; hCG application when > 3 follicles > 18 mm, oocyte retrieval performed 34 hours later. We analyzed: patient age, male age, number of follicles, estradiol serum levels at the day of hCG application, number of mature oocytes, oestradiol/oocyte index, fertilization rate, transferred embryos, transfer quality, catheter type and luteal support. Statistical analysis (SPSS 11) with chi square, ANOVA and Kruskall-Wallis was used. On having analyzed the number of metaphase II oocytes retrieval, oocytes fertilized and number of transferred embryos among three groups, the best results were obtained in group B. The differences among these variables were significant. (P = 0.014, p = 0.005 and p = 0.003, respectively). When the oestradiol/oocyte index was analyzed and the PR among groups (21.83, 36.62 and 17.80 %) we observed a significant difference (p = 0.003). It is convenient to monitor the oestradiol blood levels to offer schemes of COH less aggressive to improve the oocyte quality. The oestradiol/oocyte index is a parameter adapted as a predictive value of pregnancy.


Outcome of Kienböck's disease 22 years after distal radius shortening osteotomy.
Loading of the lunate in patients with Kienböck's disease and a negative ulnar variance provide the rationale for a radial shortening osteotomy. This osteotomy decreases forces transmitted from the radius to the lunate. We retrospectively reviewed 12 patients with Kienböck's disease who had 13 radial shortening osteotomies to ascertain whether the reported short- and medium-term results endured in the long-term. We evaluated nine osteotomies in nine of the 12 patients with a minimum of 16 years followup (average, 22 years; range, 16-31 years). Three patients died and one was lost to followup. For the nine patients, the range of motion was impaired compared with the normal side. Grip strength was on average 90% of the unaffected side. The average visual analog scale score for pain was 2.4 and the average Disabilities of the Arm, Shoulder, and Hand score was 14 at latest followup. In eight patients, the Lichtman classification of Kienböck's disease did not change at followup, but in three patients there was radiographic progression of the disease, which occurred during the first 10 years postoperatively. The medium- and long-term results therefore were comparable. We recommend radial shortening in stable wrists (Stage 3A or less) with a negative ulnar variance. The radius should be shortened to the level of the ulna, normally 4 to 6 mm, after which stable (plate) fixation should be performed under compression.


Genetic basis of tooth agenesis.
Tooth agenesis or hypodontia, failure to develop all normally developing teeth, is one of the most common developmental anomalies in man. Common forms, including third molar agenesis and hypodontia of one or more of the incisors and premolars, constitute the great majority of cases. They typically affect those teeth that develop latest in each tooth class and these teeth are also most commonly affected in more severe and rare types of tooth agenesis. Specific vulnerability of the last developing teeth suggests that agenesis reflects quantitative defects during dental development. So far molecular genetics has revealed the genetic background of only rare forms of tooth agenesis. Mutations in MSX1, PAX9, AXIN2 and EDA have been identified in familial severe agenesis (oligodontia) and mutations in many other genes have been identified in syndromes in which tooth agenesis is a regular feature. Heterozygous loss of function mutations in many genes reduce the gene dose, whereas e.g. in hypohidrotic ectodermal dysplasia (EDA) the complete inactivation of the partially redundant signaling pathway reduces the signaling centers. Although these mechanisms involve quantitative disturbances, the phenotypes associated with mutations in different genes indicate that in addition to an overall reduction of odontogenic potential, tooth class-specific and more complex mechanisms are also involved. Although several of the genes so far identified in rare forms of tooth agenesis are being studied as candidate genes of common third molar agenesis and incisor and premolar hypodontia, it is plausible that novel genes that contribute to these phenotypes will also become identified.


Perspectives on the treatment of sequelae after cancer: protocol of an interview study of primary care physiotherapists.
An increasing number of patients are living with fatigue, pain and other sequelae after cancer. About 30% of these patients express a need for physical rehabilitation and patients prefer to be involved in medical decision-making. This includes being offered individualised treatment with patient-defined goals and education during all aspects of treatment by physiotherapists with empathic skills. However, physiotherapists are often unaware of the relationship between cancer and its presenting symptoms. This can lead to inappropriate care and unrealistic goalsetting for rehabilitation. This calls for greater attention towards physiotherapist's treatment and their current perspectives on how treatment can be improved in physiotherapy clinics. The aim of this study is to explore physiotherapists perspectives on barriers, facilitators and potential solutions to improve the care of sequelae after cancer in physiotherapy clinics. This is a qualitative interview study using individual semistructured interviews with physiotherapists using a phenomenological approach to explore their lifeworld at work. We will recruit physiotherapists working in private clinics based on a variation in gender and years of working experience in private clinics. We will conduct between 10 and 16 interviews online via Microsoft Teams and thematically analyse data supported by NVivo software. Interviewing is scheduled to take place from April 2022. This is a non-intervention and qualitative study, and the local Ethics Committee in the North Denmark Region has stated that their approval is not needed. Informants will provide a written informed consent. Study information will be sent to the informant at least 3 days prior to the interview session and information will be summarised by the interviewer before the interview.Aside from publication, results will be disseminated by two teaching institutions, a regional health care provider and DEFACTUM (a public Danish research institution focusing on increasing social equality in health).


Improvements in health-related quality of life over 3 years with liraglutide 3.0 mg compared with placebo in participants with overweight or obesity.
Previously in the SCALE Obesity and Prediabetes trial, at 1 year, participants with obesity (or overweight with comorbidities) and prediabetes receiving liraglutide 3.0 mg experienced greater improvements in health-related quality of life (HRQoL) than those receiving placebo. The current study extends these findings by examining 3-year changes in HRQoL. HRQoL was assessed using the obesity-specific Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire, as well as the Short-Form 36 v2 (SF-36) health survey. At 3 years, mean change (±standard deviation) in IWQOL-Lite total score from baseline for liraglutide (n = 1472) was 11.0 ± 14.2, vs. 8.1 ± 14.7 for placebo (n = 738) (estimated treatment difference [ETD] 3.4 [95% confidence interval (CI): 2.0, 4.7], P < 0.0001). Mean change in SF-36 physical component summary (PCS) score from baseline for liraglutide was 3.1 ± 7.3, vs. 2.6 ± 7.6 for placebo (ETD 0.87 [95% CI: 0.17, 1.6], P = 0.0156). Mean change in SF-36 mental component summary score did not significantly differ between groups. Both IWQOL-Lite total score and PCS score demonstrated an association between greater HRQoL improvement with higher weight loss. Liraglutide 3.0 mg was also associated with improved health utility (Short-Form-6D and EuroQol-5D, mapped from IWQOL-Lite and/or SF-36) vs. placebo. Liraglutide 3.0 mg, plus diet and exercise, is associated with long-term improvements in HRQoL with obesity or overweight with comorbidity vs. placebo.


Preventive Benefits of U.S. Childcare Subsidies in Supervisory Child Neglect.
Using data from age 3 of the Fragile Families and Child Wellbeing Study, the current study explores the complex relationships between U.S. child care subsidies and neglect. Specifically, the study examines two research questions: (1) Are U.S. child care subsidies associated with self-reported neglect among low-income mothers? (2) What individual types of self-reported neglect are significantly reduced by receipt of child care subsidy? Using negative binomial regression examining the relationships among mothers who were income-eligible for child care subsidy, we found that child care subsidy was associated with lower levels of supervisory neglect, indicating an important role of subsidy in the lives of low-income families.


The melanoma proteoglycan: restricted expression on microspikes, a specific microdomain of the cell surface.
A cell surface chondroitin sulfate proteoglycan associated with human melanomas and defined by mAb's F24.47 and 48.7 has been characterized biochemically and localized by indirect immunogold electron microscopy. These antibodies recognize distinct epitopes on the intact proteoglycan. In addition, mAb 48.7 also recognizes an epitope on a 250,000-D glycoprotein and is therefore similar to antibody 9.2.27 (described by Bumol, T.F., and R.A. Reisfeld, 1982, Proc. Natl. Acad. Sci. USA., 79:1245-1249). Furthermore, it was shown that the glycosaminoglycan chains released by alkaline borohydride treatment of the proteoglycan recognized by mAb 48.7 had a size of approximately 60,000 D. Since the intact proteoglycan was estimated to be 420,000 D, there are probably three chondroitin sulfate chains attached to the 250,000-D core glycoprotein. Furthermore, an oligosaccharide fraction containing 42% of the 3H activity (glucosamine as precursor) was isolated. Immunolocalization studies using whole-mount electron microscopy revealed that the chondroitin sulfate proteoglycan was present almost exclusively on microspikes, a microdomain of the melanoma cell surface. These processes were present as 1-2-micron structures on the upper cell surface and as longer (up to 20 micron) structures at the cell periphery. Peripheral microspikes were involved in the initial interactions between adjacent cells and formed complex footpads that made contact with the substratum. Immunogold-labeled cells were also thin sectioned and the specific localization of the chondroitin sulfate proteoglycan antigen was quantitated. The data confirmed the results of whole-mount microscopy and demonstrated a statistically significant association of the antigen with the microspike processes as compared with other areas of the cell surface. By using two different mAb's (48.7 and F24.47) that recognize epitopes on either the core glycoprotein or the intact proteoglycan, respectively, we have demonstrated that both molecules have the same restricted distribution at the cell surface. The specific localization of the antigen to microspikes at the cell surface suggests it may play a role in cell-cell contact and cell-substratum adhesion, which could be important in the metastatic process.


Study of metabolite differences of flue-cured tobacco from different regions using a pseudotargeted gas chromatography with mass spectrometry selected-ion monitoring method.
A pseudotargeted method based on gas chromatography and mass spectrometry with selected-ion monitoring was established to investigate the metabolite differences of flue-cured tobacco from three different growing regions. The mixed solvent of acetonitrile/isopropanol/water (3:3:2, v/v/v) was chosen as the optimal extraction system based on the good repeatability and extraction efficiency. A self-developed software coupled with commercial software was used to establish the pseudotargeted method including 289 peaks and 47 groups. Multivariable statistical analysis indicated that tobacco samples can be obviously separated based on the geographical origins. On the basis of a Mann-Whitney U test, organic acids, phenols, and alkaloids had higher levels in Hunan province. In contrast, a large proportion of amino acids (including L-tyrosine, L-proline, and serine), sucrose, and linoleic acid were the highest in Yunnan province. Meanwhile, multiple metabolic pathways (including carbohydrate metabolism, tricarboxylic acid cycle, and nitrogen metabolism) were influenced by growing regions. Twenty-eight differential metabolites, which had great contributions to the classification of tobacco samples of three growing regions, were further defined. The results demonstrated that the developed pseudotargeted method was a powerful tool to investigate the metabolic profiling of tobacco leaves and discriminate tobacco leaves of different growing regions.


An acquired hemorrhagic disorder from long-acting rodenticide ingestion.
A 62-year-old man who presented with gross hematuria was found to have a severe and prolonged coagulopathy. The workup involved mixing studies, which suggested an acquired factor deficiency, and specific factor assays, which demonstrated isolated defects in vitamin K-dependent factors. With vitamin K deficiency excluded, and serum warfarin levels undetectable, so-called superwarfarin ingestion was suspected. This diagnosis was subsequently proved by biochemical evidence (an increase in the serum vitamin K epoxide-vitamin K ratio) and compatible history. This case illustrates how a logical workup can lead to a diagnosis of superwarfarin ingestion, even without a history of such an ingestion. New serum assays for specific superwarfarins are also mentioned. This case report should increase clinicians' awareness of long-acting rodenticide ingestions.


Anticonvulsant drug use and low bone mass in adults with neurodevelopmental disorders.
Use of anticonvulsant drugs among adults with neurodevelopmental disorders may be an important risk factor for both osteoporosis and skeletal fractures. To determine the relationship between anticonvulsant drug use and both low bone mass and bone fractures in such adults. Cross-sectional study of 273 adults with neurodevelopmental disorders, 40% of whom were receiving one or more anticonvulsant drugs. Single Canadian long-term care facility. Demographic data were abstracted from each resident's chart in a standardized manner, including body mass, degree of mobility, major falls within the previous 12 months, and all medications. Quantitative calcaneal ultrasonography was performed on each resident without knowledge of their current drug use. The Quantitative Ultrasound Index was employed to express 'bone stiffness'. Low bone mass was defined as a T-score 2.5 SDs below the norm for young healthy adults. Compared to non-users (15.5%), low bone mass was more prevalent among those taking either one (20.3%; OR 1.7, 95%CI 0.6-4.4) or two or more anticonvulsant agents (42.2%, OR 5.9, 95%CI 2.2-16.2). The risk of recent skeletal fractures was not significantly greater in those taking a single anticonvulsant than in non-users (28.6% vs. 21.6%; OR 1.0, 95%CI 0.4-2.8), but tended to be higher in those taking two or more (48.7%; OR 2.2, 95%CI 0.8-5.9). Adults with neurodevelopmental disorders residing in a long-term care facility have a high rate of both low bone mass and skeletal fractures, especially with concomitant use of anticonvulsant drugs. These individuals should be assessed for the presence of low bone mass, and may warrant prophylactic treatment against bone loss, including calcium and vitamin D supplementation.


The amino-terminal domain of ELL transcription elongation factor is essential for ELL function in Schizosaccharomyces pombe.
Transcriptional elongation is a critical step for regulating expression of protein-coding genes. Multiple transcription elongation factors have been identified in vitro, but the physiological roles of many of them are still not clearly understood. The ELL (Eleven nineteen Lysine rich Leukemia) family of transcription elongation factors are conserved from fission yeast to humans. Schizosaccharomyces pombe contains a single ELL homolog (SpELL) that is not essential for its survival. Therefore to gain insights into the in vivo cellular functions of SpELL, we identified phenotypes associated with deletion of ell1 in S. pombe. Our results demonstrate that SpELL is required for normal growth of S. pombe cells. Furthermore, cells lacking ell1+ exhibit a decrease in survival when exposed to DNA-damaging conditions, but their growth is not affected under environmental stress conditions. ELL orthologs in different organisms contain three conserved domains, an amino-terminal domain, a middle domain and a carboxyl-terminal domain. We also carried out an in vivo functional mapping of these conserved domains within S. pombe ELL and uncovered a critical role for its amino-terminus in regulating all its cellular functions, including growth under different conditions, transcriptional elongation potential and interaction with S. pombe EAF. Taken together our results suggest that the domain organization of ELL proteins is conserved across species, but the in vivo functions as well as the relationship between the various domains and roles of ELL show species-specific differences.


Chewing gum decreases energy intake at lunch following a controlled breakfast.
The impact of chewing gum on fasting appetite or meal intake has not been studied. We tested the hypothesis that chewing gum would decrease lunch intake after a controlled breakfast, and reduce hunger in fasting and fed states. Seventeen males and sixteen females (21.4 ± 6.3y, BMI 23.8 ± 2.7 kg/m2) participated in a randomized crossover study in which subjects chewed sugar-free gum a total of 1 h on the test day (GC), and did not chew gum on a control day (NG). The 1 h of gum chewing included 20 min while fasting, and two 20-min sessions between breakfast and lunch. Subjects rated their appetite and mood on visual analog scales. After completing the fasting measures, subjects consumed a breakfast shake containing 30% of their measured resting energy expenditure. Three hours later they consumed an ad libitum lunch with water. Fasting ratings of hunger were lower in GC than NG (t = 2.66, p = 0.01). Subjects consumed significantly less pasta (41 g, 68 kcals, t = 2.32, p = 0.03) during GC than NG. In conclusion, gum chewing decreased fasting hunger ratings and lunch energy consumed. Chewing gum may be a useful tool impacting energy balance in this population. Longer studies, especially in other populations, will be required.


Melatonin treatment against remote organ injury induced by renal ischemia reperfusion injury in diabetes mellitus.
Oxidative stress may have a role in liver damage after acute renal injury due to various reasons such as ischemia reperfusion (IR). Diabetes mellitus (DM) is an important disease for kidneys and may cause nephropathy as a long term complication. The aim of this study was to investigate protective effect of melatonin, a potent antioxidant, against distant organ injury on liver induced by renal IR in rats with or without DM. The rats were divided into six groups: control (n=7), DM (n=5), IR (n=7), DM+IR (n=7), melatonin+IR (Mel+IR) (melatonin, 4 mg/ kg during 15 days) (n=7), and Mel+DM+IR groups (n=7). Diabetes developed 3 days after single i.p. dose of 45 mg/kg streptozotocin. After 15 day, the left renal artery was occluded for 30 min followed 24 h of reperfusion in IR performed groups. DM did not alter oxidative parameters alone in liver tissue. The levels of malondialdehyde, protein carbonyl and nitric oxide with activities of xanthine oxidase and myeloperoxidase were increased in liver tissues of diabetic and non-diabetic IR groups. Nitric oxide level in DM was higher than control. The activities of catalase and superoxide dismutase were increased in IR groups in comparison with control and DM. ALT and AST levels were higher in IR and DM+IR groups than control and DM. Melatonin treatment reversed all these oxidant and antioxidant parameters to control values as well as serum liver enzymes. We concluded that renal IR may affect distant organs such as liver and oxidative stress may play role on this injury, but DM has not an effect on kidney induced distant organ injury via oxidant stress. Also, it was concluded that melatonin treatment may prevent liver oxidant stress induced by distant injury of kidney IR.


Diverse roles for HspR in Campylobacter jejuni revealed by the proteome, transcriptome and phenotypic characterization of an hspR mutant.
Campylobacter jejuni is a leading cause of bacterial gastroenteritis in the developed world. The role of a homologue of the negative transcriptional regulatory protein HspR, which in other organisms participates in the control of the heat-shock response, was investigated. Following inactivation of hspR in C. jejuni, members of the HspR regulon were identified by DNA microarray transcript profiling. In agreement with the predicted role of HspR as a negative regulator of genes involved in the heat-shock response, it was observed that the transcript amounts of 13 genes were increased in the hspR mutant, including the chaperone genes dnaK, grpE and clpB, and a gene encoding the heat-shock regulator HrcA. Proteomic analysis also revealed increased synthesis of the heat-shock proteins DnaK, GrpE, GroEL and GroES in the absence of HspR. The altered expression of chaperones was accompanied by heat sensitivity, as the hspR mutant was unable to form colonies at 44 degrees C. Surprisingly, transcriptome analysis also revealed a group of 17 genes with lower transcript levels in the hspR mutant. Of these, eight were predicted to be involved in the formation of the flagella apparatus, and the decreased expression is likely to be responsible for the reduced motility and ability to autoagglutinate that was observed for hspR mutant cells. Electron micrographs showed that mutant cells were spiral-shaped and carried intact flagella, but were elongated compared to wild-type cells. The inactivation of hspR also reduced the ability of Campylobacter to adhere to and invade human epithelial INT-407 cells in vitro, possibly as a consequence of the reduced motility or lower expression of the flagellar export apparatus in hspR mutant cells. It was concluded that, in C. jejuni, HspR influences the expression of several genes that are likely to have an impact on the ability of the bacterium to successfully survive in food products and subsequently infect the consumer.


[Autonomic dysfunction syndromes associated with orthostatic intolerance].
In recent years increased interest has focused on the nature and pathophysiology of orthostatic intolerance and syndromes associated with autonomic disorders. Understanding the pathophysiology underlying these syndromes has led to the recognition of several distinct clinical entities with overlapping features and the associated need to reclassify many of the previously unrecognized syndromes. Among the clinical manifestations, syncope and near syncope are frequently associated with orthostatic intolerance. In addition, however, a wide spectrum of symptoms have been described ranging from chronic fatigue to recurrent neurally mediated vasodepressor reactions. The present review focuses on the pathophysiology and classification of syndromes of autonomic dysfunction associated with orthostatic intolerance. Primary and secondary causes of dysautonomia as well as therapeutic approach to these frequently unrecognized syndromes is presented.


DNA data in criminal procedure in the European fundamental rights context.
Despite being one of the most useful and reliable identification tools, DNA profiling in criminal procedure balances on the border between the limitation and violation of Fundamental Rights that can occur beginning with the collection of the sample, its analysis, and its use; and ending with its processing. Throughout this complex process, violation of human or fundamental rights -such as the right to physical and moral integrity, the right not to be subject to degrading treatment, the right not to incriminate oneself, the right to family privacy together with that of not incriminating descendants or relatives in general, the right to personal development and the right to informative self-determination- is possible. This article presents an analysis of all the above-mentioned DNA treating phases in criminal process in the light of possible violations of some Fundamental Rights, while at the same time discarding some of them on the basis of European human rights protection standards. As the case-law of the European Court of Human Rights shows, the legislation on DNA collection and DNA related data processing or its implementation does not always respect all human rights and should be carefully considered before its adoption and during its application.


Findings from a Randomized Controlled Trial of SMART: An EHealth Intervention for Mild Traumatic Brain Injury.
The aim of this study was to examine the efficacy of the SMART (Self-Management After Recent Traumatic brain injury) program and potential moderators. Parallel randomized controlled trial (ClinicalTrials.gov Identifier: NCT03498495) was conducted. Eligibility criteria included treatment for mild traumatic brain injury in the emergency department and age 11-18 years. Participants were assigned equally to SMART (n = 35) or usual care (UC; n = 36). SMART included symptom monitoring and online modules supporting the return to activities and symptom management. Coping and quality of life (QoL) (primary outcomes) and post-concussive symptoms (secondary outcome) were assessed at baseline and weekly for 4 weeks. Groups did not differ in coping, QoL, or return to pre-injury symptom levels at any time point. Problem-focused engagement (PFE) moderated group differences over time (p = .02). At high PFE, UC participants reported lower QoL at time 1 (effect size [ES] = 0.60); SMART participants did not report a decline at any point. At low PFE, SMART participants reported declining QoL from pre-injury to time 1 (ES = 0.68), whereas UC participants reported an increase from time 1 to 3 (ES = 0.56). PFE also moderated group differences on the Health and Behavior Inventory (HBI) cognitive (p = .02) and somatic symptom scales (p = .05). At high PFE, SMART participants reported a more rapid return to pre-injury levels than UC participants (p = .05). Resilience also moderated group differences in QoL and HBI cognitive recovery. Effectiveness of the SMART app varied based on preinjury coping styles and resilience, underscoring the potential need to tailor treatments to individual characteristics.


Antimycobacterial activities of two newer ansamycins, R-76-1 and DL 473.
The antimycobacterial activities of two newer ansamycins, isobutylpiperazinylrifamycin SV (R-76-1) and cyclopentylrifamycin SV (DL 473), were compared with those of rifampin (RMP) both in vitro and in vivo. In terms of minimal inhibitory concentrations against a number of cultivable mycobacteria, R-76-1 was about eight times more active in vitro than RMP; whereas DL 473 was only slightly more active than RMP. Therapeutic activities of R-76-1 versus RMP and DL 473 versus RMP were compared, respectively, in the experimental infection of mice with Mycobacterium lepraemurium by different treatment schedules (immediate and delayed) and dosage regimens. R-76-1 appeared to have been three times more effective than RMP; DL 473 was also more effective than RMP in that an equivalent therapeutic effect could be obtained by fewer doses of DL 473 than of RMP, and in that DL 473 exerted a more prolonged activity than RMP. With the kinetic method and a dosage of 0.001% in the diet, R-76-1 demonstrated a bactericidal-type effect against M. leprae whereas RMP did not; with the proportional bactericidal method, R-76-1 possessed about three times the bactericidal activity of RMP against M. leprae. When drugs were administered once in 4 weeks, the RMP dose required to prevent multiplication of M. leprae in the foot pads of half of the mice was in the range of 1.25 to 2.5 mg/kg; whereas that of DL 473 was less than 0.625 mg/kg. With the proportional bactericidal method, even a single dose of 1.25 mg DL 473 per kg was active against M. leprae; whereas the smallest single active dose of RMP was 10 mg/kg. DL 473 in single doses of 5 mg/kg and 10 mg/kg was significantly more effective than RMP in equal doses and, among the intermittent regimens administered four times, once every 4 weeks, no significant differences of bactericidal activity were observed between RMP at 20 mg/kg and DL 473 at 0.625 mg/kg. A preliminary clinical trial of R-76-1 in 20 patients with lepromatous leprosy showed that the compound, administered in a dosage of 150 mg daily, was very effective.


Interstrain comparison of hepatic and renal microsomal carcinogen metabolism and liver S9-mediated mutagenicity in DA and Lewis rats phenotyped as poor and extensive metabolizers of debrisoquine.
Lewis (extensive metabolizers) and DA (poor metabolizers) rat strains show genetic polymorphism for the gene regulating debrisoquine 4-hydroxylation in a manner analogous to human drug polymorphism and show also a different toxicological response to aflatoxin B1. In order to investigate the underlying mechanism(s) of the different drug-metabolizing capacities, the in vitro metabolism and liver S9-mediated mutagenicity of several drugs and carcinogens were studied in female Lewis and DA rat strains, using untreated, 3-methylcholanthrene-treated, and phenobarbital-treated animals. S9-mediated mutagenicity of aflatoxin B1 and hepatic and renal ochratoxin A 4-hydroxylase activity were much lower in DA rats; however, the activity of a number of other hepatic and renal drug-metabolizing enzymes did not show any interstrain difference. Slight strain differences were found in the inducibility of several hepatic drug-metabolizing enzymes, except for ochratoxin A 4-hydroxylase activity; the latter was inducible only by 3-methylcholanthrene in the DA strain and appeared to be linked genetically with other Ah locus-associated monooxygenases. Our data suggest that ochratoxin A 4-hydroxylase activity, which is low in the DA strain, is catalyzed by a cytochrome P-450 isozyme different from that responsible for debrisoquine 4-hydroxylation. Our results provide some insight into why the two metabolic oxidation phenotypes show different susceptibility to cancer induction and to the toxicity of certain environmental carcinogens, such as aflatoxin B1 and ochratoxin A.


Nitrite Derived from Endogenous Bacterial Nitric Oxide Synthase Activity Promotes Aerobic Respiration.
Macrophage-derived nitric oxide (NO·) is a crucial effector against invading pathogens. Yet, paradoxically, several bacterial species, including some pathogens, are known to endogenously produce NO· via nitric oxide synthase (NOS) activity, despite its apparent cytotoxicity. Here, we reveal a conserved role for bacterial NOS in activating aerobic respiration. We demonstrate that nitrite generated from endogenous NO· decomposition stimulates quinol oxidase activity in Staphylococcus aureus and increases the rate of cellular respiration. This not only supports optimal growth of this organism but also prevents a dysbalance in central metabolism. Further, we also show that activity of the SrrAB two-component system alleviates the physiological defects of the nos mutant. Our findings suggest that NOS and SrrAB constitute two distinct but functionally redundant routes for controlling staphylococcal respiration during aerobic growth.IMPORTANCE Despite its potential autotoxic effects, several bacterial species, including pathogenic staphylococcal species, produce NO· endogenously through nitric oxide synthase (NOS) activity. Therefore, how endogenous NO· influences bacterial fitness remains unclear. Here we show that the oxidation of NO· to nitrite increases aerobic respiration and consequently optimizes central metabolism to favor growth. Importantly, we also demonstrate that cells have a "fail-safe" mechanism that can maintain respiratory activity through the SrrAB two-component signaling regulon should NOS-derived nitrite levels decrease. These findings identify NOS and SrrAB as critical determinants of staphylococcal respiratory control and highlight their potential as therapeutic targets.


[Case series with childhood bipolar disorder phenotype features].
Although outcomes of bipolar disorder with onset in late adolescence and adulthood have been reported, little is known about childhood and prepubertal onset mania. There is a considerable overlap between the diagnostic criteria for mania and disruptive behavioral disorders, particularly attention deficit hyperactivity disorder (ADHD). The overlapping diagnostic boundaries need to be described. We aimed to determine the frequency and severity of symptoms and cycling features in our patients. We reported 7 cases (between 7 and 15 years old) with bipolar phenotype features who were being followed in our unit. The Washington University at St. Louis-Kiddie and Young Adult Schedule for Affective Disorders and Schizophrenia-Present state and lifetime-B. Geller et al.1996 (WASH-U-KSADS) was used for the assessment of psychiatric diagnoses and symptomatology. The Turgay DSM-IV Disruptive Behaviour Disorders Scale was used to determine the frequency of comorbidity between ADHD symptoms and bipolar disorder phenotype features. The most frequent severe symptoms observed at the end of the assessment by WASH-U-KSADS were grandiosity, distractibility, and unusual energy. Four of the cases had mixed cycling features. Five of the cases had ultradian cycling features. All these findings suggest that more research should be carried out on psychosocial and psychopharmacological strategies and pathogenetic mechanisms for mania during the prepubertal and early adolescent years.


Prediction of recovery of left ventricular dysfunction after acute myocardial infarction: comparison between 99mTc-sestamibi cardiac tomography and low-dose dobutamine echocardiography.
The aim of this study was to evaluate the role of 99mTc-sestamibi cardiac imaging and dobutamine echocardiography in detecting myocardial viability early after acute myocardial infarction. Forty-nine patients (mean age 52 +/- 10 y) underwent coronary angiography, low-dose dobutamine echocardiography, radionuclide angiography and rest 99mTc-sestamibi imaging within 10 d after myocardial infarction. Of these patients, 19 were revascularized and 30 were treated medically. Resting echocardiogram and radionuclide angiography were repeated 8 mo later to evaluate segmental functional recovery and changes in left ventricular (LV) ejection fraction, respectively. In revascularized patients, 61 of 108 akinetic or dyskinetic segments showed functional recovery. In these patients, sensitivity in predicting segmental functional recovery was 87% for sestamibi imaging and 66% for dobutamine echocardiography (P < 0.001), whereas specificity and accuracy were comparable. Sestamibi activity (> or =55% of peak) was the strongest predictor of segmental functional recovery (P < 0.001) and of LV ejection fraction improvement > or =5% (P < 0.01) after revascularization. In medically treated patients, 60 of 149 akinetic or dyskinetic segments showed functional recovery. In these patients, the majority (94%) of segments with contractile reserve on dobutamine were viable on sestamibi imaging and 86% of them improved function at follow-up. Functional recovery was poor in segments without contractile reserve either with (38%) or without (62%) preserved sestamibi uptake. Inotropic response was the best predictor of segmental (P < 0.001) and global (P < 0.01) LV functional improvement in medically treated patients. Dobutamine echocardiography predicts spontaneous functional recovery after acute myocardial infarction. However, sestamibi imaging is useful to identify patients with dysfunctional myocardium without contractile reserve who may benefit from coronary revascularization.


Study of the aetiology of wheezing illness at age 16 in two national British birth cohorts.
Data from two national British birth cohorts were used to measure the increase in prevalence of wheezing illness at age 16 between 1974 and 1986, and to investigate the role of several potential risk factors in the increase. The occurrence of self-reported asthma or wheezy bronchitis within the past year, and the frequency of attacks of wheezing illness at age 16, were compared in 11,262 and 9266 children born in one week of 1958 and 1970, respectively. The effects of several putative risk factors for asthma--including birth weight, maternal age, birth order, breast feeding, maternal smoking in pregnancy, child's personal smoking, and father's social class--on the change in occurrence of wheezing illness at age 16 were assessed by multiple logistic regression. The annual period prevalence of asthma or wheezy bronchitis at age 16 increased from 3.8% in 1974 to 6.5% in 1986 (prevalence ratio (PR) = 1.71, 95% CI 1.52 to 1.93). The proportion of children experiencing attacks more than once a week increased from 0.2% to 0.7% (PR = 3.77, 95% CI 2.28 to 6.23). The prevalence of self-reported eczema and hayfever within the past year doubled between 1974 and 1986, suggesting that the increase in asthma was part of a general increase in the prevalence of atopic disease. However, in the complete dataset, after adjustment for the effects of the risk factors studied, the prevalence odds ratio for asthma or wheezy bronchitis in 1986 compared with 1974 was virtually unchanged from the unadjusted value at 1.77 (95% CI 1.46 to 2.15). The prevalence of wheezing illness in British teenagers increased by approximately 70% between 1974 and 1986. This increase appears to have occurred in the context of a general increase in atopic disease and was largely unexplained by changes in the distribution of maternal age, birth order, birth weight, infant feeding, maternal smoking, active smoking by the child, or father's social class.


Extracting a needle from a haystack: reanalysis of whole genome data reveals a readily translatable finding.
There is significant unmet need for more effective treatments for bipolar disorder. The drug discovery process is becoming prohibitively expensive. Hence, biomarker clues to assist or shortcut this process are now widely sought. Using the publicly available data from the whole genome association study conducted by the Wellcome Trust Case Control Consortium, we sought to identify groups of genetic markers (single nucleotide polymorphisms) in which each marker was independently associated with bipolar disorder, with a less stringent threshold than that set by the original investigators (p< or =1 x 10(-4)). We identified a group of markers occurring within the CACNA1C gene (encoding the alpha subunit of the calcium channel Cav1.2). We then ascertained that this locus had been previously associated with the disorder in both a smaller and a whole genome study, and that a number of drugs blocking this channel (including verapamil and diltiazem) had been trialled in the treatment of bipolar disorder. The dihydropyridine-based blockers such as nimodipine that bind specifically to Cav1.2 and are more penetrant to the central nervous system have shown some promising early results; however, further trials are indicated. In addition, migraine is commonly seen in affective disorder, and calcium channel antagonists are successfully used in the treatment of migraine. One such agent, flunarizine, is structurally related to other first-generation derivatives of antihistamines such as antipsychotics. This implies that flunarizine could be useful in the treatment of bipolar disorder, and, furthermore, that other currently licensed drugs should be investigated for antagonism of Cav1.2.


Isolated RingLoc Polyethylene Liner Revision for Treatment of Liner Wear.
Polyethylene wear and osteolysis has long been an issue with the survivorship of total hip arthroplasty. The purpose of this study was to assess the survivorship after isolated liner exchange with the use of the RingLoc acetabular cup. A query of our practice registry revealed 106 patients (112 hips) with a single cementless titanium plasma sprayed acetabular component (RingLoc, Zimmer Biomet, Warsaw, IN), who underwent acetabular liner exchange for treatment of polyethylene wear between January 2001 and March 2015. Eighty patients (85 hips) met inclusion criteria. Clinical outcomes were assessed with the Harris hip score and radiographic evaluation was performed. The mean follow-up after liner exchange was 6 years (range, 2-15.7 years). Harris hip scores improved from 70.9 (range, 28-100) preoperatively to 79 (range, 29-100) at most recent evaluation (p < 0.001). Subsequent surgery was required in 11 patients (11 hips, 13%). Components were revised in 7 hips (8.2%). One acetabular revision was performed for aseptic loosening and four for instability (4.7%). One metal-polyethylene sandwich liner was revised for metal hypersensitivity. One patient underwent two-staged exchange for infection. In our early to mid-term experience with the RingLoc acetabular cup, isolated liner exchange for treatment of polyethylene wear yielded 98.8% acetabular survival for aseptic loosening at up to 15 years. (Journal of Surgical Orthopaedic Advances 29(2):59-64, 2020).