5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators.
A series of nonsteroidal human progesterone receptor (hPR) agonists, 5-alkyl 1,2-dihydrochromeno[3,4-f]quinolines, was synthesized and evaluated in cotransfection and competitive receptor binding assays. The 5-alkyl substitution was shown to be responsible for the agonist activity and substitution at C9 dramatically enhanced the potency. A number of analogues in this series showed activities similar to or better than progesterone in the cotransfection and binding assays and analogue 15 exhibited similar in vivo activity as medroxyprogesterone acetate (MPA) in murine uterine wet weight/mammary gland morphology assays.


SUPERFICIAL--surface mapping of proteins via structure-based peptide library design.
The determination of protein surfaces and the detection of binding sites are essential to our understanding of protein-protein interactions. Such binding sites can be characterised as linear and non-linear, the non-linear sites being prevailant. Conventional mapping techniques with arrays of synthetic peptides have limitations with regard to the location of discontinuous or non-linear binding sites of proteins. We present a structure-based approach to the design of peptide libraries that mimic the whole surface or a particular region of a protein. Neighbouring sequence segments are linked by short spacers to conserve local conformation. To this end, we have developed SUPERFICIAL, a program that uses protein structures as input and generates library proposals consisting of linear and non-linear peptides. This process can be influenced by a graphical user interface at different stages, from the surface computation up to the definition of spatial regions. Based on 3D structures, SUPERFICIAL may help to negotiate some of the existing limitations, since binding sites consisting of several linear pieces can now be detected.


Response of a fast muscle from normal and dystrophic (dy2j) mice to a local decrease in extracellular Ca2+ induced at different stages of postnatal life.
It has previously been reported that reducing Ca2+ entry into muscle fibres was beneficial to dystrophic muscles. In this study, we examined the effect, on the force output and contractile properties of the tibialis anterior muscle, of a local decrease in extracellular Ca2+, produced in normal and dystrophic mice at various stages of postnatal life by applying a small strip of silicon rubber containing a calcium chelator (BAPTA). Lowering extracellular Ca2+ in this way at an early stage of postnatal life (11-16 days) interferes with normal development in that, 3-5 weeks after the initial operation, the treated TA muscles from normal mice are weaker and their contractile speed is slower than that of their untreated counterparts. In contrast, the same procedure has a beneficial effect on dystrophic muscles in that they produce more force than untreated controls. Our results show that these changes are not related to changes in the total number of muscle fibres or fibre type proportions. These changes are temporary and by 8-12 weeks after the operation, the treated muscles are indistinguishable from controls. Finally, our results also indicate that skeletal muscles from older animals, both normal and dystrophic, become insensitive to this manipulation. These results provide the first evidence for a difference in the sensitivity of normal immature and normal adult skeletal muscles to their extracellular Ca2+ environment. They also suggest that in this context, dystrophic muscles might already differ from normal at a stage prior to the clinical expression of the symptoms of the disease.


Decreased fecundity and sperm DNA methylation patterns.
To evaluate the relationship between epigenetic patterns in sperm and fecundity. Prospective study. Academic andrology and in vitro fertilization laboratory. Twenty-seven semen samples from couples who conceived within 2 months of attempting a pregnancy and 29 semen samples from couples unable to achieve a pregnancy within 12 months. None. Genomewide assessment of differential sperm DNA methylation and standard semen analysis. We analyzed DNA methylation alterations associated with fecundity in 124 semen samples, and identified regions of interest in 27 semen samples from couples who conceived within 2 months of attempting a pregnancy and a total of 29 semen samples from couples who were unable to achieve a pregnancy within 12 months. No differences in sperm count, sperm morphology, or semen volume were observed between the patients achieving a pregnancy within 2 months of study time and those not obtaining a pregnancy within 12 months. However, using data from the human methylation 450k array analysis we did identify two genomic regions with statistically significantly decreased (false discovery rate <0.01) methylation and three genomic regions with statistically significantly increased methylation in the failure-to-conceive group. The only two sites where decreased methylation was associated with reduced fecundity are at closely related genes known to be expressed in sperm, HSPA1L and HSPA1B. Our data suggest that there are genomic loci where DNA methylation alterations are associated with decreased fecundity. We have thus identified candidate loci for future study to verify these results and investigate the causative or contributory relationship between altered sperm methylation and decreased fecundity.


Animal cognition: Wild mountain chickadees follow the abstract rules.
concept formation is a cognitive skill that nonhuman animals have been shown to possess. Most often, this ability has been shown in laboratory tasks; a new study sheds light on what role abstract concept formation may play in the wild.


Lewis acid catalysed methylation of N-(9H-fluoren-9-yl)methanesulfonyl (Fms) protected lipophilic α-amino acid methyl esters.
This work reports an efficient Lewis acid catalysed N-methylation procedure of lipophilic α-amino acid methyl esters in solution phase. The developed methodology involves the use of the reagent system AlCl3/diazomethane as methylating agent and α-amino acid methyl esters protected on the amino function with the (9H-fluoren-9-yl)methanesulfonyl (Fms) group. The removal of Fms protecting group is achieved under the same conditions to those used for Fmoc removal. Thus the Fms group can be interchangeable with the Fmoc group in the synthesis of N-methylated peptides using standard Fmoc-based strategies. Finally, the absence of racemization during the methylation reaction and the removal of Fms group were demonstrated by synthesising a pair of diastereomeric dipeptides.


Emulating Target Trials Comparing Early and Delayed Intubation Strategies.
Whether intubation should be initiated early in the clinical course of critically ill patients remains a matter of debate. Results from prior observational studies are difficult to interpret because of avoidable flaws including immortal time bias, inappropriate eligibility criteria, and unrealistic treatment strategies. Do treatment strategies that intubate patients early in the critical care admission improve 30-day survival compared with strategies that delay intubation? We estimated the effect of strategies that require early intubation of critically ill patients compared with those that delay intubation. With data extracted from the Medical Information Mart for Intensive Care-IV database, we emulated three target trials, varying the flexibility of the treatment strategies and the baseline eligibility criteria. Under unrealistically strict treatment strategies with broad eligibility criteria, the 30-day mortality risk was 7.1 percentage points higher for intubating early compared with delaying intubation (95% CI, 6.2-7.9). Risk differences were 0.4 (95% CI, -0.1 to 0.9) and -0.9 (95% CI, -2.5 to 0.7) percentage points in subsequent target trial emulations that included more realistic treatment strategies and eligibility criteria. When realistic treatment strategies and eligibility criteria are used, strategies that delay intubation result in similar 30-day mortality risks compared with those that intubate early. Delaying intubation ultimately avoids intubation in most patients.


Sexual satisfaction and self-esteem in women with acne.
A significant number of problems related to mental and social functioning is a common occurrence in patients with acne. The aim of our study was to determine how acne affects self-esteem and sexual satisfaction in the affected women. The study was conducted among 90 women, aged 18-51 years (mean 30.29 ± 7.10), diagnosed with acne. Demographic data, medical history and information concerning their sexual life were obtained from all study participants. After dermatological assessment of lesion location and severity, all subjects completed the following questionnaires: Rosenberg Self-Esteem Scale, Sexual Self-Esteem Inventory, Body Attitudes Questionnaire, and Whitley Sexual Satisfaction Inventory. Two factors-lesion severity and self-assessment of the body-proved to shape the sexual satisfaction of women, but the influence turned out to be mediated through self-esteem. Acne proves to play an important negative role in female sexuality and satisfaction.


Carbohydr Polym Special Issue Invited contribution: Click chemistry for block polysaccharides with dihydrazide and dioxyamine linkers - A review.
Engineered block polysaccharides is a relatively new class of biomacromolecules consisting of chemical assembly of separate block structures at the chain termini. In contrast to conventional, laterally substituted polysaccharide derivatives, the block arrangement allows for much higher preservation of inherent chain properties such as biodegradability and stimuli-responsive self-assembly, while at the same time inducing new macromolecular properties. Abundant, carbon neutral, and even recalcitrant biomass is an excellent source of blocks, opening for numerous new uses of biomass for a wide range of novel biomaterials. Among a limited range of methodologies available for block conjugation, bifunctional linkers allowing for oxyamine and hydrazide 'click' reactions have recently proven useful additions to the repertoire. This article focuses the chemistry and kinetics of these reactions. It also presents some new data with the aim to provide useful protocols and methods for general use towards new block polysaccharides.


Effects of EDTA on lead uptake by Typha orientalis Presl: a new lead-accumulating species in southern China.
A series of field investigations have been conducted at Yongzhou Pb/Zn/Cu mine tailings, Hunan Province, southern China. The specific aim was to search for new lead accumulators with fast growth rate and large biomass. The results of tissue analyses identified Typha orientalis Presl has a strong accumulation of lead. The average lead concentrations in the leaves and roots are 619 and 1,233 mg/kg, respectively. The growth and Pb content of the plant were also studied by hydroponic culture with different concentrations of Pb(NO(3))(2). Growth of the plant was not affected by Pb up to 300 mg/L. The Pb concentrations in the leaves and roots increased with increasing of Pb level in the modified Hoagland's nutrient solution. The maximum concentrations of Pb in the leaves and roots were 16,190 and 64,405 mg/kg, respectively. The study also demonstrated that EDTA not only increased the amount of Pb taken up by plants but also speeded up the metal translocation from roots to leaves.


Adjustment of conformational flexibility of glyceraldehyde-3-phosphate dehydrogenase as a means of thermal adaptation and allosteric regulation.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Thermotoga maritima (TmGAPDH) is a thermostable enzyme (Tm = 102 degrees C), which is fully active at temperatures near 80 degrees C but has very low activity at room temperature. In search for an explanation of this behavior, we measured the conformational flexibility of the protein by hydrogen-deuterium exchange and compared the results with those obtained with GAPDH from rabbit muscle (RmGAPDH). At room temperature, the conformational flexibility of TmGAPDH is much less than that of RmGAPDH, but increases with increasing temperature and becomes comparable to that of RmGAPDH near the physiological temperature of Thermotoga maritima. Using the available three-dimensional structures of the two enzymes, we compared the B factors that reflect the local mobility of protein atoms. The largest differences in B factors are seen in the coenzyme and NAD binding regions. The likely reason for the low activity of TmGAPDH at room temperature is that the motions required for enzyme functions are restricted. The findings support the idea of "corresponding states" which claims that over the time span of evolution, the overall conformational flexibility of proteins has been preserved at their corresponding physiological temperatures.


Diabetes, Glycated Hemoglobin (HbA1c), and Neuroaxonal Damage in Parkinson's Disease (MARK-PD Study).
Diabetes is associated with incidence and prevalence of Parkinson's disease (PD). Furthermore, glycated hemoglobin (HbA1c) levels have been linked with motor function and progression. We evaluated the relationship between prevalent diabetes and HbA1c levels with serum neurofilament light chain (NfL) levels as marker of neuroaxonal damage. NfL concentrations were analyzed with Simoa in serum of 195 PD patients with available HbA1c values. Motor (MDS-UPDRS III, Hoehn & Yahr [H&Y]) and cognitive (Montreal Cognitive Assessment [MoCA]) function was assessed and vascular comorbidities were documented from medical records. PD patients with prevalent diabetes had higher serum NfL levels and lower MoCA scores independent of age, body mass index (BMI), and vascular risk factors. Furthermore, diabetes was associated with higher H&Y stages in unadjusted and age/BMI-adjusted models. Higher HbA1c levels were associated with increased NfL in unadjusted and age/BMI-adjusted models. In PD patients, diabetes and high HbA1c are associated with increased neuroaxonal damage and cognitive impairment. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.


Author Correction: A common variant of the pregnancy-associated plasma protein-A (PAPPA) gene encodes a protein with reduced proteolytic activity towards IGF-binding proteins.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Role of cytochrome P4502D6 in the metabolism of brofaromine. A new selective MAO-A inhibitor.
The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.


The evolution of the field of legal medicine: A holistic investigation of global outputs with bibliometric analysis.
The purpose of this study is to make a holistic summary of the articles published in the field of Legal Medicine/Forensic Science through bibliometric methods, determine the top cited publications in the field, and to determine the most active journals and especially trend topics. The articles published in the field of Legal Medicine between the years 1975 and 2018 were downloaded from the Web of Science index and were analyzed using bibliometric methods. The correlations between the number of publications of the countries and the Gross Domestic Product (GDP), and the Gross Domestic Product per capita (GDP PPP) values was analyzed using the Spearman's correlation coefficient. The number of articles to be published in the field of Legal Medicine between the years 2019 and 2022 was estimated with linear regression analysis. The results showed that there were totally 38845 articles published in the field of Legal Medicine. Regression analysis results indicate that it will exceed 2500 publications after 2022. The most productive countries in the field of Legal Medicine were the USA (12.448, 32.045%). A high correlation was found between legal medicine publication productivity and GDP and GDP PPP (r = 0.726, p < 0.001; r = 0.703, p < 0.001). As for the collaboration between countries, analysis results showed that the network web indicated the most important factor as the geographical location. This study will provide important information to a forensic scientist (a doctor, academic, and practitioner).


Early physical and sexual abuse associated with an adverse course of bipolar illness.
There is growing awareness of the association between physical and sexual abuse and subsequent development of psychopathology, but little is known, however, about their relationship to the longitudinal course of bipolar disorder. We evaluated 631 outpatients with bipolar I or II disorder for general demographics, a history of physical or sexual abuse as a child or adolescent, course of illness variables, and prior suicide attempts, as well as SCID-derived Axis I and patient endorsed Axis II comorbidity. Those who endorsed a history of child or adolescent physical or sexual abuse, compared with those who did not, had a history of an earlier onset of bipolar illness, an increased number of Axis I, II, and III comorbid disorders, including drug and alcohol abuse, faster cycling frequencies, a higher rate of suicide attempts, and more psychosocial stressors occurring before the first and most recent affective episode. The retrospectively reported associations of early abuse with a more severe course of illness were validated prospectively. Greater appreciation of the association of early traumatic experiences and an adverse course of bipolar illness should lead to preventive and early intervention approaches that may lessen the associated risk of a poor outcome.


Evaluation of patient-centered outcomes associated with the acceleration of canine retraction by using minimally invasive surgical procedures: A randomized clinical controlled trial.
Only a few studies in the literature have reported patient-centered outcomes associated with minimally invasive corticotomy, and thus, related scientific evidence is limited. The objective of this study was to evaluate patient-centered outcomes associated with upper canine retraction assisted with piezocision or laser-assisted flapless corticotomy (LAFC). Thirty-two patients (19 females, 13 males) at a mean age of 18.25 ±3.05 years were randomly divided into 2 equal groups: the LAFC group (LG; n = 16) and the piezocision group (PG; n = 16). In each group, the surgical procedure was randomly assigned to one side of the maxillary arch, and the other side served as the control. Standardized questionnaires using the numerical rating scale (NRS) were distributed to all patients during the 1st month after the surgical procedure at 4 time points: 24 h (T1); 3 days (T2); 7 days (T3); and 14 days (T4). The patients' responses were obtained, regarding their feelings of pain, discomfort, swelling, eating difficulty, jaw movement restriction, analgesic consumption, and satisfaction. The levels of pain, discomfort, swelling, and difficulty in chewing were significantly greater at the experimental sides as compared to the control sides only at T1 in both groups (p < 0.05). The levels of pain and discomfort in LG were significantly lower than those in PG only at T1 (p = 0.013 and p = 0.009, respectively) whereas there were no significant differences between the groups regarding swelling, eating difficulty, jaw movement restriction, and analgesic consumption. The patients in both groups reported high levels of satisfaction, with no significant differences. The levels of pain, discomfort, swelling, eating difficulty, and jaw movement restriction were dramatically decreased 1 day after flapless corticotomy treatment in both groups (p < 0.05). Both LAFC and piezocision were associated with high levels of pain, discomfort, swelling, and difficulty in chewing at T1. Laser-assisted flapless corticotomy caused less pain and discomfort than piezocision.


Morphological differentiation of embryonic rat sympathetic neurons in tissue culture. I. Conditions under which neurons form axons but not dendrites.
We have examined the morphology of fetal rat sympathetic neurons grown in serum-free medium in the absence of nonneuronal cells. Because cell density can affect phenotypic expression in vitro, the morphological analysis was subdivided into the study of isolated neurons (neurons whose somata were at least 150 micron from their nearest neighbor) and of more highly aggregated neurons. When isolated neurons were injected with intracellular markers, it was found that most (79%) had a single process emanating from their somata and that this unipolar state persisted for at least 8 weeks in vitro. The processes of unipolar sympathetic neurons had the appearance of axons in that they were thin and long, had a constant diameter, and were relatively unbranched. Cytochemical methods revealed that such processes had other axonal characteristics: (1) they were more reactive with a monoclonal antibody against phosphorylated forms of the M and H neurofilament subunits than with an antibody to nonphosphorylated forms of these proteins; (2) they also reacted with antibodies to the tau microtubule-associated protein and to the phosphorylated forms of the H neurofilament subunit; and (3) they contained only small amounts of RNA as determined by [3H]uridine autoradiography. These data indicate that neurons which normally form dendrites in vivo need not express this capacity in vitro and that axonal and dendritic growth can be dissociated under some conditions in culture. While most isolated neurons were unipolar, neurons in regions of high neuronal cell density were usually multipolar. In addition to axons, multipolar neurons had processes with some of the characteristics expected of rudimentary dendrites: they ended locally (usually within 100 micron), were often highly branched, and reacted with an antibody to nonphosphorylated forms of the M and H neurofilament subunits. The effects of density were most prominent when neurons were within aggregates in which the somata were in close apposition. Density-dependent changes in morphology were less frequently observed when neuronal somata were separated by greater distances (30-100 micron). These data indicate that the morphology of sympathetic neurons is subject to environmental regulation and that neuron-neuron interactions can promote the extension of rudimentary dendrites in vitro.


Protein-enabled detection of ibuprofen and sulfamethoxazole using solid-state nanopores.
Enabled by proteins, we present an all-electrical method for rapid detection of small pharmaceuticals (ibuprofen and sulfamethoxazole [SMZ]) in aqueous media using silicon nitride pores. Specifically, we use carrier proteins, bovine serum albumin (BSA), and take advantage of their interactions with two small drug molecules to form BSA-drug complexes which can be detected by nm-diameter pores, thereby confirming the presence of small pharmaceuticals. We demonstrate detection of ibuprofen and SMZ at concentrations down to 100 nM (∼21 μg/L) and 48.5 nM (12 μg/L), respectively. We observe changes in electrical signal characteristics (reflected in event durations, rates, current magnitudes, and estimated particle diameters) of BSA-drug complexes compared to BSA-only, and differences between these two small pharmaceuticals, possibly paving a path toward developing selective sensors by identifying "electrical fingerprints" of these molecules in the future. These distinct electrical signals are likely a combined result of diffusion, electrophoretic and electroosmotic effects, interactions between the pore and particles, which depend on pore diameters, pH, and the resulting surface charges. The use of single-molecule-counting nanopores allows sensing of small pharmaceuticals, studies of protein conformational changes, and may aid in efforts to evaluate the impact of small drug molecules on aquatic and human life.


[Current status of stuttering therapy in preschool and school-age children in the Federal Republic of Germany: results of a questionnaire study among therapists and analysis of the literature].
It is evident that no empirical research has been carried out within the preschool age-group of stuttering children and also that information on the subject published in international and especially in the Anglo-American literature has not received the attention of German therapists. Rather than concentrating upon the stuttering child's speech and language, they attempt to convey to the child a greater pleasure in speaking and in communicating; this may result in symptoms that could aggravate prognosis. More than half of the therapists maintain the same attitude toward school-age children. The review of the literature and the replies to the questionnaire show that German therapists require new orientation toward scientific investigation and new concepts in the treatment of stuttering preschool children.


Ceramic soft tissue trimming bur: A new tool for gingival depigmentation.
Pigmentation of the gingiva plays a negative role in an otherwise acceptable "smile window". In the present world, people are more concerned about their aesthetics. Several techniques have been employed such as scalpel surgery, electrosurgery, cryosurgery, chemical agents, abrasion and LASER method for the removal of melanin hyper-pigmentation. The present study is aimed at comparing the efficacy of LASER and soft tissue trimmer for gingival depigmentation. A randomized split-mouth study was conducted for twenty patients with gingival pigmentation. Dummet Oral Pigmentation Index (DOPI), Gingival Pigmentation Index (GPI) for pigmentation, bleeding factor, wound healing factor, gingival colour and visual analogue scale (VAS) score for pain were evaluated for both the groups at baseline, 7th day, 1st month and 6th month. Intra-group comparison between baseline and 6th month showed highly significant difference for both LASER and bur groups. There was no statistically significant difference found between both the groups at 6th month using gingival pigmentation index. It can be concluded that LASER and soft tissue trimmer both are comparable in achieving aesthetic satisfaction. Hence, the soft tissue trimmer could also be used for depigmentation as it is very cost effective, readily available and acceptable by the patients.


Expression of a phenoloxidase cascade inhibitor enhances the virulence of the fungus Beauveria bassiana against the insect Helicoverpa armigera.
Entomopathogenic fungi have high potential for controlling insect pests, although the slow killing speed has blocked their widespread application. To increase the virulence of entomopathogenic fungi, genetic modification can be employed. Egf1.0 is an immunosuppressive protein encoded by polydnavirus, carried by parasitoid wasp Microplitis demolitor, which blocks the prophenoloxidase (PPO) activation response of host insects. In this study, we explored the feasibility of genetically modifying entomopathogenic fungi with increased virulence by expressing Egf1.0. In comparison with the wild-type parents, the median lethal concentration (LC50) of Beauveria bassiana expressing Egf1.0 against Helicoverpa armigera was reduced by 2.7-fold, and the median lethal time (LT50) was reduced by 22.8%. In vitro assay showed that recombinant Egf1.0 was able to inhibit the PPO activation response of H. armigera. In vivo assay revealed that the expression of Egf1.0 in B. bassiana caused a higher degree of suppression to PPO activation response of H. armigera. These assays suggested that the increased virulence of the transgenic fungi is due to the increased ability to suppress the host insect's immune response. Moreover, colony growth, conidia yield, and germination assays revealed that the expression of Egf1.0 in B. bassiana had no effect on its growth and development. In conclusion, the expression of Egf1.0 can significantly enhance the pathogenicity of B. bassiana against host insects.


Synthesis and anticonvulsant activity of some quinazolin-4-(3H)-one derivatives.
A number of 3-substituted-2-(substituted-phenoxymethyl) quinazolin-4(3H)-one derivatives 4a,b, 5a-c, 6, 7a-f, 8a-e and 9a,b have been synthesized. Their structures have been elucidated on the basis of elemental analyses and spectroscopic studies (IR, 1H-NMR, MS). A preliminary evaluation of the anticonvulsant activity of the prepared compounds has indicated that compounds 4b, 7b-f, 8a and 9b exhibit significant anticonvulsant activity, while compounds 6, 8b and 8d show mild to moderate activity.


Biomarker evaluation does not confirm efficacy of computer-tailored nutrition education.
To evaluate the efficacy of computer-tailored nutrition education with objective outcome measures. A 3-group randomized, controlled trial with posttests at 1 and 6 months post-intervention. Worksites and 2 neighborhoods in the urban area of Rotterdam. A convenience sample of healthy Dutch adults (n = 442). A computer-tailored intervention delivered on CD-ROM; a computer-tailored intervention delivered in print; and a generic information condition. Blood lipids (total, high-density lipoprotein, and low-density lipoprotein cholesterol, and triacylglycerol) were measured by analyzing venous blood samples. Linear mixed model procedure. There were no significant differences among the 3 intervention groups in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triacylglycerol. Contrary to results based on self-report data, no effects of the computer-tailored interventions were found based on objective outcomes. This contradiction calls for a critical reflection on the use of computer-tailored nutrition education interventions and the need to improve those interventions. Furthermore, this study indicates that feasible methods are needed to objectively assess the impact of computer-tailored nutrition education interventions in free-living subjects.


Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India.
We previously reported independent links between the IGF system and the development of impaired glucose tolerance and cardiovascular risk. This study tests the hypothesis that the lifestyle change which accompanies population migration, with attendant increases in cardiovascular risk, is reflected by changes in the IGF system. We compared a specific Gujarati community in Sandwell, UK (n=205), with people still resident in the same villages of origin near Navsari, India (n=246). We performed anthropometry and measured fasting plasma insulin, IGF-I, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3. Daily calorie intake, BMI and WHR were significantly higher in UK Gujaratis than in Indian Gujaratis. IGFBP-1 was significantly lower in UK migrants (mean 29.5 [95% CI 25.9-33.0] vs 56.5 [50.6-62.5] microg/l; F=48.4, p<0.001). Conversely, fasting insulin, IGFBP-3 and IGF-I were all higher in UK Gujaratis (mean IGF-I 145.9 [138.1-153.6]ng/ml in UK Gujaratis and 100.9 [94.6-107.3] ng/ml in Navsari Gujaratis; F=76.6, p<0.001). These differences were still apparent when adjustment was made for BMI by location for IGF-I (F=57.4, p<0.001) and IGFBP-3 (F=5.7, p=0.02), but were no longer apparent for IGFBP-1 and insulin. At the population level, the decrease in IGFBP-1 for a given increase in insulin was significantly smaller in UK Gujaratis, suggesting greater hepatic insulin resistance in this group. Environmental factors have profound effects on circulating IGF system components and on the relationship between IGFBP-1, IGF-I and related metabolic variables. This may have long-term implications for the development of worsening glucose tolerance and cardiovascular disease.


The function of microRNAs in renal development and pathophysiology.
MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that modulate diverse biological processes predominantly by translation inhibition or induction of mRNA degradation. They are important regulatory elements involved in renal physiology and pathology. Dysregulation of miRNAs disrupts early kidney development, renal progenitor cell differentiation and the maintenance of mature nephrons. miRNAs are also reported to participate in various renal diseases, including chronic kidney disease, acute kidney injury, allograft acute rejection and renal cell carcinoma. Differentially regulated miRNAs may represent innovative biomarkers for diagnosis and prognosis. Therefore, determining the roles of miRNAs in different types of renal diseases will help to clarify the pathogenesis and facilitate the development of novel therapies.


[Anterior retroperitoneal L5-S1 arthrodesis and fixation with cage and plate. Prospective study in 40 cases with a follow-up of one to 2.2 year (mean 1.5 year)].
The aim of this prospective clinical study was to assess outcome after anterior retroperitoneal interbody arthrodesis for L5-S1 discopathy. We used a cage filled with an autologous corticocancellous graft and plate fixation. Forty patients with low back pain unresponsive to medical treatment for more than six months were included in this series. We noted the clinical signs and radiculalgia. Patients were assessed preoperatively, postoperatively, at one year and at last follow-up using the Oswestry score and a visual analog scale (VAS). The plain X-rays disclosed 30 cases of discopathy (16 primary and 14 postdiscectomy) and 10 cases of spondylolisthesis by L5 isthmic lysis (three Meyerding grade 0 and seven grade 1). MRI revealed signs of disc degeneration in all cases with a black disc or modification of the endplate signals (Modic type 1 in 23 and type 2 in 13). The anterior retroperitoneal approach was used in all cases for complete discectomy, arthrodesis with cage insertion and an autologous corticocancellous graft harvested from the iliac bone and fixation using a triangular plate (Pyramid, Medtronic, Memphis TN). Clinical and radiographic follow-up data were available at six weeks and three, six and 12 months in addition to last follow-up. A follow-up using MRI was performed in the event of complications. The population was composed of 25 women and 15 men, mean age 44 years and eight months (range 29-693 years). Thirteen patients presented radiculalgia. There were no vascular or gastrointestinal complications with the anterior approach. Bone healing was achieved at one year in 38 patients (95%). The mean Oswestry score improved from 52 to 16% and the mean VAS from 7.8 to 1.83 at 18 months follow-up. All occupationally-active patients but one resumed their former activity at mean 4.7 months. There were no sexual complications in this series. Low back pain persisted in three patients and five developed transient facet joint symptoms. Two patients developed secondary radiculalgia. We noted two cases of nonunion, in one grade 1 spondylolisthesis and in one grade 1 spondlylolisthesis (with revision for complementary posterior arthrodesis and a good outcome at latest follow-up). Anterior L5-S1 interbody fusion with a cage filled with a corticocancellous autograft fixed with a plate provides good clinical and radiographic results for the stabilization of painful discopathy. The results have been good for isolated L5-S1 discopathy and for grade 0 spondylolisthesis. The limit for this technique would appear to be grade 1 spondylolisthesis with a degraded disc. Performed via an anterior retroperitoneal approach, this method is a good alternative to the classical posterior approach, enabling very low morbidity.


Multicenter performance evaluation of a transcription-mediated amplification assay for screening of human immunodeficiency virus-1 RNA, hepatitis C virus RNA, and hepatitis B virus DNA in blood donations.
The performance of the recently launched Procleix Ultrio (Chiron/Gen-Probe) human immunodeficiency virus-1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) blood screening assay was evaluated in a European multicenter study. Serial dilutions of reference materials were tested to determine the detection limits. Robustness and specificity were assessed by testing alternating high-load HCV RNA-positive and -negative samples, and 2912 test pools of eight donations. The added value of minipool and single-donation HBV nucleic acid testing protocols was compared to the currently used Prism (Abbott GmbH & Co. KG) hepatitis B surface antigen (HBsAg) and Auszyme (Abbott GmbH & Co. KG) dynamic HBsAg tests in 15 HBV seroconversion panels. The 95 percent detection limits (and 95% confidence interval [CI]) on the WHO International Standards was 26 (16-58) IU per mL for HIV-1 RNA, 4.6 (3.7-6.5) IU per mL for HCV RNA, and 11 (7.3-22) IU per mL for HBV DNA. No cross-contamination was observed. Testing 2912 pools of eight donations revealed 16 initial reactive samples; 11 were confirmed. The specificity after initial testing and percentage of invalid results were 99.83 and 0.48 percent, respectively. The HBV window-period (WP) reductions relative to HBsAg seroconversion in Prism and Auszyme dynamic HBsAg were, respectively, 6 days (95% CI, 3-8) and 9 days (95% CI, 7-12) in 1:8 minipool (MP) testing. The performance characteristics of Procleix Ultrio assay and the Procleix HIV-1 and HCV assay are comparable. The sensitivity for HIV-1 and HCV met the directives of the Paul-Ehrlich Institute and the FDA. The assay can reduce the WP for HBV by 6 days to 2 weeks when used in small MP (<1:8) or single-donation screening protocols.


Increased expression of low density granulocytes in juvenile-onset systemic lupus erythematosus patients correlates with disease activity.
Neutrophils are implicated in a wide range of non-infectious inflammatory conditions. A subset of neutrophils in the peripheral circulation of systemic lupus erythematosus (SLE) patients has been described and termed low density granulocytes (LDGs). This study investigates the expression of LDG in juvenile-onset SLE (JSLE) patients compared to controls, and any correlations with disease activity.Neutrophils and LDGs were isolated from JSLE (n = 13) and paediatric non-inflammatory control patients (n = 12). Cell populations were assessed and compared using flow cytometry and morphological analysis. Standard clinical data, which included disease activity markers/scores, were collected for each patient.Significantly increased LDG expression (%mean ± SEM, range) was observed in JSLE patients (10.4 ± 3.26, 3.41-36.3) compared to controls (2.4 ± 0.44, 0.36-5.27; p = 0.005). A statistically significant positive correlation was observed between LDG expression and the British Isles Lupus Activity Group (correlation coefficient 0.685; p = 0.010) and SLE Disease Activity Index (correlation coefficient 0.567; p = 0.043) and the biomarker of dsDNA-antibodies (correlation coefficient 0.590; p = 0.043).Here we observe increased expression in LDGs in JSLE patients, which correlate with dsDNA antibody concentration and scores of disease activity. These correlations indicate that the increased LDG expression observed in this study may have a potential role in the pathogenesis of JSLE, and may be a useful biomarker.


Sorption of fluoroquinolones and sulfonamides in 13 Brazilian soils.
Animal production is a leading economic activity in Brazil and antibiotics are widely used. However, the occurrence, behavior, and impacts of antibiotics in Brazilian soils are still poorly known. We evaluated the sorption behavior of four fluoroquinolones (norfloxacin, ciprofloxacin, danofloxacin, and enrofloxacin) and five sulfonamides (sulfadiazine, sulfachloropyridazine, sulfamethoxazole, sulfadimidine, and sulfathiazole) in 13 Brazilian soils with contrasting physical, chemical, and mineralogical properties. Fluoroquinolone sorption was very high (Kd≥544 L kg(-1)) whereas sulfonamide sorption ranged from low to high (Kd=0.7-70.1 L kg(-1)), consistent with previous reports in the literature. Soil texture and cation exchange capacity were the soil attributes that most affected sorption. Cation exchange was the most important sorption mechanism for the fluoroquinolones in highly weathered tropical soils, although cation bridging and ion pairing could not be ruled out. Hydrophobic partition played an important role in the sorption of the sulfonamides, but sorption was also affected by non-hydrophobic interactions with organic and/or mineral surfaces. Sorption for both compound classes tended to be higher in soils with high Al and Fe oxihydroxide contents, but they were not correlated with Kd values. No direct effect of soil pH was seen. The fluoroquinolones are not expected to leach even in worst-case scenarios (soils rich in sand and poor in organic carbon), whereas soil attributes dictate leaching potential for the sulfonamides.


The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol.
Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. Arimoclomol has been found to be neuroprotective in a number of neurodegenerative disease models, including Amyotrophic Lateral Sclerosis (ALS), and in mutant Superoxide Dismutase 1 (SOD1) mice that model ALS, Arimoclomol rescues motor neurons, improves neuromuscular function and extends lifespan. The therapeutic potential of Arimoclomol is currently under investigation in a Phase II clinical trial for ALS patients with SOD1 mutations. In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. ALS is a complex, multifactorial disease affecting a number of cell types and intracellular pathways. Cells and pathways affected by ALS pathology and which may be targeted by a heat shock protein-based therapy are also discussed in this review. For example, protein aggregation is a characteristic pathological feature of neurodegenerative diseases including ALS. Enhanced heat shock protein expression not only affects protein aggregation directly, but can also lead to more effective clearance of protein aggregates via the unfolded protein response, the proteasome-ubiquitin system or by autophagy. However, compounds such as Arimoclomol have effects beyond targeting protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress. Therefore, by targeting multiple pathological mechanisms, compounds such as Arimoclomol may be particularly effective in the development of a disease-modifying therapy for ALS and other neurodegenerative disorders.


Developmental and hormonal regulation of FBN1 and OR4M1 mRNA in bovine granulosa cells.
Recent studies have reported hormonal regulation of expression of fibrillin 1 (FBN1), the gene that encodes asprosin, in bovine theca cells, however, hormonal regulation of gene expression of FBN1 and the asprosin receptor, olfactory receptor 4M1 (OR4M1), has not been evaluated in granulosa cells (GC). This study was designed to characterize FBN1 and OR4M1 gene expression in GC during development of bovine dominant ovarian follicles, and to determine the hormonal regulation of FBN1 and OR4M1 mRNA expression in GC. GC FBN1 mRNA abundance was greater (P < 0.05) in medium (5.1-8 mm) estrogen inactive (EI) follicles than in large (>8.1 mm) or small (1-5 mm) EI follicles. In comparison, GC OR4M1 mRNA abundance was greater (P < 0.05) in small EI follicles than in large or medium EI follicles. Abundance of OR4M1 mRNA in GC of follicles collected on days 3 to 4 (early growth phase) and on days 5 to 6 (late growth phase) was similar, whereas FBN1 mRNA abundance was greater (P < 0.05) on days 5 to 6 vs days 3 to 4. Hormonal regulators for FBN1 mRNA abundance in cultured small-follicle GC were identified: TGFβ1 causing a 2.45-fold increase, WNT3A causing a 1.45-fold increase, and IGF1 causing a 65% decrease. Steroids, leptin, insulin, growth hormone, follicle stimulating hormone, fibroblast growth factor 9 and epidermal growth factor had no effect on FBN1 mRNA abundance. Abundance of OR4M1 mRNA in GC was regulated by progesterone with 3.55-fold increase, but other hormones did not affect GC OR4M1 mRNA abundance. Findings indicate that both FBN1 and OR4M1 gene expression are hormonally and developmentally regulated in bovine follicles, and thus may affect asprosin production and its subsequent role in ovarian follicular function in cattle.


Electron donor properties of the antitumour drug amsacrine as studied by fluorescence quenching of DNA-bound ethidium.
The effect of the antitumour acridine derivative amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide] on the fluorescence lifetime of DNA-bound ethidium has been investigated using a synchronously pumped cavity dumped dye laser producing picosecond pulses for sample excitation and a time-correlated single photon counting detection system. As the proportion of DNA-bound amsacrine on the synthetic DNA polymer poly[deoxyadenylic-thymidylic acid] is increased, the fluorescence decay curve of ethidium can be accurately resolved into two exponential components. The short lifetime component, whose proportion increases with increasing proportions of DNA-bound amsacrine, has a lifetime of between 3 and 4 ns, significantly longer than that of ethidium in aqueous solution (1.63 ns). The magnitude of the long lifetime component decreases from 25.4 to 14 ns with increasing proportions of bound amsacrine. It is concluded that a new fluorescence state of ethidium (lifetime 3-4 ns) is present, probably resulting from reversible electron transfer between ethidium and amsacrine. The ability of various 9-anilinoacridine derivatives to quench the fluorescence of DNA-bound ethidium appears to be related to the electron donor properties of the substituents on the anilino ring, as well as to experimental antitumour activity. The electron donor properties of DNA-bound amsacrine may therefore be relevant to its antitumour action.


Temperature and pH dependent changes of immunoglobulin G structure.
1. The temperature and pH functions of the myeloma IgG(K) conformation were studied by optical rotatory dispersion, circular dichroism, thermal perturbation difference spectroscopy, solvent perturbation difference spectroscopy, electrochemical iodination and difference adiabatic scanning microcalorimetry. 2. The IgG studied was found to be capable of a fully reversible structural change between pH 6.5 and 6.0. A transition occurring at low pH is accompanied by an increase of exposure of the chromophores to the solvent. 3. The "alkaline state" was found to be capable of a fully reversible S-like transition at temperatures between 25 and 35 degrees C. The changes occurring at the higher temperature are accompanied by the screening of 14-15 tyrosine residues and probably by a small increase in the helicity of the protein. These changes are not accompanied by an appreciable heat effect. The thermal denaturation of the "alkaline state" occurs only at 64 degrees C in the narrow temperature interval (3-4 degrees C). 4. The "acid state" is not accompanied by S-like transition at 25-35 degrees C. The thermal denaturation of the "acid state" occurs at 54 degrees C in the wide temperature interval (8-9 degrees C). 5. It was proposed that the ionisation of the invariant histidine residues situated in the "cavity" between the constant and variable domains causes the pH transition studied. The temperature changes in the interval 25-35 degrees C are explained by the alteration of the domains interposition. Similar alterations were investigated as a result of antigen-antibody reaction.


Treating Opioid Withdrawal With Buprenorphine in a Community Hospital Emergency Department: An Outreach Program.
We assess the feasibility of using our community hospital emergency department (ED) as an immediate portal to medication-assisted treatment for patients in opioid withdrawal. This was a prospective observational cohort study. In collaboration with an outpatient substance abuse treatment center, we alerted the public through media outlets that individuals could receive immediate buprenorphine treatment for opioid withdrawal in the ED, with rapid referral for medication-assisted treatment. If medication-assisted treatment intake was delayed, patients could return for up to 2 more days for buprenorphine administration to treat their withdrawal symptoms. We measured compliance with initial follow-up and continued treatment engagement at 30 and 90 days. The study was conducted during 12 months. A total of 62 patients were enrolled, evaluated for buprenorphine criteria, and referred for medication-assisted treatment. Fifty subjects were compliant with their first medication-assisted treatment follow-up visit (81% [95% confidence interval 71% to 91%]), and 43 of these 50 patients were still engaged in medication-assisted treatment at 30 days (86% [95% confidence interval 76% to 96%]), with 33 of the 50 still engaged at 90 days (66% [95% confidence interval 53% to 79%]). We observed no instances of precipitated withdrawal or other adverse reactions in the ED. A substantial number of patients responded to this program and received accelerated engagement in medication-assisted treatment. Such a program is feasible in the community hospital ED and may prevent some individuals from relapsing into high-risk illicit drug use when immediate medication-assisted treatment is not otherwise available.


Cone-shaped epiphyses in the toes and trifurcation of the soft palate in oral-facial-digital syndrome type-I.
A rare case of oral-facial-digital syndrome type I is presented. The patient had two features that have not been previously described: cone-shaped epiphyses in the toes and trifurcation of the soft palate.


Japanese encephalitis clinical update: Changing diseases under a changing climate.
Japanese encephalitis virus (JEV) is a mosquito-borne arbovirus endemic to the Asia-Pacific that causes high morbidity and mortality in those who develop symptomatic disease. Prior to 2021, only five locally acquired cases had been detected in Australia, all in northern Australia. Following a sentinel case in 2021, widespread dissemination of JEV was detected in northern and south-eastern Australia, accompanied by an increase in locally acquired cases, which have been detected as far south as Victoria. This expansion has occurred in the setting of warmer and wetter conditions under the influence of climate change. To provide Australian general practitioners (GPs) an overview of JEV, given its recent expansion, and the potential for sustained endemicity. As the distribution of JEV expands under the influence of climate change, Australian GPs need to be familiar with this condition, especially those practicing in rural areas and where detections have occurred.


Collagen cross-linking using rose bengal and green light to increase corneal stiffness.
Photochemical cross-linking of corneal collagen is an evolving treatment for keratoconus and other ectatic disorders. We evaluated collagen cross-linking by rose bengal plus green light (RGX) in rabbit eyes and investigated factors important for clinical application. Rose bengal (RB, 0.1%) was applied to deepithelialized corneas of enucleated rabbit eyes for 2 minutes. The diffusion distance of RB into the stroma was measured by fluorescence microscopy on frozen sections. RB-stained corneas were exposed to green (532-nm) light for 3.3 to 9.9 minutes (50-150 J/cm(2)). Changes in the absorption spectrum during the irradiation were recorded. Corneal stiffness was measured by uniaxial tensiometry. The spatial distribution of the stromal elastic modulus was assessed by Brillouin microscopy. Viable keratocytes were counted on H&E-stained sections 24 hours posttreatment. RB penetrated approximately 100 μm into the corneal stroma and absorbed >90% of the incident green light. RGX (150 J/cm(2)) increased stromal stiffness by 3.8-fold. The elastic modulus increased in the anterior approximately 120 μm of stroma. RB was partially photobleached during the 2-minute irradiation, but reapplication of RB blocked light transmission by >70%. Spectral measurements suggested that RGX initiated cross-linking by an oxygen-dependent mechanism. RGX did not decrease keratocyte viability. RGX significantly increases cornea stiffness in a rapid treatment (≅12 minutes total time), does not cause toxicity to keratocytes and may be used to stiffen corneas thinner than 400 μm. Thus, RGX may provide an attractive approach to inhibit progression of keratoconus and other ectatic disorders.


Magnetic super-hydrophilic carbon nanotubes/graphene oxide composite as nanocarriers of mesenchymal stem cells: Insights into the time and dose dependences.
Among nanostructured materials, multi-walled carbon nanotubes (MWCNT) have demonstrated great potential for biomedical applications in recent years. After oxygen plasma etching, we can obtain super-hydrophilic MWCNT that contain graphene oxide (GO) at their tips. This material exhibits good dispersion in biological systems due to the presence of polar groups and its excellent magnetic properties due to metal particle residues from the catalyst that often remain trapped in its walls and tips. Here, we show for the first time a careful biological investigation using magnetic superhydrophilic MWCNT/GO (GCN composites). The objective of this study was to investigate the application of GCN for the in vitro immobilization of mesenchymal stem cells. Our ultimate goal was to develop a system to deliver mesenchymal stem cells to different tissues and organs. We show here that mesenchymal stem cells were able to internalize GCN with a consequent migration when subjected to a magnetic field. The cytotoxicity of GCN was time- and dose-dependent. We also observed that GCN internalization caused changes in the gene expression of the proteins involved in cell adhesion and migration, such as integrins, laminins, and the chemokine CXCL12, as well as its receptor CXCR4. These results suggest that GCN represents a potential new platform for mesenchymal stem cell immobilization at injury sites.


PSP-Richardson syndrome mimics: An overview and pragmatic approach.
Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a sporadic atypical parkinsonian syndrome with levodopa-unresponsive axial-predominant parkinsonism, early postural instability, vertical supranuclear gaze palsy, dysarthria, executive dysfunction and behavioural changes. PSP-RS can be mimicked by numbers of other disorders, generally known as PSP mimics, or PSP-like syndromes. Their aetiological spectrum includes neurodegenerative (mostly genetic), vascular, infectious and drug-induced illnesses as well as other causes. Based on the available data, we have tried to create a definition of PSP-RS mimics: a syndrome resembling PSP-RS with at least one of the following red flags: 1) positive family history; 2) onset before 45 years of age; 3) rapid or stepwise progression; 4) acute or subacute onset; 5) atypical symptoms and/or signs; 6) normal or atypical brain MRI; 7) history of HIV or untreated syphilis, aortal surgery or recent therapy with dopamine-blocking agents. We have suggested a short diagnostic algorithm leading to the identification of PSP-RS mimics and the recommended diagnostic work-up. The key point of the diagnostic process is the early identification and treatment of potentially treatable PSP-RS mimics.


Evaluating the effect of using anti-stress balls as a distraction technique in reducing pain during inferior alveolar nerve block injection: a randomized clinical trial.
The aim of this study is to evaluate the effect of using anti-stress balls in reducing patients' pain during injection of the inferior alveolar nerve block (IANB). In this randomized clinical trial, 32 individuals were divided into two groups. The conventional method of anesthesia injection was performed using IANB conventional injection technique. During the injection, individuals in the anti-stress ball group were asked to use the anti-stress ball as a distraction technique. For the control group, no supersede methods were used for pain control. Finally, both groups were asked to record their pain utilizing the numerical rating scale (NRS). The participants' vital signs were monitored before and after injection. Kolmogorov-Smirnov test, independent T-test, and Fisher's exact chi-square test were performed for statistical analysis (α = 0.05). Sixteen females and 16 males in the age range of 40 to 20 years old participated in this study. The mean pain score in the anti-stress ball group was significantly lower (p < 0.001). In both sexes, the pain score in the anti-stress ball group was significantly lower (males p < 0.001 and females p = 0.001). In addition, in all age ranges, the pain score in the control group was higher except for the above 35 years old participants (p = 0.078). Moreover, there were no significant differences in individuals' vital signs (p > 0.05). Utilizing an anti-stress ball reduces patients' pain significantly during IANB in both sexes and individuals who are below 35 years without changing vital signs. IRCT20220815055704N1.


Male patients' preferences for opioid use treatment programs.
A patient-centered approach to the treatment of substance use is helpful in achieving positive treatment outcomes. This study aimed to explore male patients' preferences for opioid use treatments. A qualitative study was conducted in Isfahan, a city in the center of Iran. The study sample included 64 male participants who had started treatment for opioid use disorder (OUD). Using a purposive maximum variation sampling procedure, seven treatment centers were selected as interview venues. The semi-structured face-to-face interviews were conducted in a private room in the selected centers. A hybrid inductive/deductive approach was used to thematize the interview transcripts. A total of three themes and 13 subthemes on opioid treatment preferences were identified: treatment concerns (anonymity, social stigma, fear of treatment distress, and family concerns), treatment attributes (treatment cost, location of the treatment center, treatment period, frequency of attendance, informed treatment, and treatment personnel), and treatment type (maintenance or abstinence and residential and community treatments). The study showed that all treatment programs were perceived to have their own strengths and weaknesses. The results showed that patients with OUD carefully compare the positive and negative aspects of existing treatment programs, and they consider a treatment program to be a package of favorable and non-favorable qualities. The identified themes could inform policymakers about the treatment preferences of male patients and provide an opportunity to promote better treatment options for OUD.


[Treatment of refractory asthma with antibodies].
Current guidelines of the global initiative for asthma (GINA) recommend the addition of biologics in step 5 of the stepwise asthma treatment approach. This review gives an overview on the effects and the clinical role of antibodies targeting immunoglobulin E, IgE (Omalizumab), Interleukin-5, IL-5 (Mepolizumab, Reslizumab) or the IL-5 receptor (Benralizumab). In addition, potential future treatment options of refractory asthma with antibodies (for instance Dupilumab) are discussed.


Alternative approaches to well-being and engagement in Vanuatu.
This article describes some innovative approaches to understanding, measuring and attributing value to traditional wisdom in Vanuatu. The article uses decolonising methodologies to privilege indigenous perspectives. In particular, the study features the use of endogenous practices, such as sand drawing, as a vehicle for facilitating community engagement in the research. The results of the project reveal that, in the context of broad structural support for customary practices, communities leveraging traditional wisdom into commercial realms are able to generate livelihoods and maintain cultural heritage transmission. Local communities report increased pride and pleasure in the resurgence and innovation of cultural practices.


Computed tomography-planned interstitial brachytherapy for locally advanced gynecologic cancer: Outcomes and dosimetric predictors of urinary toxicity.
To identify dosimetric predictors of outcome and toxicity in patients receiving CT-planned interstitial brachytherapy (ISBT) for gynecologic cancers. Patients who received ISBT between 2009 and 2014 were reviewed. Demographic, disease specific, treatment, and toxicity data were collected. Logistic regression was used to model toxicity. A least absolute shrinkage and selection operator penalty was used to identify relevant predictors. Receiver operating characteristic curves were used to analyze the relation between dosimetric factors and urinary toxicity. Seventy-three patients received ISBT (21 at time of cancer recurrence and 52 at the first presentation). Thirty-six patients had cervical cancer, 16 had vaginal cancer, 13 had uterine cancer, and 8 had vulvar cancer. ISBT was performed using both high-dose-rate and low-dose-rate 192Ir sources (27 low dose rate and 46 high dose rate). With a median followup of 12 months, Grade 3 vaginal, urinary, and rectal toxicity occurred in 17.8%, 15.1%, and 6.8% of patients, respectively. No patients experienced Grade 4 or 5 toxicity. Dose to 0.1cc of urethra predicted for development of Grade 3 urinary toxicity (area under the curve of 0.81; 95% confidence interval: 0.66, 0.96). A 10% probability of a Grade 3 urinary toxicity associated with a dose of 23.1 equivalent dose in 2 Gy fractions (95% confidence interval: 9.51, 36.27 equivalent dose in 2 Gy fractions). ISBT is a safe treatment for gynecologic malignancies. The dose to 0.1cc significantly predicts for severe urinary toxicity. Our data suggests that dose to a small urethral volume may be the most significant predictor of urinary toxicity in patients receiving ISBT for gynecologic cancer.


Natural History of Acute Subdural Hematoma.
Because published guidelines for surgical decision-making in patients with acute subdural hematomas (ASDHs) are based largely on case series and other weak evidence, management often must be individualized. Nonoperative management is a viable option in many cases. The literature is divided about the effects of anticoagulant and antiplatelet medications on rapid growth of ASDHs and on their likelihood of progression to large chronic subdural hematomas. Close clinical and radiologic follow-up is needed, both acutely to detect rapid expansion of an ASDH, and subacutely to detect formation of a large subacute or chronic subdural hematoma.


Strain-specific occurrence of two ornithine decarboxylase species in mouse kidney.
Ornithine decarboxylase in the crude extract from the kidney of androgen-treated mice was labeled by reaction with radioactive alpha-difluoromethylornithine and analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis followed by autoradiography. Two species of ornithine decarboxylase with molecular weights of 54,000 and 52,000 were observed in the crude extracts from BALB, C57BL, C58, SJL, and dd mice but only the species with a molecular weight of 54,000 was observed in the crude extracts from AKR and C3H mice, indicating strain-specific occurrence of at least two species of mouse ornithine decarboxylase.


Continuity of care and caring: what matters to parents of children with life-threatening conditions.
This article presents parents' perceptions regarding continuity and coordination of care of children with life-threatening conditions as revealed through qualitative analysis of interviews with 36 bereaved parents of children who died after receiving care at three geographically dispersed teaching hospitals in the United States. Parental concerns about and experience of continuity of care were framed primarily in terms of the quality and continuity of relationships with healthcare providers throughout a child's illness and death and the continuity and consistency of information that they received about their child's condition and care. Continuity in relationships was perceived as key in ensuring that clinicians knew and cared about the child and parents, which in turn contributed to parents' confidence that their child would receive the best possible care. In the absence of continuous, caring relationships with staff, parents reported frustration, hypervigilance, and mistrust about the quality of care that their child received.


Determination of metaldehyde in human serum by headspace solid-phase microextraction and gas chromatography-mass spectrometry.
A rapid headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) method has been developed for the determination of metaldehyde in human serum samples. Metaldehyde is extensively used as a molluscicide for the control of slugs and snails, and cases of metaldehyde poisoning have been reported. Metaldehyde was headspace-extracted on a polydimethylsiloxane (PDMS) fiber at 70 degrees C for 25 min, desorbed, and analyzed rapidly by GC-MS. The method was validated for limit of detection (LOD), linearity, precision, and recovery. Although the recovery of the sample was very low, the method itself was rapid with a low detection limit of 0.25 microg/ml, R.S.D. value 12.6%, and linearity range 0.5-25.0 microg/ml (r(2)=0.999). The results demonstrated that the SPME-GC-MS method for the analysis of metaldehyde is simple, rapid, solvent-free, and does not require any pre-analysis conversions.


The pharmacoeconomic impact of antimicrobial therapy for peptic ulcer disease in a large urban jail.
To determine the pharmacoeconomic impact of antimicrobial treatment of peptic ulcer disease (PUD) in a large urban jail. Retrospective comparison of PUD-related pharmacy and laboratory expenditures over a 2-year period before and after the institution of a PUD treatment protocol with the priority of Helicobacter pylori eradication for inmates in Rikers Island Correctional Facility. After the protocol was adopted, total pharmacy-related and laboratory-related expenses for PUD care decreased by 40.2%, and expenditures for ranitidine declined by 52.2%. There was an increase in spending for antimicrobial agents and H. pylori antibody testing, but this was insignificant compared to the savings generated by decreased ranitidine usage. Annual savings in our facility as a result of this intervention were $123,449. Modern therapeutic strategies for PUD aimed at eradicating H. pylori can result in significant savings in the institutional setting; these savings are largely attributable to the decreased usage of histamine-2 receptor antagonists.


Synthesis and biological evaluation of novel 4,5-disubstituted 2H-1,2,3-triazoles as cis-constrained analogues of combretastatin A-4.
A series of combretastatin A-4 (CA-4) analogues have been prepared from (Z)-substituted diarylacrylonitriles (1a-1p) obtained in a two-step synthesis from appropriate arylaldehydes and acrylonitriles. The resulting 4,5-disubstituted 2H-1,2,3-triazoles were evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The diarylacrylonitrile analogue 2l exhibited the most potent anti-cancer activity in the screening studies, with GI₅₀ values of <10 nM against almost all the cell lines in the human cancer cell panel and TGI values of <10 nM against cancer cell lines SF-539, MDA-MB-435, OVCAR-3 and A498. Furthermore, in silico docking studies of compounds 2l, 2e and 2h within the active site of tubulin were carried out in order to rationalize the mechanism of the anti-cancer properties of these compounds. From the in silico studies, compound 2e was predicted to have better affinity for the colchicine binding site on tubulin compared to compounds 2l and 2h. Analogue 2e was also evaluated for its anti-cancer activity by colony formation assay against 9LSF rat gliosarcoma cells and afforded an LD₅₀ of 7.5 nM. A cell cycle redistribution assay using analogue 2e was conducted to further understand the mechanism of action of these CA-4 analogues. From this study, analogues 2e and 2l were the most potent anti-cancer agents in this structural class, and were considered lead compounds for further development as anti-cancer drugs.


Editorial Commentary: Superior Capsular Reconstruction for Irreparable Supraspinatus Tear Reveals Improved Biomechanics With a Thicker Graft Placed in 15° to 45° of Shoulder Abduction.
Biomechanical study of superior capsular reconstruction for irreparable supraspinatus tears has lower subacromial contact pressures with a thicker graft placed in 15° to 45° of shoulder abduction. Whether this translates to the clinical situation of massive rotator cuff insufficiency remains to be determined.


Panspecies molecular assays detect viral pathogens missed by real-time PCR/reverse-transcriptase PCR among pneumonia patients, Sarawak, Malaysia.
In a year-long pneumonia etiology study conducted June 2017 to May 2018 in Sarawak, Malaysia, 599 patients' nasopharyngeal swab specimens were studied with real-time polymerase chain reaction (rPCR)/ reverse-transcription (rRT-PCR) assays for respiratory pathogens known to contribute to the high burden of lower respiratory tract infections. The study team sought to compare real-time assay results with panspecies conventional molecular diagnostics to compare sensitivities and learn if novel viruses had been missed. Specimens were studied for evidence of adenovirus (AdV), enterovirus (EV) and coronavirus (CoV) with panspecies gel-based nested PCR/RT-PCR assays. Gene sequences of specimens positive by panspecies assays were sequenced and studied with the NCBI Basic Local Alignment Search Tool software. There was considerable discordance between real-time and conventional molecular methods. The real-time AdV assay found a positivity of 10.4%; however, the AdV panspecies assay detected a positivity of 12.4% and the conventional AdV-Hexon assay detected a positivity of 19.6%. The CoV and EV panspecies assays similarly detected more positive specimens than the real-time assays, with a positivity of 7.8% by the CoV panspecies assay versus 4.2% by rRT-PCR, and 8.0% by the EV panspecies assay versus 1.0% by rRT-PCR. We were not able to ascertain virus viability in this setting. While most discordance was likely due to assay sensitivity for previously described human viruses, two novel, possible zoonotic AdV were detected. The observed differences in the two modes of amplification suggest that where a problem with sensitivity is suspected, real-time assay results might be supplemented with panspecies conventional PCR/RT-PCR assays.


Effect of immunisation on the early influx of neutrophils during staphylococcal mastitis in ewes.
The neutrophil influx into mammary secretions was studied in unimmunised, and in systemically and locally immunised, lactating and non-lactating ewes experimentally infected with Staphylococcus aureus. Systemic immunisation was effected by subcutaneous injection of live bacteria or by intramuscular injection of killed bacteria in Freund's incomplete adjuvant. The initial inflammatory response to infection of the mammary glands of systemically immunised lactating ewes was at first comparable with that for unimmunised, lactating ewes. However by eight hours after challenge the leucocyte concentrations were lower in systemically immunised ewes. In non-lactating ewes immunised with live vaccine, higher leucocyte concentrations and higher proportions of neutrophils were recorded four hours after infection (hpi) than for unimmunised ewes or ewes immunised with killed vaccine. Prior local immunisation, by unilateral infusion of killed bacteria into mammary glands, enhanced the initial neutrophil influx in comparison to infection of unimmunised contralateral glands of non-lactating ewes by four hpi. For these animals the proportion of neutrophils in washings from immunised glands were significantly greater than for unimmunised glands four and six hpi. In two of three locally immunised lactating ewes there was a larger neutrophil influx into secretions of locally immunised glands than unimmunised glands six hpi. Neutrophils comprised more than 93 per cent of leucocytes from all infected glands by eight hpi. The results suggest that differences in the rate of influx of neutrophils into infected mammary glands of immunised and unimmunised ewes could be attributed to immunological enhancement of neutrophil recruitment or to limitation of toxic damage to tissues with consequently diminished neutrophil invasion.


Quaternary structure of vaccinia virus thymidine kinase.
Thymidine kinase enzymes isolated from a variety of sources are generally considered to have a native molecular weight of 80-90 kDa composed of two 40-45 kDa subunits. Although these parameters may accurately describe the atypical deoxypyrimidine kinases expressed by members of the Herpesviridae, the nucleotide sequences of thymidine kinase genes isolated from human, mouse, chicken and variety of poxviruses (vaccinia virus, monkeypox virus, variola virus, fowlpox virus and capripoxvirus) predict molecular weights on the order of 20-25 kDa for the derived primary translation products. To resolve this apparent dilemma, velocity sedimentation centrifugation, gel filtration chromatography and protein cross-linking procedures were employed to provide experimental evidence that enzymatically-active vaccinia virus thymidine kinase is a homotetrameric complex of 20 kDa monomers with a native Mr of 80 kDa.


L-carnitine treatment partially restores urinary bladder function of streptozotocin diabetic rats.
Diabetes mellitus is associated with urinary bladder dysfunction. This study determined whether or not detrusor responses were altered and reversed by L-carnitine treatment in the urinary bladders of diabetic rats. Three groups of animals were used: streptozotocin-treated (45 mg x kg(-1) i.p., 8 weeks), parallel L-carnitine-treated (0.6 g x kg(-1) x day(-1) i.p.), and control rats. Contractile and relaxant responses were measured using isolated bath techniques. Serum glucose levels in diabetic rats were partially reversed after L-carnitine treatment. Detrusor strips from diabetic rats exhibited an increase in response to electrical field stimulation (EFS; 0.5-32 Hz). Treatment with L-carnitine restored the hyperreactivity to EFS-induced contractility. The response to direct activation of the smooth muscle with carbachol and KCl remained unaltered. In relaxation studies, the urinary bladders of diabetic rats displayed a diminished response to isoprenaline, an unchanged response to ATP, and an increased response to adenosine of the ATP metabolite. L-carnitine treatment restored the hyporesponsiveness of isoprenaline and the hyperresponsiveness of adenosine-elicited relaxation. These findings show that carnitine can be implicated in the contractile response of noradrenergic noncholinergic nerve stimulation and the relaxation response of isoprenaline and adenosine. Hence, L-carnitine deficiency can contribute to voiding deficiency in diabetic patients.


Effects of antiglaucoma drugs on the ocular surface in rabbits: a fixed-combination drug versus two concomitant drugs.
We investigated the effects of a fixed-combination antiglaucoma drug and compared it with two concomitant antiglaucoma drugs on the ocular surface. Twenty-four rabbits were randomized into four groups. Group 1 was administered timolol, group 2 travoprost, group 3 a travoprost/timolol fixed-combination solution, and group 4 timolol and travoprost. Conjunctival impression cytology specimens were collected at baseline and weeks 1, 3, and 6, and conjunctival biopsy specimens at week 6. The impression cytology study results were as follows: No statistically significant differences among group 1-3 at any time (p > 0.05); a statistically significant difference between groups 3 and 4 at week 6 (p = 0.003); a statistically significant difference between baseline and group 4 at week 6 (p = 0.008). Conjunctival biopsy specimens of group 1-3 showed no distortion of the conjunctival epithelial structures, but group 4 showed decreased layers of epithelial cells with fewer periodic acid-Schiff (PAS) (+) goblet cells. A fixed-combination antiglaucoma drug is beneficial in reducing adverse ocular surface changes in long-term use. This is believed to be due to the smaller concentration of preservatives contained in the fixed-combination drug.


A spontaneous sarcoma dependent on host tumor-specific immune lymphocytes.
The immune surveillance theory postulates that spontaneous tumors are normally rejected by the immune system and appear only when they override host-immune recognition and rejection mechanisms. The present mini-review describes a spontaneous tumor system, the reticulum cell sarcomas (RCS) in SJL/J mice, that is dependent on host tumor-specific immune lymphocytes for growth. This continuous tumor-specific response results in tumor progression and death of the host. This tumor system contradicts the basic concept of immune surveillance. We propose as an explanation that some highly antigenic tumors, like the RCS, may have evolved in a non-autonomous fashion but, nevertheless, have lost regulatory controls of cell proliferation. In the RCS system, the tumor expresses Class II MHC I-E like specificities that are not expressed on the host cells and which selectively stimulate a subpopulation of I-E specific T cells, the V beta 17 a+ clonotype, leading to their expansion and continuous nurturing of the tumor via secreted lymphokines. This neoantigenic stimulation bypasses the tumor regulatory response that might have resulted if the tumor had not expressed neoantigens. Furthermore, passive administration of anti-clonotypic antibody to tumor-bearing mice results in tumor regression and long-term survival through removal of the tumor reactive T cells. Thus, in this tumor system, immunosuppressive treatments are the prescription for tumor rejection.


Umbilical mesenchymal stem cell-derived exosomes promote spinal cord functional recovery through the miR-146b/TLR4 -mediated NF-κB p65 signaling pathway in rats.
Spinal cord injury (SCI) is an incurable central nervous system impairment that lack of efficient treatment. Exosomes derived from mesenchymal stem cells (MSCs) are widely applied in disease treatment. This work aimed to determine the promising therapeutic effects of MSC-derived exosomal miRNA146b on SCI. A rat spinal cord injury (SCI) model and lipopolysaccharide (LPS)-induced PC12 cell model were established. Exosomes were extracted from human umbilical cord mesenchymal stem cells (hUCMSCs). The identification of exosomes was performed by using transmission electronic microscope (TEM) and nanoparticle tracking analysis (NTA). Hematoxylin and eosin (HE) staining and TUNEL assay were performed to assess tissue damage and apoptosis, respectively. ELISA was performed to detect levels of inflammatory cytokines. Cell viability was checked by cell counting kit 8 (CCK-8). Gene expression and protein levels were detected by qPCR and western blotting assay. The interaction between miR-146 b and Toll-like receptor 4 (TLR4) was assessed by luciferase reporter gene assay. The hUCMSC-derived exosomes could notably alleviate the spinal cord injury and cell apoptosis. The exosomal miR-146 b treatment suppressed the release of IL-1 β, IL-6, and TNFα. The miR-146 b suppressed the expression of TLR4, directly interact with the 3'-untranslated region (3'UTR) of TLR4, and inactivated the nuclear factor κB (NF-κB) signaling. The hUCMSCs-derived exosomal miR-146 b protects neurons from spinal cord injury through targeting the TLR4 and inactivating the NF-κB signaling. Our findings supported the application of hUCMSCs-derived exosomal miR-146 b for the protection of SCI.


Five-year clinical evaluation of universal adhesive applied following different bonding techniques: A randomized multicenter clinical trial.
To evaluate the clinical performance of a universal adhesive system (Futurabond U, Voco) when applied following different adhesive strategies in non-carious cervical lesions (NCCLs) after 5 years. Fifty participants were included. Futurabond U (Voco) was applied in NCCLs using four adhesive strategies (n = 50 each): only self-etch (SE); selective enamel etching + self-etch (SET + SE); etch-and-rinse with dry dentin (ERD); and etch-and-rinse with wet dentin (ERW). All cavities were restored with Admira Fusion composite resin (Voco). Restorations were evaluated after 1, 3, and 5 years using the World Federation criteria (FDI) and the modified United States Public Health Service (USPHS) criteria. After 5 years, retention rates were 81 % (65.8-90.5) for SE, 87 % (73.2-94.4) for SET + SE, 84 % (69.6-92.6) for ERD, and 78 % (63.6-88.9) for ERW (p > 0.05). Thirty-five restorations were considered to have minor discrepancies in marginal adaptation at the 5-year recall (14 for SE, 9 for SET + SE, 6 for ERD, and 6 for ERW; p > 0.05). Sixteen restorations were detected as a minor marginal discoloration (6 for SE, 4 for SET + SE, 1 for ERD, and 5 for ERW; p > 0.05) and one restoration showed a recurrence of caries (1 for ERW; p > 0.05) at the 5-year recall. No restorations showed postoperative sensitivity after 5 years. NCCLs restorations using a universal adhesive showed satisfactory clinical performance after 5 years, regardless of the adhesive strategy.


Downregulation of MCF2L Promoted the Ferroptosis of Hepatocellular Carcinoma Cells through PI3K/mTOR Pathway in a RhoA/Rac1 Dependent Manner.
The levels of MCF2L were detected by PCR and western blotting assay. The effect of MCF2L on ferroptosis was confirmed by MTT, colony formation assay, Brdu, in vivo animal experiment, and the content of Iron, GSH, ROS, and MDA. The underlying mechanisms were explored by PCR, western blotting, and affinity precipitation assay. Our findings demonstrated that MCF2L is remarkedly upregulated in HCC tissues, and sorafenib can induce the levels of MCF2L, suggesting that MCF2L might function in sorafenib resistance of HCC. Further analysis showed that downregulation of MCF2L enhances HCC cell death induced by sorafenib, and ferroptosis inhibitor can reverse this process. Subsequent experiments showed that downregulation of MCF2L elevates the content of Iron, ROS, and MDA, which are all indicators of ferroptosis. Finally, mechanism analysis showed that MCF2L regulates the PI3K/AKT pathway in a RhoA/Rac1 dependent manner. Our study showed that targeting MCF2L may be a hopeful method to overcome sorafenib-resistance through inducing ferroptosis in HCC.


Noninvasive Continuous Glucose Monitoring Using a Multisensor-Based Glucometer and Time Series Analysis.
Daily continuous glucose monitoring is very helpful in the control of glucose levels for people with diabetes and impaired glucose tolerance. In this study, a multisensor-based, noninvasive continuous glucometer was developed, which can continuously estimate glucose levels via monitoring of physiological parameter changes such as impedance spectroscopy at low and high frequency, optical properties, temperature and humidity. Thirty-three experiments were conducted for six healthy volunteers and three volunteers with diabetes. Results showed that the average correlation coefficient between the estimated glucose profiles and reference glucose profiles reached 0.8314, with a normalized root mean squared error (NRMSE) of 14.6064. The peak time of postprandial glucose was extracted from the glucose profile, and its estimated value had a correlation coefficient of 0.9449 with the reference value, wherein the root mean square error (RMSE) was 6.8958 min. Using Clarke error grid (CEG) analysis, 100% of the estimated glucose values fell in the clinically acceptable zones A and B, and 92.86% fell in zone A. The application of a multisensor-based, noninvasive continuous glucometer and time series analysis can endure the time delay between human physiological parameters and glucose level changes, so as to potentially accomplish noninvasive daily continuous glucose monitoring.


Effects of potassium halides on bacterial bioluminescence.
The effects of potassium halides KCl, KBr and KI on NADH:FMN-oxidoreductase-luciferase bioluminescent coupled enzyme system were studied. The influence of salt additions on bioluminescence intensity and bioluminescence light yield was investigated. The inhibition and activation parameters of the salts were calculated using their dependencies on concentration of the salts. The correlation between the inhibition of bioluminescence intensity and the halide mass was demonstrated: the inhibiting ability of the salts increases with the increase of atomic weight of the anions. The inhibition parameters increase and the activation parameters decrease, accordingly.


Clinical efficacy of metagenomic next-generation sequencing for rapid detection of Mycobacterium tuberculosis in smear-negative extrapulmonary specimens in a high tuberculosis burden area.
The aim of this study was to assess the clinical utility of metagenomic next-generation sequencing (mNGS) on smear-negative extrapulmonary specimens collected in China. Specimens were tested by mNGS and other routine tests for tuberculosis (TB). The diagnostic accuracy of mNGS was calculated and compared with the final clinical diagnosis. The sensitivity of mNGS was found to be significantly higher than the sensitivities of the other routine TB tests. Receiver operating characteristic curve analysis showed that mNGS achieved the highest area under the curve (AUC) value of 0.79. The mNGS positive rate was highest for tuberculous meningitis. All non-tuberculous extrapulmonary pathogens were directly and simultaneously detected. mNGS appeared to be superior to all previous etiological tests for TB on smear-negative extrapulmonary specimens and could identify all possible pathogens at once within 48 h.


Significance of lymph node metastasis in cancer dissemination of head and neck cancer.
Lymph node metastasis (LNM) in many solid cancers is a well-known prognostic factor; however, it has been debated whether regional LNM simply reflects tumor aggressiveness or is a source for further tumor dissemination. Similarly, the metastatic process in head and neck cancer (HNC) has not been fully evaluated. Thus, we aimed to investigate the relative significance of LNM in metastatic cascade of HNC using functional imaging of HNC patients and molecular imaging in in vivo models. First, we analyzed (18)Fluorodeoxyglucose positron emission tomography (PET) parameters of 117 patients with oral cancer. The primary tumor and nodal PET parameters were measured separately, and survival analyses were conducted on the basis of clinical and PET variables to identify significant prognostic factors. In multivariate analyses, we found that only the metastatic node PET values were significant. Next, we compared the relative frequency of lung metastasis in primary ear tumors versus lymph node (LN) tumors, and we tested the rate of lung metastasis in another animal model, in which each animal had both primary and LN tumors that were expressing different colors. As a result, LN tumors showed higher frequencies of lung metastasis compared to orthotopic primary tumors. In color-matched comparisons, the relative contribution to lung metastasis was higher in LN tumors than in primary tumors, although both primary and LN tumors caused lung metastases. In summary, tumors growing in the LN microenvironment spread to systemic sites more commonly than primary tumors in HNC, suggesting that the adequate management of LNM can reduce further systemic metastasis.


Liquid chromatography-mass spectrometry of trace compounds with a moving-belt interface and multi-dimensional chromatography.
A high-performance liquid chromatographic method with on-line mass spectrometric detection is described for the structural analysis of a number of synthetic impurities, present at trace levels in almitrine. To obtain mass spectra with various ionization methods and high-resolution mass measurements, a moving-belt liquid chromatograph-mass spectrometer interface is used. A two-column switching system allows the injection of large amounts of almitrine, from which the trace compounds are trapped on a second column, while discarding the major component. This permits the introduction of the impurities into the mass spectrometer by elution of the second column, without the risk of introducing too large an amount of the major compound into the mass spectrometer. The mass spectra thus obtained are of sufficient quality to permit a correct structural assignment of the impurities.


Stem cell mobilization in idiopathic steroid-sensitive nephrotic syndrome.
Steroid-sensitive nephrotic syndrome (SSNS) is classically thought to be a T-cell disorder. The aim of this study was to examine whether or not thymus homeostasis was affected in SSNS. Mature and naive T cell recent thymic emigrants were quantified in the peripheral blood of nephrotic patients and controls. Because the generation of new T cells by the thymus ultimately depends on hematopoietic stem cells, CD34+ cells were also included in the study. Nineteen patients with SSNS during relapse, 13 with SSNS during proteinuria remission, and 18 controls were studied. Cell-surface markers (CD3, CD4, CD8, CD19, CD16, CD56, CD45RA, CD62L, CD34, and CD38) were analyzed by flow cytometric analysis. T-cell rearrangement excision circles (TRECs) were quantified in CD2+ cells by real-time polymerase chain reaction. Stroma cell-derived factor-1 (SDF-1) genotype and metalloproteinase-9 (MMP-9) plasma levels were also determined. Mature T cells (CD4+ and CD8+), circulating naive T cells (CD62L+ and CD3+ CD62L+), and recent thymic emigrants (CD45RA+) as well as TRECs, that measure thymus production, had a similar level in the three groups of patients. Conversely, CD34+ hematopoietic stem cells displayed a two-fold increase in SSNS patients during relapse either compared with controls or SSNS patients at remission. In addition, compared with controls, SSNS patients at remission displayed (1) a decrease in CD19+ cells (B cells) and (2) an increase in CD16CD56+ cells [natural killer (NK) cells]. In conclusion, thymus homeostasis is not significantly affected in nephrotic patients. Hematopoietic stem-cell mobilization at proteinuria relapse, as well as changes in B and NK cells during remission, suggest that SSNS might be due to a general disturbance of hematopoietic and immune cell trafficking.


[The habit of black lacquering of teeth and dental caries].
The habit of applying black lacquer to teeth is widespread in Vietnam. Observations are reported on its effect on the incidence of dental caries and its usefulness in caries treatment.


Histopathological aspects of cardiac biopsy in pediatric patients with dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is a heart muscle disease with cardiac dysfunction and a heterogeneous disorder. This disease may show various histopathological aspects of the myocardium, but little is known about these in children. Histopathological findings of endomyocardial biopsy from 20 pediatric patients with DCM were analyzed and compared with those in adult patients. Advanced histopathology, including myocytolysis and/or fragmentation of muscle bundles, was frequently observed in patients with poor prognosis. Patchy fibrosis was predominantly demonstrated in the pediatric patients, whereas perivascular fibrosis was mostly observed in the older adults. The myocarditic index, assessed in terms of the findings of fibrosis, size variation of myocytes, disarrangement of muscle bundles and mononuclear cell infiltration was higher in the pediatric patients than in the older adults (P < 0.05). Bizarre myocardial hypertrophy with disorganization, which tends to be frequently demonstrated in hypertrophic cardiomyopathy, was revealed in 30% of the pediatric patients, whereas it was disclosed in none of the older adult patients (P < 0.05). These results suggest that the major pathogenetic factors of DCM in children may be different from those in adults.


Biometric comparison of bur and electrosurgical retraction methods.
A biometric comparison of two retraction methods was made on 20 adult patients who received complete crowns. Free gingival tissue height was recorded after 4, 8, and 12 weeks. The conclusions were (1) the electrosurgical method showed more tissue loss at each time interval than the bur method, (2) electrosurgical retraction showed more subject variability than the bur method, (3) clinically, the tissue appearance of both groups was indiscernable at the time intervals tested, and (4) the electrosurgical method provided for a greater bulk of impression material at the margin than the bur method.


NT-proBNP Levels Following IVIG Treatment of Multisystem Inflammatory Syndrome in Children.
N-terminal of probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels are often elevated in multisystem inflammatory syndrome in children (MIS-C) secondary to inflammation, myocardial dysfunction, or increased wall tension. Intravenous immunoglobulin (IVIG), accepted treatment of MIS-C, may transiently increase myocardial tension and contribute to an increase in NT-proBNP. We sought to study the association between pre- and post-IVIG levels of NT-proBNP and CRP and their clinical significance. This single-center, retrospective, cohort study included consecutive children, aged ≤21 years, with diagnosis of MIS-C who received IVIG from April 2020 to October 2021. Data collection included clinical characteristics, laboratory tests, management, and outcomes. Study cohort consisted of patients who received IVIG and had NT-proBNP levels available pre- and post-IVIG. Among 35 patients with MIS-C, 30 met inclusion criteria. Twenty-four, 80%, showed elevation in NT-proBNP post-IVIG. The median NT-proBNP level pre-IVIG was 1921 pg/mL (interquartile range 548-3956), significantly lower than the post-IVIG median of 3756 pg/mL (interquartile range 1342-7634)) (P = .0010). The median pre-IVIG CRP level was significantly higher than the post-IVIG level (12 mg/dL vs 8 mg/dL, P = .0006). All but 1 recovered before discharge, and none had signs of worsening cardiac function post-IVIG. In those who recovered, NT-proBNP had normalized by discharge or 1-week follow-up. Our study shows that NT-proBNP levels often transiently increase immediately after IVIG therapy without signs of worsening myocardial function. These values should be interpreted in the context of CRP levels and clinical recovery.


Novel steroidal vinyl fluorides as inhibitors of steroid C17(20) lyase.
20-fluoro-17(20)-pregnenolone derivatives were designed as enol mimics of pregnenolone. All of the targeted, novel fluoroolefins were potent inhibitors of C17(20) lyase.


Combination of Deauville score and quantitative positron emission tomography parameters as a predictive tool of anti-CD19 chimeric antigen receptor T-cell efficacy.
Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an effective treatment for approximately 40% of relapsed/refractory large B cell lymphomas (LBCL), and early identification of patients at risk for relapse or progression after CAR T-cell therapy represents a clinical need. The authors conducted a single-center prospective study on 47 relapsed/refractory LBCL receiving CAR T-cell therapy to evaluate the prognostic value of baseline and after infusion 18 F-fluorodeoxyglucose positron emission tomography (PET)-computed tomography. Qualitative and quantitative metabolic parameters were evaluated before lymphodepletion, at day 30 and 90 post-infusion. Deep variation of standardized uptake value (SUV)mean between baseline and day 30 correlated with response at day 90 (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.01-2.2); p = .04) and better progression-free survival (PFS) (HR, 0.63; 95% CI, 0.41-0.97); p = .04). In the overall population, 1-year PFS was 63% for Deauville score (DS)1-3 and 39% for DS4-5 patients, respectively (p = .02), however, the prognostic role of DS was lost when survivals are analyzed by considering 38 patients not progressing at 30 days. In these patients, in partial response or stable disease, the combination of DS and variation of SUVmean allowed identification of three groups with different prognosis: patients with DS1-3 and those with DS4-5 and decreased SUVmean had similar 1-year PFS of 62% and 61%, whereas patients with DS4-5 and increased SUVmean had a poorer 1-year PFS of 33% (p = .04). PET parameters and association of DS and variation of SUVmean at 30 days could help in identify patients at high risk of CAR T-cell failure. This is a single-center prospective study on 47 lymphoma patients receiving commercial chimeric antigen receptor T-cell therapy aimed to evaluate the prognostic value of baseline and after infusion 18 F-fluorodeoxyglucose positron emission tomography. Among patients in partial remission or stable disease at day 30, the authors observed two subgroups with significantly different prognosis; patients with Deauville score (DS)4-5 and a concomitant reduction of standardized uptake value (SUV)mean had higher probability of long-lasting response than those with DS4-5 and an increase of SUVmean .