Long noncoding RNA KCNQ1OT1 induces pyroptosis in diabetic corneal endothelial keratopathy.
Diabetic corneal endothelial keratopathy is an intractable ocular complication characterized by corneal edema and endothelial decompensation, which seriously threaten vision. It has been suggested that diabetes is associated with pyroptosis, a type of programmed cell death via the activation of inflammation. Long noncoding RNA KCNQ1OT1 is commonly associated with various pathophysiological mechanisms of diabetic complications, including diabetic cardiomyopathy and diabetic retinopathy. However, whether KCNQ1OT1 is capable of regulating pyroptosis and participates in the pathogenesis of diabetic corneal endothelial keratopathy remains unknown. The aim of this study was to investigate the mechanisms of KCNQ1OT1 in diabetic corneal endothelial keratopathy. Here, we reveal that KCNQ1OT1 and pyroptosis can be triggered in diabetic human and rat corneal endothelium, along with the high glucose-treated corneal endothelial cells. However, miR-214 expression was substantially decreased in vivo and in experiments with cultured cells. LDH assay was also used to verify the existence of pyroptosis in high glucose-treated cells. Bioinformatics prediction and luciferase assays showed that KCNQ1OT1 may function as a competing endogenous RNA binding miR-214 to regulate the expression of caspase-1. To further analyze the KCNQ1OT1-mediated mechanism, miR-214 mimic and inhibitor were introduced into the high glucose-treated corneal endothelial cells. The results showed that upregulation of miR-214 attenuated pyroptosis; conversely, knockdown of miR-214 promoted it. In addition, KCNQ1OT1 knockdown by a small interfering RNA decreased pyroptosis factors expressions but enhanced miR-214 expression in corneal endothelial cells. To understand the signaling mechanisms underlying the prepyroptotic properties of KCNQ1OT1, si-KCNQ1OT1 was cotransfected with or without miR-214 inhibitor. The results showed that pyroptosis was repressed after silencing KCNQ1OT1 but was reversed by cotransfection with miR-214 inhibitor, suggesting that KCNQ1OT1 mediated pyroptosis induced by high glucose via targeting miR-214. Therefore, the KCNQ1OT1/miR-214/caspase-1 signaling pathway represents a new mechanism of diabetic corneal endothelial keratopathy progression, and KCNQ1OT1 could potentially be a novel therapeutic target.


Extended human leukocyte antigen haplotype EH18.1 influences progression to hepatocellular carcinoma in patients with hepatitis C virus infection.
Our aim was to investigate whether different human leukocyte antigen (HLA) genes might be associated with hepatitis C virus (HCV) infection. DNA obtained from 141 Spanish patients with HCV infection (48 with alanine aminotransferase levels in the range considered to be normal, 47 with liver cirrhosis, and 46 with hepatocellular carcinomas [HCCs]) and from 116 control subjects were typed for HLA-B, HLA-DRB1, and HLA-DQB1 alleles, as well as for major histocompatibility complex class I chain-related gene A (MICA) transmembrane polymorphism. The frequency of HLA-DR11 was increased in HCV carriers, compared with patients with end-stage liver disease (ESLD) (corrected P value [Pc],.0002) and, especially, with patients who had HCC (Pc=.003). The frequency of the HLA-B18 allele was increased in patients with HCC, and the allele was absent in HCV carriers (Pc=.003). The MICA-A4 allele was overrepresented in patients with HCC, compared with HCV carriers (Pc=.0002). The DR3/MICA-A4/B18 haplotype was associated with HCC (Pc=.01). In conclusion, HLA-DR11 seems to be protective against the development of severe forms of infection, and the DR3/MICA-A4/B18 haplotype may be an important factor in the progression to the most severe HCV-infection status.


Perinatal androgens organize sex differences in mast cells and attenuate anaphylaxis severity into adulthood.
Mast cell (MC)-associated diseases, including allergy/anaphylaxis and neuroinflammatory pain disorders, exhibit a sex bias, with females at increase risk. While much attention has been directed toward adult sex hormones as drivers of sex differences, that female sex bias in MC-associated diseases is evident in prepubertal children, suggesting early-life origins of sex differences which have yet to be explored. Utilizing rodent models of MC-mediated anaphylaxis, our data here reveal that, 1) compared with females, males exhibit significantly reduced severity of MC-mediated anaphylactic responses that emerge prior to puberty and persist into adulthood, 2) reduced severity of MC-mediated anaphylaxis in males is linked with the naturally high level of perinatal androgens and can be recapitulated in females by perinatal exposure to testosterone proprionate, 3) perinatal androgen exposure guides bone marrow MC progenitors toward a masculinized tissue MC phenotype characterized by decreased concentration of prestored MC granule mediators (e.g., histamine, serotonin, and proteases) and reduced mediator release upon degranulation, and 4) engraftment of MC-deficient Kit W-sh/W-sh mice with adult male, female, or perinatally androgenized female MCs results in MC-mediated anaphylaxis response that reflects the MC sex and not host sex. Together, these data present evidence that sex differences in MC phenotype and resulting disease severity are established in early life by perinatal androgens. Thus, factors affecting levels of perinatal androgens could have a significant impact on MC development and MC-associated disease risk across the life span.


Drosophila melanogaster Hedgehog cooperates with Frazzled to guide axons through a non-canonical signalling pathway.
We report that the morphogen Hedgehog (Hh) is an axonal chemoattractant in the midline of Drosophila melanogaster embryos. Hh is present in the ventral nerve cord during axonal guidance and overexpression of hh in the midline causes ectopic midline crossing of FasII-positive axonal tracts. In addition, we show that Hh influences axonal guidance via a non-canonical signalling pathway dependent on Ptc. Our results reveal that the Hh pathway cooperates with the Netrin/Frazzled pathway to guide axons through the midline in invertebrates.


Tissue-specific expression of the rat glutathione S-transferases.
Tissue-specific patterns of rat glutathione S-transferase expression have been demonstrated by in vitro translation of purified poly(A) RNAs and by protein purification. Poly(A) RNAs from six rat tissues including heart, kidney, liver, lung, spleen, and testis were used to program in vitro translation with the rabbit reticulocyte lysate system and [35S]methionine. The glutathione S-transferase subunits synthesized in vitro were purified from the translation products by affinity chromatography on S-hexylglutathione-linked Sepharose 6B columns. The affinity bound fractions were analyzed by Na dodecyl SO4-polyacrylamide gel electrophoresis and fluorography. A subunit of Mr = 22,000 detected in the in vitro translation products of poly(A) RNAs from heart, kidney, lung, spleen, and testis is missing from the translation products of liver poly(A) RNAs. This Mr = 22,000 subunit is present only in the anionic glutathione S-transferase fraction purified from rat heart, kidney, lung, spleen, and testis. Purified anionic glutathione S-transferase from rat liver does not contain this subunit. The relative specific activities toward a dozen different substrates also demonstrate the nonidentity between liver and kidney anionic glutathione S-transferases. In addition, among the glutathione S-transferase subunits expressed in the liver, some of them could not be detected in the other tissues investigated. Our results indicate that tissue-specific expression of rat glutathione S-transferases may occur pretranslationally.


Availability and accessibility of HIV self-tests and self-sample kits at community pharmacies in the Netherlands.
In 2016 the WHO declared HIV self-testing and self-sampling an effective and safe test option that can reduce testing barriers. HIV self-tests and self-sampling kits (HIVST/HIVSS) are available for purchase at Dutch community pharmacies since 2019. We investigated the availability and accessibility of HIVST/HIVSS in community pharmacies, and factors associated with test availability. An online survey among all Dutch community pharmacies (n = 1,987) was conducted between April and June 2021. Availability of HIVST/HIVSS and experiences of pharmacists with the test offer were analyzed with descriptive statistics. The association of pharmacy and pharmacists' characteristics with HIVST/HIVSS availability was explored by logistic regression analysis. In total, 465 pharmacists completed the questionnaire. Of the responding pharmacists, 6.2% (n = 29) offered HIVST/HIVSS. The majority (82.8%) sold between 0 and 20 tests per year. In total, pharmacies sold an estimated 370 HIVST/HIVSS per year. Pharmacies having HIVST/HIVSS available were less often located in moderately-urbanized to rural neighborhoods (OR 0.35, 95%CI 0.16-0.77 versus highly-urbanized), and were less often located in moderate-to-low SES neighborhoods (OR 0.40, 95%CI 0.18-0.88 versus high-SES). Reasons for not offering HIVST/HIVSS by pharmacists were no or little demand (69.3%), and not being familiar with these tests (17.4%). 52% of the pharmacists provided information about testing to test buyers. Reported options to improve the test offer were giving advice about (performing) the test to test buyers (72.4%), placing tests visible on the counter (51.7%), and advertisement (37.9%). HIVST/HIVSS have a limited practical availability in Dutch community pharmacies since their introduction in 2019, especially in lower-urbanized and lower-SES areas. Further research is needed to explore how to expand access to HIVST/HIVSS through community pharmacies in the Netherlands, and how to tailor it to the needs of pharmacy clients.


Duration and Timing of In Utero Opioid Exposure and Incidence of Neonatal Withdrawal Syndrome.
To evaluate the association between prenatal prescription opioid analgesic exposure (duration, timing) and neonatal opioid withdrawal syndrome (NOWS). We conducted a retrospective cohort study of Wisconsin Medicaid-covered singleton live births from 2011 to 2019. The primary outcome was a NOWS diagnosis in the first 30 days of life. Opioid exposure was identified with any claim for prescription opioid analgesic fills during pregnancy. We measured exposure duration cumulatively in days (1-6, 7-29, 30-89, and 90 or more) and identified timing as early (first two trimesters only) or late (third trimester, regardless of earlier pregnancy use). We used logistic regression modeling to assess NOWS incidence by exposure duration and timing, with and without propensity score matching. Overall, 31,456 (14.3%) of 220,570 neonates were exposed to prescription opioid analgesics prenatally. Among exposed neonates, 19,880 (63.2%) had 1-6 days of exposure, 7,694 (24.5%) had 7-29 days, 2,188 (7.0%) had 30-89 days, and 1,694 (5.4%) had 90 or more days of exposure; 15,032 (47.8%) had late exposure. Absolute NOWS incidence among neonates with 1-6 days of exposure was 7.29 per 1,000 neonates (95% CI 6.11-8.48), and incidence increased with longer exposure: 7-29 days (19.63, 95% CI 16.53-22.73); 30-89 days (58.96, 95% CI 49.08-68.84); and 90 or more days (177.10, 95% CI 158.90-195.29). Absolute NOWS incidence for early and late exposures were 11.26 per 1,000 neonates (95% CI 9.65-12.88) and 35.92 per 1,000 neonates (95% CI 32.95-38.90), respectively. When adjusting for confounders including timing of exposure, neonates exposed for 1-6 days had no increased odds of NOWS compared with unexposed neonates, whereas those exposed for 30 or more days had increased odds of NOWS (30-89 days: adjusted odds ratio [aOR] 2.15, 95% CI 1.22-3.79; 90 or more days: 2.80, 95% CI 1.36-5.76). Late exposure was associated with elevated odds of NOWS (aOR 1.57, 95% CI 1.25-1.96) when compared with unexposed after adjustment for exposure duration. More than 30 days of prenatal prescription opioid exposure was associated with NOWS regardless of exposure timing. Third-trimester opioid exposure, irrespective of exposure duration, was associated with NOWS.


Gene mutations in the Ras pathway and the prognostic implication in Korean patients with juvenile myelomonocytic leukemia.
Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in children. Hyperactivation of the Ras pathway from gene mutations is known to be the key culprit in the development of JMML. In this study, we investigated Ras pathway mutations and prognostic implication in Korean patients with JMML. A total of 22 Korean patients with JMML were recruited from two institutions (19 boys and three girls; median age, 17 months; range, 1-74 months). Hematologic and cytogenetic findings were reviewed. Mutation analyses involved PTPN11, KRAS, NRAS, and CBL genes by direct sequencing analyses (selected exons except in CBL). Survival analysis was performed by the Kaplan-Meier method. Cytogenetic and/or gene mutations were detected in 18 patients out of 22 (82%). Four patients (18%) had chromosomal abnormalities, with monosomy 7 being the most common. Seventeen (77%) had gene mutations. PTPN11 mutations were detected in 13 patients (59%). The patient heterozygous for c.854T>C had Noonan syndrome. NRAS and KRAS mutations were detected in two patients (9%) and one patient (5%), respectively. A homozygous CBL mutation was detected in one patient (5%; c.1228-2A>G). All mutations detected were previously reported mutations. Survival analyses suggested an unfavorable prognostic implication of PTPN11 mutation, albeit without a statistical significance. Collectively, the results from molecular genetics study and survival analyses suggested a relatively higher frequency and unfavorable prognostic implication of PTPN11 mutations in Korean patients with JMML.


Association Between Bowel Obstruction or Intussusception and Endometriosis.
To evaluate the association between endometriosis and bowel obstruction or intussusception using a large population database. This was a population-based study using data from the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) from 2005 to 2014. We studied women aged 18 to 55 years without inflammatory bowel disease or cancer. Multivariate logistic regression was used to examine the association between endometriosis and bowel obstruction. Of the 18 427 520 women who met the criteria for inclusion, 96 539 had experienced bowel obstruction, for an overall prevalence of 52 per 10 000, and 3825 had experienced intussusception, for an overall prevalence of 2 per 10 000. When adjusted for sociodemographic characteristics, women with pelvic endometriosis had a consistently higher likelihood of bowel obstruction (odds ratio [OR] 2.6; 95% confidendence interval [CI] 2.3-3.00, P <0.01). In particular, intestinal endometriosis was associated with a 14.6-fold increased risk of bowel obstruction (95% CI 11.4-18.8, P <0.01), while rectovaginal endometriosis was associated with a 2.00-fold increased risk (95% CI 1.5-2.6, P <0.01). Pelvic endometriosis was significantly associated with adhesive bowel obstruction (adjusted OR: 3.2; 95% CI 2.6-3.9) and non-adhesive bowel obstruction (adjusted OR 2.4; 95% CI 2.0-2.8). The rates of endometriosis among women with or without intussusception were comparable. Pelvic endometriosis, in particular rectovaginal and intestinal endometriosis is strongly associated with bowel obstruction, independent of the presence of intra-abdominal adhesions. We did not find any association between pelvic endometriosis and intussusception.


Psychometric properties of the Malay version of the difficulties in Emotion Regulation Scale-18 in Malaysian adolescents.
The Difficulties in Emotion Regulation Scale-18 (DERS-18) is an instrument used to measure deficits in emotion regulation. However, the instrument has not been adapted to Malaysians and has never been validated in the Malay language. This study aimed to examine the psychometric properties of the Malay version of DERS-18. The DERS-18 underwent forward-backward translation and assessment of face and content validity. Both Malay version of the DERS-18 and DASS-21 were completed by 701 adolescents (44.4% boys) aged 13 and 14 years old. To assess its dependability, a floor and ceiling effect evaluation and Cronbach's analysis were both performed. A series of confirmatory factor analyses (CFA), bivariate correlation, and regression were performed to evaluate the construct and criterion validity, respectively. The Malay version of DERS-18, after excluding "Awareness", indicated excellent reliability (Cronbach's α = 0.93), and acceptable internal consistency for each subscale (range of α from 0.63 to 0.82). Floor or ceiling effects were observed at item level and subscale level, but not at total level. CFA results revealed that the Malay version of the DERS-18 bifactor model (excluding "Awareness") portrayed the best construct validity (χ2/df = 2.673, RMSEA = 0.049, CFI = 0.977, TLI = 0.968) compared to a single factor, a correlated factor, and a higher-order factor model. The DERS-18 subscales (except "Awareness") and DERS-18 total scores were significantly correlated with stress, anxiety, and depression in a positive direction (r ranged from 0.62 to 0.64, p < 0.01). The general factor of the DERS-18 and its specific factors ("Clarity", "Goals", and "Non-Acceptance") significantly predicted the symptoms of stress, anxiety, and depression (R2 ranged from 0.44 to 0.46, p < 0.001). The Malay version of the DERS-18, excluding "Awareness", possessed good reliability, construct validity, and criterion validity to assess emotion dysregulation among Malaysian adolescents.


Hoarseness after thyroidectomy: blame the endocrine surgeon alone?
Hoarseness is a postoperative complication of thyroidectomy, mostly due to damage to the recurrent laryngeal nerve (RLN). Hoarseness may also be brought about via vocal cord dysfunction (VCD) due to injury of the vocal cords from manipulations during anesthesia, as well as from psychogenic disorders and respiratory and upper-GI related infections. We reviewed the literature aiming to explore these potential surgical and non-surgical causes of hoarseness beyond thyroidectomy and the role of the endocrine surgeon. Is he/she alone to blame? The MEDLINE/PubMed database was searched for publications with the medical subject heading "hoarseness" and keywords "thyroidectomy", "RLN", "VCD" or "intubation". We restricted our search till up to May 2013. In our final review we included 80 articles and abstracts that were accessible and available in English. We demonstrated the incidence of hoarseness stemming from surgical and non-surgical causes and also highlighted the role of intubation as a potential cause of injury-related VCD. Hoarseness is a relatively common complication of thyroidectomy, which can be attributed to many factors including surgeon's error or injuries during intubation as well as to other non-surgical causes. However, compared to procedures such as cervical spine surgery, mediastinal surgery, esophagectomy and endarterectomy, thyroidectomy would seem to be a procedure with a relatively low rate of recurrent laryngeal nerve palsies (RLNPs). It is often difficult to determine whether the degree of hoarseness after thyroidectomy should be attributed only the surgical procedure itself or to other causes, for example intubation and extubation maneuvers. The differential diagnosis of postoperative hoarseness requires the use of specific tools, such as stroboscopy and intra- and extralaryngeal electromyography, while methods like acoustic voice analysis, with estimation of maximum phonation time and phonation frequency range, can distinguish between objective and subjective deterioration in the voice. The importance of medical history should be also emphasized.


Effects of a topical alpha2 adrenergic agonist on ciliary blood flow and aqueous production in rabbits.
The relationship between ciliary perfusion and aqueous production is poorly understood. It was recently reported that aqueous production decreases when ciliary blood flow is reduced by lowering the ocular perfusion pressure, and hypothesized that drug-induced reduction of ciliary blood flow would also decrease aqueous production. In the present study, we test this hypothesis with an alpha2 adrenergic agonist (brimonidine) formulated for topical application. When used acutely, brimonidine decreases intraocular pressure (IOP) by suppressing aqueous production, although its mechanism of action is unclear. The experiments were performed in four groups of anesthetized rabbits (n=33) in which the following variables were measured: ocular mean arterial pressure (OMAP), IOP, orbital venous pressure (OVP), aqueous flow, ciliary blood flow, ciliary oxygen tension (PO2), episcleral venous pressure (EVP), carotid blood flow and heart rate. The measurements were made before and after brimonidine (0.15%, 40 microl) was applied to the cornea. Brimonidine decreased IOP (-33%, p<0.01), aqueous flow (-39%, p<0.01), ciliary blood flow (-37%, p<0.01), EVP (-42%, p<0.01) and ciliary PO2 (-32%, p<0.05). We conclude that topical brimonidine is a ciliary vasoconstrictor, and that alpha2 adrenergic agonist-induced decreases in ciliary blood flow decrease aqueous production.


Impact of mental imagery on enhancing surgical skills learning in novice's surgeons: a pilot study.
Mental imagery (MI) has long been used in learning in both fields of sports and arts. However, it is restrictively applied in surgical training according to the medical literature. Few studies have evaluated its' feasibility and usefulness. The aim of this study is to assess the impact of mental imagery on surgical skills learning among novice's surgeons. In this pilot prospective randomized comparative study; we recruited 17 residents and interns of surgery education curriculum. They were all included in their first semester of the curricula. Two groups were randomly designed. Group (a) including "Mental Imagery" volunteers (n = 9) which benefited from a mental imagery rehearsal exercise prior to physical practice, while the control group (b) (n = 8) didn't underwent any MI process prior to surgery practice. Each participant of both groups was invited to perform an intestinal hand-sewn anastomosis on bovine intestine. Each procedure was evaluated and analyzed according to 14 qualitative criteria while each criterion was scored 0, 1 or 2 respectively assigned to the gesture was not acquired, gesture was performed with effort, or mastered gesture. The final score is 28 for those who master all 14 gestures. A non-parametric statistical comparison between the both studied groups was performed. Both groups of surgery students demonstrated equivalent age, sex ratio, laterality, and surgical experience. The mean overall score is significantly higher in the MI group (a) (17.78; SD = 2.42) compared to the control group (b) (10.63, SD = 2.85). However, advanced analysis of individual assessment items showed significant statistical difference between both groups only in 6 out of 14 assessed items. Indeed, mental imagery will not be able to substitute the traditional learning of surgery for novice surgeons; it is an important approach for improving the technical skills acquisition and shortening the physical learning.


Cell Type-Specific Expression Analysis of the Inner Ear: A Technical Report.
The cellular diversity of the inner ear has presented a technical challenge in obtaining molecular insight into its development and function. The application of technological advancements in cell type-specific expression enable clinicians and researchers to leap forward from classic genetics to obtaining mechanistic understanding of congenital and acquired hearing loss. This understanding is essential for development of therapeutics to prevent and reverse diseases of the inner ear, including hearing loss. The objective of this study is to describe and compare the available tools for cell type-specific analysis of the ear, as a means to support decision making in study design. Three major approaches for cell type-specific analysis of the ear including fluorescence-activated cell sorting (FACS), ribosomal and RNA pulldown techniques, and single cell RNA-seq (scRNA-seq) are compared and contrasted using both published and original data. We demonstrate the strength and weaknesses of these approaches leading to the inevitable conclusion that to maximize the utility of these approaches, it is important to match the experimental approach with the tissue of origin, cell type of interest, and the biological question. Often, a combined approach (eg, cell sorting and scRNA-seq or expression analysis using 2 separate approaches) is required. Finally, new tools for visualization and analysis of complex expression data, such as the gEAR platform (umgear.org), collate cell type-specific gene expression from the ear field and provide unprecedented access to both clinicians and researchers. N/A Laryngoscope, 131:S1-S16, 2021.


Proliferative response of murine B-cell leukemia (BCL1) to poly(L-lysine).
Peripheral blood lymphocytes (PBL) isolated from BALB/c mice bearing a B-cell leukemia (BCL1) showed a marked proliferative response upon two days culturing with poly(L-lysine) (PLL) of various molecular weights. An inverse relationship was noted between the molecular weight of the PLL and the dose required for optimal proliferative response. PLL showed no proliferative activity when cultured with normal PBL or with lymphocytes isolated from the spleen or other lymphoid organs of BCL1-bearing mice. Double exposure to PLL and lipopolysaccharide (LPS) had a marked synergistic effect on BCL1 PBL stimulation but not on PBL isolated from normal mice. The data suggest that PLL, in contrast to LPS, may cause a selective proliferation of a subpopulation(s) of B-tumor cells at a particular stage(s) of differentiation.


Responses of gerbil utricular afferents to translational motion.
In the present study, we report the sensitivity of utricular afferents to sinusoidal translational motion in the horizontal plane. The head orientation was altered relative to the direction of translational travel in 30 degrees increments to allow determination of the head orientation that elicited the maximal and minimal responses of each afferent neuron. We determined gain and phase relationships at a constant peak linear acceleration of 0.1 g applied at frequencies between 0.20 and 2.0 Hz for multiple head orientations. The response dynamics and vector of maximal sensitivity for the utricular afferents are consistent with those reported for other mammalian species. Irregularly (CV>0.3) and intermediate (0.1</=CV</=0.3) discharging units demonstrated gain enhancement at higher frequencies. Regular units (CV<0.1) showed lower gains and flat response dynamics. The mean gains of the irregular, intermediate, and regular units at 0.5 Hz were 256, 118, and 69 spikes s(-1) g(-1), respectively. The phase of the response was independent of the vector of orientation except near the null response orientation where phase and gain were difficult to accurately measure. Phase leads (relative to acceleration) in irregular units at lower frequencies were reduced at higher frequencies. All afferents demonstrated simple one-dimensional tuning with their vectors of maximal sensitivity distributed throughout the 360 degrees of the horizontal plane, though the majority were directed out of the contralateral ear.


Synthesis of heterocyclic N-(β-D-glucopyranosyl)carboxamides for inhibition of glycogen phosphorylase.
In a DCC-mediated coupling 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylamine and propiolic acid gave N-propynoyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylamine which was transformed by 1,3-dipolar cycloadditions with aromatic azides and nitrile-oxides to the corresponding O-peracetylated N-(β-D-glucopyranosyl)-1-substituted-1,2,3-triazole-4-carboxamides and N-(β-D-glucopyranosyl)-3-substituted-isoxazole-5-carboxamides, respectively. These compounds were O-deacetylated by Zemplén's protocol to be tested as inhibitors of rabbit muscle glycogen phosphorylase b. The best inhibitors of the two series were N-(β-D-glucopyranosyl)-1-(3,5-dimethyl-phenyl)-1,2,3-triazole-4-carboxamide (K(i)=34 μM) and N-(β-D-glucopyranosyl)-3-(indol-2-yl)-isoxazole-5-carboxamide (K(i)=164 μM).


Applying in-situ visible photopolymerization for fabrication of electrospun nanofibrous carrier for meloxicam delivery.
Despite meloxicam's many benefits, it will cause many drawbacks if the meloxicam release rate is not controlled. Accordingly, we introduced a technique based on the electrospinning process to control the release rate and also to reduce side effects. For this purpose, different nanofibers were used as drug couriers. Nanofibers were prepared using polyurethane, polyethylene glycol, and light curable poly (ethylene glycol) diacrylate (PEGDA) by electrospinning. In fact, light curable poly (ethylene glycol) diacrylate (PEGDA) was synthesized as a hydrophilic functional group. Next, PEGDA and polyurethane were used simultaneously to fabricate the drug carrier nanofiber in a single processing step, and the electrospinning apparatus was equipped with a blue light source for in-situ photopolymerization during the electrospinning process. The molecular structures of nanofibers and PEGDA were investigated by FT-IR, 1H NMR, 13C NMR, SEM, TEM, XRD, and DSC analyses. Finally, we reduced in vitro drug release to 44% within ten hours, while the minimum release of meloxicam from the tablet was 98%.


(R)-(+)-Rosmarinic Acid as an Inhibitor of Herpes and Dengue Virus Replication: an In Silico Assessment.
Since ancient times, viruses such as dengue, herpes, Ebola, AIDS, influenza, chicken meat, and SARS have been roaming around causing great health burdens. Currently, the prescribed antiviral drugs have not cured the complications caused by viruses, whereas viral replication was not controlled by them. The treatments suggested are not only ineffectual, but also sometimes inefficient against viruses at all stages of the viral cycle as well. To fight against these contagious viruses, people rely heavily on medicinal plants to enhance their innate and adaptive immune systems. In this research, the preparation of ligands and proteins was performed using the Maestro V.13.2 module tool. This software, consisting of LigPrep, Grid Generation, SiteMap, and Glide XP, has each contributed significantly to the preparation of ligands and proteins. Ultimately, the research found that (R)-(+)-rosmarinic acid was found to have significant docking scores of - 10.847 for herpes virus, of - 10.033 for NS5, and - 7.259 for NS1. In addition, the Prediction of Activity Spectra for Substances (PASS) server indicates that rosmarinic acid possesses a diverse spectrum of enzymatic activities, as probability active (Pa) values start at > 0.751, whereas it has fewer adverse effects than the drugs prescribed for viruses. Accordingly, it was found the rate of acute toxicity values of (R)-(+)-rosmarinic acid at doses LD50 log10 (mmol/g) and LD50 (mg/g) in different routes of administration, such as intraperitoneal, intravenous, oral, and subcutaneous. Ultimately, the present study concluded that (R)-(+)-rosmarinic acid would expose significant antiviral effects in in vitro and in vivo experiments, and this research would be a valuable asset for the future, especially for those who wish to discover a drug molecule for a variety of viruses. The online version contains supplementary material available at 10.1007/s43450-023-00381-y.


[Porphyria cutanea tarda in a 4-year-old child with uroporphyrinogen decarboxylase deficiency].
A 4 years old girl presents a typical case of patent form of cutaneous late porphyria with a reduced activity of the erythrocyte, uroporphyrinogen decarboxylase (UROD) genetically transmitted over 3 generations; a multifactor inheritance (HLA A3, a normal phenotype of alpha 1 antitrypsin, exogenous toxins, or viral infections) is discussed.


Piperacillin 2 g/tazobactam 0.5 g is as effective as imipenem 0.5 g/cilastatin 0.5 g for the treatment of acute uncomplicated pyelonephritis and complicated urinary tract infections.
This randomised, double-blind, multicentre trial compared piperacillin/tazobactam (2 g/0.5 g/q8h) and imipenem/cilastatin (0.5 g/0.5 g/q8h) as monotherapy in patients with acute pyelonephritis or complicated urinary tract infections. In total, 237 patients were randomised to receive either piperacillin/tazobactam (n=161) or imipenem/cilastatin (n=166). At the early follow-up (=test-of-cure-visit) 5-9 days after antibiotic therapy, clinical success was noted in 122/147 (83.0%) piperacillin/tazobactam recipients compared with 123/154 (79.9%) imipenem/cilastatin recipients, thus proving that both treatments were equally effective. On a descriptive level, an advantage of piperacillin/tazobactam was demonstrated. Microbiological success at the early follow-up was 78/135 (57.8%) for piperacillin/tazobactam and 70/144 (48.6%) for imipenem/cilastatin. These results were confirmed by equivalent success rates on the last therapy day. Both drugs were generally well tolerated.


A combined prosthodontic and orthodontic treatment approach in a case of growth inhibition induced by dental implants: a case report.
Functional and esthetic results can improve significantly when a combined prosthodontic-orthodontic treatment approach is employed in cases requiring extensive oral rehabilitation. The patient presented in this case report was treated in his late teens with dental implants as a replacement for his maxillary incisors. Ten years later, the entire maxillary anterior segment was in infraocclusion compared to the rest of the dentition and lip line. Since prosthodontic follow-up treatment alone could not achieve an optimal functional and esthetic outcome, the patient was treated orthodontically prior to renewing the restoration. A fixed appliance was used to intrude the mandibular anterior teeth as well as vertically align the infrapositioned maxillary lateral incisors.


Posterior reversible leukoencephalopathy in a case of postpartum eclampsia.
This case report describes an atypical presentation of eclampsia. A 26-year-old lady presented 5 days' postpartum with a series of grand mal seizures after an uneventful pregnancy and delivery. An MRI scan of the brain showed areas of low signal involving cerebral white matter and right cerebellum. Within 2 weeks, all symptoms and radiologic abnormalities had resolved.


Measurement Properties of the Hand Grip Strength Assessment: A Systematic Review With Meta-analysis.
The aim of this study was to critically appraise, compare, and summarize the quality of the measurement properties of grip strength (GS) in patients with musculoskeletal, neurologic, or systemic conditions and healthy participants without these conditions. We followed the Consensus-based Standards for the Selection of Health Measurement Instruments guideline. To identify studies on measurement properties of GS, we searched the MEDLINE, Embase, Cumulative Index to Nursing and Allied Health, Physiotherapy Evidence, and Cochrane Library databases from inception until June 2019. Meta-analyses were carried out using a random effects model and 95% CIs were calculated. Studies were included if they reported at least 1 measurement property of hand GS in a population with musculoskeletal, neurologic, and systemic conditions or a healthy population without these conditions. The extracted data included the study population, setting, sample size, measurement evaluated, and the test interval. Twenty-five studies were included with 1879 participants. The pooled results indicated excellent intraclass correlation coefficient (ICC) of 0.92 (95% CI, -0.88-0.94 for healthy participants without any conditions, ICC of 0.95 (95% CI, -0.93-0.97) for upper extremity conditions, and an ICC of 0.96 (95% CI, -0.94-0.97) for patients with neurologic conditions. Minimum clinically important difference (MCID) scores for hand GS were 5.0 kg (dominant side) and 6.2 kg (nondominant side) for patients post stroke, 6.5 kg for the affected side after distal radius fracture, 10.5 lb and 10 kPa for immune-mediated neuropathies, 17 kg for patients with lateral epicondylitis, and 0.84 kg (affected side) and 1.12 kg (unaffected side) in the carpometacarpal osteoarthritis group; MCID GS estimates were 2.69-2.44 kg in the healthy group without conditions. Our synthesized evidence indicated that GS assessment is a reliable and valid procedure among healthy participants as well as across various clinical populations. Furthermore, our MCID summary scores provided useful information for evaluating (clinical importance) new interventions regarding hand GS.


Alcohol, vitamin A, and cancer.
Chronic and excessive alcohol intake is associated with an increased risk of a variety of cancers (e.g., oral cavity, larynx, esophagus, liver, lung, colorectal, and breast). Retinoids (vitamin A and its derivatives) are known to exert profound effects on cellular growth, cellular differentiation, and apoptosis, thereby controlling carcinogenesis. Lower hepatic vitamin A levels have been well documented in alcoholics. Substantial research has been done, investigating the mechanisms by which excessive alcohol interferes with retinoid metabolism. More specifically, (1) alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases; (2) alcohol-induced cytochrome P450 enzymes (CYP), particularly CYP2E1, enhance catabolism of vitamin A and retinoic acid; and (3) alcohol alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. As a consequence, long-term and excessive alcohol intake results in impaired status of retinoic acid, the most active derivative of vitamin A and a ligand for both retinoic acid receptors and retinoid X receptors. Moreover, this alcohol-impaired retinoic acid homeostasis interferes with (1) retinoic acid signaling (e.g., down-regulates retinoid target gene expression) and (2) retinoic acid "cross-talk" with the mitogen-activated protein kinase [(MAPK), including Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 kinase] signaling pathway. In addition, restoration of retinoic acid homeostasis by retinoic acid supplementation restored the normal status of both retinoid and MAPK signaling, thereby maintaining normal cell proliferation and apoptosis in alcohol-fed animals. These observations would have implications for the prevention of alcohol-promoted liver (and peripheral tissue) carcinogenesis. However, a better understanding of the alcohol-retinoid interaction and the molecular mechanisms involved is needed before retinoids can be pursued in the prevention of alcohol-related carcinogenesis in human beings, particularly regarding the detrimental effects of polar metabolites of vitamin A.


Metabolomics reveals the effects of different storage times on the acidity quality and metabolites of large-leaf black tea.
Most aged tea has superior sensory qualities and good health benefits. The content of organic acids determines of the quality and biological effects of aged tea, but there are no reports of the effect of storage on the composition and relative proportion of acidic compounds in black tea. This study analyzed and compared the sourness and metabolite profile of black tea produced in 2015, 2017, 2019 and 2021 using pH determination and UPLC-MS/MS. In total, 28 acidic substances were detected, with 17 organic acids predominating. The pH of black tea decreased significantly during storage from pH 4.64 to pH 4.25 with significantly increased in l-ascorbic acid, salicylic acid, benzoic acid and 4-hydroxybenzoic acid. The metabolic pathways ascorbate biosynthesis, salicylate degradation, toluene degradation, etc. were mainly enriched. These findings provide a theoretical basis to regulate the acidity of aged black tea.


Insertion of a second intraocular lens following traumatic expulsion of a posterior chamber lens.
Traumatic expulsion of an intraocular lens has rarely been reported in the literature. Successful implantation of a second intraocular lens following a traumatic expulsion has not been reported. This paper reports such a case.


Weight management interventions for adults living with overweight or obesity and severe mental illness: a systematic review and meta-analysis.
When compared with the general population, people living with severe mental illness (SMI) are 1·8 times more likely to have obesity while in adult mental health secure units, rates of obesity are 20 % higher than the general population. In England, there are currently 490 000 people living with SMI. The aim of this systematic review was to collate and synthesise the available quantitative and qualitative evidence on a broad range of weight management interventions for adults living with SMI and overweight or obesity. Primary outcomes were reductions in BMI and body weight. Following sifting, eighteen papers were included in the final review, which detailed the results of nineteen different interventions; however, there was a lack of qualitative evidence. Pooled results for three studies (MD - 3·49, 95 % CI - 6·85, -0·13, P = 0·04) indicated a small effect in terms of body weight reduction but no effect on BMI for four studies (MD - 0·42, 95 % CI - 1·27, 0·44, P = 0·34). Key recommendations for future research included integration of qualitative methodology into experimental study design, a review of outcome measures and for study authors to follow standardised guidelines for reporting to facilitate complete and transparent reporting.


[Synthesis and evaluation of the adaptive control system for the ventricular assist device by using the circulatory system simulator].
An on-line digital simulator using microcomputer system was developed to mimic the hemodynamic behavior of the human circulatory system under ventricular assist device (VAD) pumping. This simulator could calculate the response to the variation of the cardiac function or the driving mode of VAD in the real-time fashion. This simulator was used as the mock controlled object to evaluate and improve the algorithm of an adaptive controller of the drive unit for VAD. The adaptive one-step ahead controller was introduced as the precompensator for the PI-controller, which decides the outflow volume from VAD in order to follow up the reference flow value by changing the systolic duration. It was confirmed that the proposed adaptive control system improved the response speed of the VAD driving system automatically according to the variation of the controlled object.


Diagnostic performance and role of the contrast enema for low intestinal obstruction in neonates.
We aim to evaluate the diagnostic performance and relationship between clinical characteristics, imaging findings, and final diagnosis for the neonatal contrast enema (CE). Retrospective 10-year review of all neonatal CEs including imaging findings, clinical information, indication, and final diagnosis from discharge summaries, surgical reports, and pathology (reference standard). Two blinded pediatric radiologists reinterpreted 366 CEs for obstruction, microcolon, rectosigmoid index (RSI), serrations, meconium, ileal cut-off, transition zone, diagnosis, and level of confidence. CE diagnostic performance was calculated versus reference standard. Diagnoses included Hirschsprung disease (HD) (15.8%), small left colon syndrome (14.8%), small intestinal atresia/colonic atresia (SIA/CA) (12.6%), meconium ileus (MI) (4.4%), and normal (48.9%). CE had a moderate specificity (87.7%) and low sensitivity (65.5%) for HD; abnormal RSI and serrations showed high specificities (90.3%, 97.4%) but low sensitivities (46.6%, 17.2%). CE showed high specificity (97.4%) and low sensitivity (56.3%) for MI blinded to cystic fibrosis status. Microcolon was specific (96.6%) but not sensitive (68.8%) for MI. CE showed highest PPV (73.1%) (specificity 95.6%, sensitivity 82.6%) for SIA/CA. Microcolon with an abrupt cut-off was specific (99.1%) but not sensitive (41.3%) for atresias. Neonatal CE demonstrates high specificities and low to moderate sensitivities across all diagnoses, with lowest performance in HD. None.


An implicit non-self-report measure of attitudes to speeding: development and validation.
Speeding is a major contributor to road trauma and attitudes toward speeding are hypothesised to be a key determinant of the behaviour. Attitudinal research is limited by reliance on self-report measures and the attendant possibility of reporting biases. The Implicit Association Test (IAT) aims to measure attitudes without reliance on self-report, by assessing the association between a target-concept and an evaluation, in terms of reaction time for compatible versus non-compatible pairings. The present research aimed to develop and evaluate an IAT to measure attitudes to speeding. Forty-five licensed drivers completed the speed-related IAT, and drove a driving simulator. Participants also completed a questionnaire that assessed self-reported attitudes to speeding, and several variables theoretically related to attitudes, including speeding behaviour. Observed IAT results suggested that attitudes toward speeding are negative, and were generally consistent with results derived from the simulated driving and self-reported behaviours, beliefs, and attitudes. Thus, the speed-related IAT appears to be a valid measure of attitudes toward speeding, which might be used to measure attitudes in road safety research without reliance on self-report.


Rapid drop in the reproduction number during the Ebola outbreak in the Democratic Republic of Congo.
The Democratic Republic of Congo (DRC) experienced a confined rural outbreak of Ebola virus disease (EVD) with 69 reported cases from July to October 2014. Understanding the transmission dynamics during the outbreak can provide important information for anticipating and controlling future EVD epidemics. I fitted an EVD transmission model to previously published data of this outbreak and estimated the basic reproduction number R 0 = 5.2 (95% CI [4.0-6.7]). The model suggests that the net reproduction number Rt fell below unity 28 days (95% CI [25-34] days) after the onset of symptoms in the index case. This study adds to previous epidemiological descriptions of the 2014 EVD outbreak in DRC, and is consistent with the notion that a rapid implementation of control interventions helped reduce further spread.


Antioxidants in skeletal muscle physiology, a radically different approach.
Regular physical exercise has many health benefits (1). Paradoxically, it is also clear that contracting skeletal muscles generate reactive oxygen species (ROS) and that prolonged and intense exercise can result in oxidative damage to cellular constituents (2-4). Reactive oxygen species production is dependent on the intensity of the exercise with higher amount of ROS generated by strenuous exercise (5, 6). Antioxidants may reduce the adverse effects of exercise-induced ROS (2-4). However, ROS are not only toxic but rather play an important role in cell signalling and in the regulation of gene expression (7, 8) and force production in skeletal muscle (9). Thus, we have recently raised questions about the validity of using oral antioxidant supplementation during training by athletes (10, 11). We have found that redox sensitive signaling pathways are inolved in skeletal muscle atrophy due to disuse and aging (12). Loss of skeletal muscle mass and function is an important limiting factor in the maintenance of health and well-being both in the young and in the old population (13, 14). I will report experiments showing that both hormonal (15) and non-hormonal interventions (13) are effective in the maintenance of redox homeostasis and in the prevention of skeletal muscle atrophy.


Spatio-temporal dynamics of odor representations in the mammalian olfactory bulb.
We explored the spatio-temporal dynamics of odor-evoked activity in the rat and mouse main olfactory bulb (MOB) using voltage-sensitive dye imaging (VSDI) with a new probe. The high temporal resolution of VSDI revealed odor-specific sequences of glomerular activation. Increasing odor concentrations reduced response latencies, increased response amplitudes, and recruited new glomerular units. However, the sequence of glomerular activation was maintained. Furthermore, we found distributed MOB activity locked to the nasal respiration cycle. The spatial distribution of its amplitude and phase was heterogeneous and changed by sensory input in an odor-specific manner. Our data show that in the mammalian olfactory bulb, odor identity and concentration are represented by spatio-temporal patterns, rather than spatial patterns alone.


The oxidation of cytochrome c peroxidase by hydrogen peroxide. Characterization of products.
H2O2 reacts with cytochrome c peroxidase in a variety of ways. The initial reaction produces cytochrome c peroxidase Compound I. If more than a 10-fold excess of H2O2 is added to the enzyme, a portion of the H2O2 will react with Compound I to produce molecular oxygen. The remainder oxidizes the heme group and various amino acid residues in the protein. If less than a 10-fold excess of H2O2 is added to the enzyme, essentially all the H2O2 is utilized by oxidation of amino acid residues in the protein. The oxidation of the amino acid residues by H2O2 substantially modifies the reactivity of cytochrome c peroxidase. The modification of reactivity could be the direct result of amino acid oxidation or an indirect result caused by a perturbation of the protein structure at the active site. The products oxidized at pH 8 lose their ability to react with H2O2. The products oxidized at pH4 react with H2O2 but their reactivity toward Fe(CN)4-6 is substantially reduced.


VACTERL with hydrocephalus. A distinct entity with a variable spectrum of multiple congenital anomalies.
In this report we describe the experience and follow-up data in 4 patients presenting the "VACTERL-hydrocephaly association". A review of the literature and the present data show that the inheritance pattern of this association is not clear at the present time and that data on the long-term prognosis are scarse.


De novo synthesis and specific assembly of keratin filaments in nonepithelial cells after microinjection of mRNA for epidermal keratin.
Poly(A)+ RNA isolated from bovine muzzle epidermis was microinjected into nonepithelial cells containing only intermediate-sized filaments of the vimentin type. In recipient cells keratin polypeptides are synthesized and assemble into intermediate-sized filaments at multiple dispersed sites. We describe the time course and the pattern of de novo assembly of keratin filaments within living cells. These filaments were indistinguishable, by immunofluorescence and immunoelectron microscopic criteria, from keratin filament arrays present in true epithelial cells. The presence of extended keratin fibril meshworks in these injected cells is compatible with cell growth and mitosis. Double immunolabeling revealed that newly assembled keratin was not codistributed with microfilament bundles, microtubules or vimentin filaments. We suggest that assembly mechanisms exist which in vivo sort out newly synthesized cytokeratin polypeptides from vimentin.


Preventive effect of oleate on palmitate-induced insulin resistance in skeletal muscle and its mechanism of action.
Insulin resistance in skeletal muscle is a feature associated with exposure to an excess of saturated fatty acids such as palmitate. Oleic acid has been shown to blunt palmitate-induced insulin resistance in muscle cells. However, there is no literature available regarding the effect of oleic acid on palmitate-induced insulin resistance in intact muscle. Therefore, this study investigated the effect of oleic acid on palmitate-induced insulin resistance in rat soleus muscle and its underlying mechanisms. For these purposes, oleic acid (1 mM) was administered for 12 h in the absence or presence of palmitate (2 mM). At the end of the experiment, plasmalemmal GLUT4, the phosphorylation of AS160 and Akt-2, and the total expression of these signaling proteins were examined. We found that treatment with palmitate for 12 h reduced insulin-stimulated GLUT4 translocation and the phosphorylation of AS160 and Akt-2. However, the administration of oleic acid fully restored insulin-stimulated GLUT4 translocation (P < 0.05), as well as AS160 and Akt-2 phosphorylation (P < 0.05) despite the continuous presence of palmitate. Wortmannin, an inhibitor of PI3-K, only slightly prevented the oleic acid-induced improvements in insulin-stimulated GLUT4 translocation, and AS160 phosphorylation. However, this treatment completely inhibited the oleic acid-induced improvement in insulin-stimulated Akt-2 phosphorylation. In contrast, the oleic acid-induced improvement in insulin signaling was not affected by compound C, an AMPK specific inhibitor. In conclusion, the results clearly indicate that oleic acid administration alleviates palmitate-induced insulin resistance by promoting GLUT4 translocation in muscle, at least in part, by activating the PI3K pathway.


Evidence for two distinct cross-bridge populations in tetanized frog muscle fibers stretched with moderate velocities.
When a tetanized frog skeletal muscle fiber is stretched with moderate velocities (< 1 L0/S), the tension developed above the level of isometric tension starts to decay after a sudden reduction of stretch velocity by more than 40-50%, though the fiber is still being stretched. We analyzed the decay of tension responses caused by the sudden reduction of stretch velocity, by applying three different types of stretch, i.e. a 1.5% stretch with velocity V1 (stretch 1), a 1.5% stretch with velocity V2 < V1 (stretch 2), and a 3% stretch consisting of stretches 1 and 2 applied in succession (stretch 3) and comparing the corresponding tension responses, TR 1, TR 2 and TR 3. It was found that TR 3 to stretch 3 was equal to algebraical sum of TR 1 to the preceding stretch 1 and TR 2 to the subsequent stretch 2. In other words, TR 2 started on the falling tension baseline equal to the decay of TR 1 after completion of stretch 1, These results can be explained by assuming two distinct cross-bridge populations mechanically acting in parallel with each other.


Diprotonative stabilization of ring-opened carbocationic intermediates: conversion of tetrahydroisoquinoline to triarylmethanes.
Superacid-promoted conversion of tetrahydroisoquinolines to triarylmethanes via tandem reactions of C-N bond scission, Friedel-Crafts alkylation, C-O bond scission, and electrophilic aromatic amidation was developed. Dication formation was important for stabilizing the ring-opened carbocationic intermediate, which is a new role for diprotonation in reaction mechanisms.


Metabolism and the UPR(mt).
During mitochondrial dysfunction or the accumulation of unfolded proteins within mitochondria, cells employ a transcriptional response known as the mitochondrial unfolded protein response (UPR(mt)) to promote cell survival along with the repair and recovery of defective mitochondria. Considerable progress has been made in understanding how cells monitor mitochondrial function and activate the response, as well as in identifying scenarios where the UPR(mt) plays a protective role, such as during bacterial infection, hematopoietic stem cell maintenance, or general aging. To date, much of the focus has been on the role of the UPR(mt) in maintaining or re-establishing protein homeostasis within mitochondria by transcriptionally inducing mitochondrial molecular chaperone and protease genes. In this review, we focus on the metabolic adaptations or rewiring mediated by the UPR(mt) and how this may contribute to the resolution of mitochondrial unfolded protein stress and cell-type-specific physiology.


Neurological dysfunction in a large sample of three year old children: a report from the Dunedin Multidisciplinary Child Development Study.
The prevalence of neurological abnormalities was examined in a large sample of Dunedin three-year-old children. About 10 percent of those assessed had one or more abnormalities at three and 2 percent had abnormalities which were judged to have an effect on the child's functioning. The presence of abnormalities at three was associated with language and motor delays at that age and predictive of later IQ deficit. However, abnormalities were not stable over time and their significance for predictive purposes with individual cases is questioned.


The cosmeceutical realm.
The cosmeceutical realm is composed of functional cosmetics designed to adorn face and body without changing the structure of the human form. Although this may seem confusing, indeed cosmeceuticals have never been well defined. Cosmeceuticals developed for facial application typically claim to induce more even skin tone, improve skin texture, increase skin radiance, decrease the appearance of skin wrinkling, and provide antiaging benefits. Nondrug active ingredients are usually incorporated into moisturizing vehicles designed to accomplish the aforementioned claims. There is no doubt that cosmeceuticals represent the most rapidly expanding frontier in dermatology.


Does location of rapid influenza diagnostic testing influence treatment time and ancillary testing in a paediatric emergency department?
Influenza causes a significant burden of disease. Our aim was to assess whether location of rapid influenza diagnostic testing (RIDT) for patients with influenza-like illness (ILI) has an impact on ED treatment time or ancillary testing. This was a retrospective observational study in a tertiary paediatric ED during 2017 influenza season. All patients with ILI were included. Some had RIDT performed (ED bedside or at the laboratory). Primary outcome measure was the correlation of RIDT location to treatment time compared to patients with ILI with no RIDT. Secondary outcome measures were the correlation of RIDT location to ancillary testing and treatment with antibiotics. A total of 1451 patients with ILI were included. Eighty patients for whom RIDT was performed at the laboratory had a shorter treatment time in the ED when compared to the 215 patients for whom RIDT was performed bedside (2.8 and 3.4 h, respectively; P < 0.0001). However, treatment time was not statistically different when sub-analysed for admitted and discharged patients separately. Overall, patients with ILI and no RIDT had the shortest treatment time in the ED (1.7 h). There was no difference in ancillary testing and treatment with antibiotics between ILI patients for whom RIDT was performed bedside or at the laboratory regardless of admission. Location of RIDT may not have a significant impact on treatment time, ancillary testing and treatment with antibiotics. When RIDT was not performed, patients had the shortest treatment time.


Stress responses of testosterone and corticosterone-binding globulin in a multi-brooded species, Eurasian Tree Sparrows (Passer montanus): Does CBG function as a mediator?
In avian plasma, testosterone (T) and corticosterone (CORT) compete to bind with corticosterone-binding globulin (CBG). Elevation of CBG may function to "buffer" the tissues against high circulating levels of T and stress-induced levels of CORT. To demonstrate the effects of acute stress on CBG and T levels and their biological functions, we investigated seasonal changes of baseline and stress-induced T and CBG levels in Eurasian Tree Sparrows (Passer montanus) during different life stages using the capture-handling-restraint stress method. Our results show that (1) male sparrows had significantly higher baseline T levels and CBG capacities during the nest building, the first egg-laying, and the first nestling stages, and significantly decreased stress-induced T levels only during the nest building and the first egg-laying stages. They also expressed significantly increased stress-induced CBG capacities during the second nestling stage. (2) Females showed significantly higher baseline CBG capacities but significantly decreased stress-induced CBG capacities during the nest building stage, and females also showed significantly increased stress-induced CBG capacities during the second egg-laying and the second nestling stages. Therefore, the seasonal fluctuations of baseline CBG in both sexes and baseline T in males reflect their adaptive strategies for optimizing their physiological and behavioral states to the life history cycle. The different patterns of stress-induced CBG in females suggest CBG functions as an essential mediator in regulating stress response to unpredictable perturbations. Our results highlight the need for future studies of stress-induced CBG and T levels on a wide range of vertebrate species that vary in different life history stages to gain a full understanding of the mechanisms that underlie biological functions of CBG and T for unpredictable stressors.


Spinal epidural abscess.
The incidence of spinal epidural abscesses (SEAs) is rising. Although increased awareness has led to decreased mortality, morbidity remains unacceptably high, with rapid deterioration of neurological status when there is a delay in initiation of treatment. Therefore, we need to build a better understanding of prognostic factors and management strategies. The goal of this article is to identify various prognostic factors, the role of inflammatory markers, optimal management strategies, and the relationship between timing of intervention and outcome. A computer search of health records in our institution revealed 20 cases of spinal epidural abscess over the past 5 years. A retrospective analysis of clinical, radiological, laboratory, and surgical findings was performed. A scoring system ranging from 1 (complete neurological recovery) to 5 (dead) was used to assess outcomes. We also analyzed the prognostic value of several factors, including demographics, clinical presentation, comorbidities, inflammatory markers, imaging findings, and timing of intervention. Fifteen of 20 patients had a good outcome (score of 1 or 2) in this series. Erythrocyte sedimentation rate, muscle strength at time of admission, and timing of intervention were found to have a statistically significant relationship with outcome. C-reactive protein, comorbidities, age, sex, and degree of thecal sac compression were found to have no prognostic value. Although many prognostic factors have been suggested and analyzed, the most important contributor to outcome in SEA remains a high clinical suspicion, prompt investigation, and immediate intervention.


Fetal Alcohol Spectrum Disorders in a Pacific Southwest City: Maternal and Child Characteristics.
There are limited data on the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers from the general population in the United States. During the 2012 and 2013 academic years, first-grade children in a large urban Pacific Southwest city were invited to participate in a study to estimate the prevalence of FASD. Children who screened positive on weight, height, or head circumference ≤25th centile or on parental report of developmental concerns were selected for evaluation, along with a random sample of those who screened negative. These children were examined for dysmorphology and neurobehavior and their mothers or collateral sources were interviewed. Children were classified as fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), or No FASD. A total of 854 children were evaluated; 5 FAS, 44 pFAS, 44 ARND, and 761 No FASD. Children with FAS or pFAS were more likely to have dysmorphic features, and 32/49 (65.3%) of those met criteria for neurobehavioral impairment on cognitive measures with or without behavioral deficits. In contrast, 28/44 (63.6%) of children with ARND met criteria on behavioral measures alone. Mothers of FASD children were more likely to recognize pregnancy later, be unmarried, and report other substance use or psychiatric disorders, but did not differ on age, socioeconomic status, education, or parity. Mothers of FASD children reported more drinks/drinking day each trimester. The risk of FASD was elevated with increasing number of drinks/drinking day prior to pregnancy recognition, even at the level of 1 drink per day (adjusted odds ratio 3.802, 95% confidence interval 1.634, 8.374). Data from this general population sample in a large urban region in the United States demonstrate the variability of expression of FASD and point to risk and protective factors for mothers in this setting.


Association between ferrous iron accumulation and pentachlorophenol degradation at the paddy soil-water interface in the presence of exogenous low-molecular-weight dissolved organic carbon.
Fourteen low-molecular-weight organic acids (organic acids) and eight neutral monosaccharides (monosaccharides) were used to investigate the intrinsic link between ferrous iron [Fe(II)] accumulation and pentachlorophenol (PCP) degradation at the paddy soil-floodwater interface. Using logistic curve fitting, significant differences were observed between Fe(II) accumulation with organic acids and monosaccharides. These differences were attributed to large variations in the dissociation constants and the number of carbon atoms per molecule. A significant relationship was observed between the maximum capacity of Fe(II) accumulation and PCP degradation. Correlations were established between environmental variables including PCP, NaOAc-/HCl-extractable Fe(II), water soluble organic carbon (WSOC), anodic peak oxidation potential (Ep) of Fe(II) species, oxidation-reduction potential (ORP), and pH. The increase in pH combined with WSOC consumption caused a decrease in Ep, which greatly enhanced the HCl-extractable Fe(II) accumulation and subsequently contributed to PCP degradation.


Studies on the capacity of some polysaccharides to elicit antibody formation in man.
Purified levan is antigenic in man and subcutaneous injection of 1 mg. leads to the production of precipitins and skin sensitivity. Apple amylopectin, maize glycogen, and synthetic polyglucose did not stimulate antibody production in small numbers of individuals injected. Quantitative precipitin studies carried out with several levan preparations employing human antilevan show variations in immunochemical behavior indicating structural differences among levans. Evidence that precipitins formed in response to levan injection are antilevan antibodies was obtained by analysis of specific precipitates formed in the region of antibody excess for ketosugar. Injection of levan giving rise to production of antilevan failed in one individual to give a non-specific anamnestic rise in either antidextran or antiblood group A precipitins. Laminarin, a neutral polysaccharide, was found to give precipitation with normal human sera.


CONTENT OF 70 kDa STRESS PROTEIN DURING ACCLIMATION OF MUSSEL MYTILUS EDULIS L. TO LOW SALINITY.
The paper deals with the dynamics of stress-proteins content in gill epithelium of bivalved mollusks Mytilus edulis in the course of their phenotypic adaptation to the changes of environmental salinity. It has been shown that in low salinity (10 ‰) causing the work of «isolating reflex», the induction of stress proteins from HSP70 family comes on the 5th day of the acclimation. Parallel measurements of the mussels extravisceral liquid osmolarity have shown that the signal for stress-protein induction in these mollusks is the osmolarity of their inner medium, but not the salinity of marine water outside.


The Relationship between Whole-Milk Dairy Foods and Metabolic Health Highlights an Opportunity for Dietary Fat Recommendations to Evolve with the State of the Science.
The science of dietary fats has evolved, and a body of evidence indicates they are complex bioactive nutrients that have different effects on health depending on their food source, chain length, degree of saturation, and other factors that can be affected by food processing, handling, and storage. As such, it is becoming increasingly clear that the effects of foods on obesity and metabolic health cannot be predicted simply with their fat content. The aim of this opinion article is to provide a brief overview of select recent research on the effects of whole-milk dairy foods on body composition and indicators of metabolic health across the lifespan to show the gap between current knowledge and dietary guidance. As the state of the science on dietary fats and human health evolves to consider the complexity of food matrices, the total nutrient package they deliver, and the health impacts associated with dietary patterns, so too must guidelines for dietary fat.


The risk ratio for development of hereditary sensorineural hearing loss in consanguineous marriage offspring.
This study aims to define the relative risk of development of hearing loss in offspring of consanguineous marriages. This is a retrospective case-control study conducted in a tertiary referral center in Jeddah, KSA. The study group included 1600 probands (848 males, 752 females), with age range 0.5-12 years (6.6 ± 3.6). The study group comprised of two equal, age and sex matched subgroups; Hearing Loss (HL) group and Normal Hearing (NH) group. The children included in the HL group should have idiopathic or non syndromic genetic sensorineural hearing loss. The HL Group comprised 800 children with variable degrees of sensorineural hearing loss. Profound and severe degrees of hearing loss were the most prevalent degrees (P <0.05%). The prevalence of consanguineous marriage offspring in the NH group was 42.5%, while in the HL group it was 68.9% (P < 0.05). The differences between both study subgroups regarding the distribution of different degrees of parental consanguinity (first, second, double first, and first once removed cousins) were insignificant (P > 0.05). The relative risk and 95% confidence interval (RR, 95% CI) for development of hearing loss in offspring of consanguineous marriage was 1.76 (95% CI 1.57-1.97, P < 0.001). There was 76% increased risk for consanguineous marriage progeny to develop SNHL when compared to non consanguineous progeny.


Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis.
Anaphylaxis is an acute, severe, and potentially fatal systemic allergic reaction. Immunoglobulin E (IgE), mast cells, and histamine have long been associated with anaphylaxis, but an alternative pathway mediated by IgG has been suggested to be more important in the elicitation of anaphylaxis. Here, we showed that basophils, the least common blood cells, were dispensable for IgE-mediated anaphylaxis but played a critical role in IgG-mediated, passive and active systemic anaphylaxis in mice. In vivo depletion of basophils but not macrophages, neutrophils, or NK cells ameliorated IgG-mediated passive anaphylaxis and rescued mice from death in active anaphylaxis. Upon capture of IgG-allergen complexes, basophils released platelet-activating factor (PAF), leading to increased vascular permeability. These results highlight a pivotal role for basophils in vivo and contrast two major, distinct pathways leading to allergen-induced systemic anaphylaxis: one mediated by basophils, IgG, and PAF and the other "classical" pathway mediated by mast cells, IgE, and histamine.


FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia.
FLT3-ITD mutations occur in approximately 25% of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Despite initial efficacy, short duration of response and high relapse rates limit clinical use of selective FLT3 inhibitors. Combination approaches with other targeted therapies may achieve better clinical outcomes. Anti-leukemic activity of multikinase inhibitor olverembatinib (HQP1351), alone or in combination with BCL-2 inhibitor lisaftoclax (APG-2575), was evaluated in FLT3-ITD mutant AML cell lines in vitro and in vivo. A patient-derived FLT3-ITD mutant AML xenograft model was also used to assess the anti-leukemic activity of this combination. HQP1351 potently induced apoptosis and inhibited FLT3 signaling in FLT3-ITD mutant AML cell lines MV-4-11 and MOLM-13. HQP1351 monotherapy also significantly suppressed growth of FLT3-ITD mutant AML xenograft tumors and prolonged survival of tumor-bearing mice. HQP1351 and APG-2575 synergistically induced apoptosis in FLT3-ITD mutant AML cells and suppressed growth of MV-4-11 xenograft tumors. Combination therapy improved survival of tumor bearing-mice in a systemic MOLM-13 model and showed synergistic anti-leukemic effects in a patient-derived FLT3-ITD mutant AML xenograft model. Mechanistically, HQP1351 downregulated expression of myeloid-cell leukemia 1 (MCL-1) by suppressing FLT3-STAT5 (signal transducer and activator of transcription 5) signaling and thus enhanced APG-2575-induced apoptosis in FLT3-ITD mutant AML cells. FLT3 inhibition by HQP1351 downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 to potentiate cellular apoptosis in FLT3-ITD mutant AML. Our findings provide a scientific rationale for further clinical investigation of HQP1351 combined with APG-2575 in patients with FLT3-ITD mutant AML.


Covalent cross-linking of kinases with their corresponding peptide substrates.
Protein phosphorylation represents the most dominant and evolutionary conserved posttranslational modification for information transfer in cells and organisms. The human genome encodes >500 protein kinases, and thousands of phosphorylation sites are present in mammalian proteome. To develop a global view of phosphorylation network, there is a need to map the connectivity between kinases and phosphoproteome. We developed a chemical kinase-substrate cross-linker 1 that converts transient kinase-substrate interactions into a covalently linked kinase-substrate complex in vitro and in the presence of cell lysates. The method can be applied to identify unknown upstream kinases responsible for phosphorylation events in cell lysates.


Anabolic Androgenic Steroid Use as a Cause of Fulminant Heart Failure.
A 39-year-old male weightlifter presented in fulminant heart failure. An echocardiogram revealed severe global biventricular failure. Left ventricular (LV) systolic function was estimated at 15%. His dilated cardiomyopathy was attributed to his use of both testosterone and boldenone in the 3-month period before his presentation. Although the deleterious effects of androgenic- anabolic steroids on diastolic function are well known, the effects of these drugs on systolic function is an area of ongoing investigation. Our case suggests that androgenic anabolic steroid use should be considered in the differential diagnosis of patients presenting with acute heart failure.


Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription.
The ARID1A subunit of SWI/SNF chromatin remodeling complexes is a potent tumor suppressor. Here, a degron is applied to detect rapid loss of chromatin accessibility at thousands of loci where ARID1A acts to generate accessible minidomains of nucleosomes. Loss of ARID1A also results in the redistribution of the coactivator EP300. Co-incident EP300 dissociation and lost chromatin accessibility at enhancer elements are highly enriched adjacent to rapidly downregulated genes. In contrast, sites of gained EP300 occupancy are linked to genes that are transcriptionally upregulated. These chromatin changes are associated with a small number of genes that are differentially expressed in the first hours following loss of ARID1A. Indirect or adaptive changes dominate the transcriptome following growth for days after loss of ARID1A and result in strong engagement with cancer pathways. The identification of this hierarchy suggests sites for intervention in ARID1A-driven diseases.


Measurement of neutrophil adhesion under conditions mimicking blood flow.
Neutrophil migration from blood into tissues is required for effective innate immune responses against infection. Adhesion of the neutrophil in blood to the vascular endothelium and eventual migration through the vessel wall and accumulation at the site of infection involves different classes of adhesion molecules. In vivo intravital microscopy studies show that different adhesion molecules mediate binding events under shear forces associated with blood flow vs binding events that take place under static conditions. To fully analyze the function of these adhesion molecules in vitro, assays must reflect the hemodynamic forces associated with blood flow. We outline two approaches used to study neutrophil adhesion under conditions that mimic blood flow.


Improved Diagnosis through Diastolic Hyperemia-Free Ratio (DFR) over Fractional Flow Reserve (FFR) in Intermediate Coronary Lesions.
To compare the fractional flow reserve (FFR) and diastolic hyperemia-free ratio (DFR) measurements in a population with intermediate coronary artery stenosis and improve the diagnosis. Visual assessment of coronary artery stenosis severity, particularly in intermediate lesions, is prone to errors in decision-making. FFR provides a reliable assessment of functional severity in these cases but requires hyperemia induction by adenosine, which has side effects and increased cost. DFR is a novel hyperemia-independent index, which could be used as an alternative to adenosine-based hyperemia induction. Between September 2019 to March 2020, 25 patients with 38 intermediate coronary stenotic lesions were included in the study. All patients underwent assessment of whole cycle Pd/Pa (ratio of distal coronary pressure to proximal aortic pressure), DFR and FFR. Mean whole cycle Pd/Pa, DFR and FFR were 0.93±0.06, 0.88±0.09, and 0.85±0.08, respectively. A significant positive correlation between DFR and FFR [r = 0.74; p<0.001] was observed. Receiver operating characteristic analysis showed an area under the curve of 0.90. DFR-only strategy with a treatment cut-off of ≤0.89 showed a diagnostic agreement with the FFR-only strategy in 74% of lesions, with a sensitivity of 54%, specificity of 82%, a positive predictive value of 60%, and a negative predictive value of 79%. Real-time DFR measurements show a clinically reliable correlation with FFR. Hence, using DFR is likely to avoid adenosine administration as well as reduce the cost and procedural time. Further studies with a larger sample size would be ideal to evaluate specific cut-off values and endpoints.


Effect of low density lipoprotein on DNA synthesis of cultured human arterial smooth muscle cells.
Increased concentration of plasma low-density lipoprotein (LDL) is one of the risk factors in atherosclerosis. We studied how DNA synthesis of human arterial smooth muscle cells (SMC) was influenced in the culture added with or without small dose (25 micrograms of protein/ml) of LDL. LDL were ultracentrifugally obtained from normal subjects and diabetics. DNA synthesis was investigated at 6-h intervals during 36 h in the culture with or without LDL using [methyl-3H]thymidine. We found that DNA synthesis reached a maximum value at 24 h after addition of LDL. On the other hand sequential changes were not detectable in the culture without LDL addition. This effect of diabetic LDL was significantly (P less than 0.001) greater than that of normal LDL. These results suggested that LDL induces synchronization of the cultured SMC to synthesize DNA and diabetic LDL may play an atherogenic role more strongly than normal LDL in the arterial wall even in the normal range of LDL concentration.


Morphology of enamel in primary teeth from children in Thailand exposed to environmental lead.
Lead is one of the major environmental pollutants and a health risk. Dental hard tissues have a capacity to accumulate lead from the environment. Eighty exfoliated primary teeth were collected from children residing around a shipyard area in southern Thailand, known for its lead contamination. The morphology of the enamel was examined by polarized light microscopy (PLM), microradiography (MRG), and scanning electron microscopy (SEM). The specimens derived from two groups of children, one group with high blood levels of lead (57 teeth) and one group having low blood levels of lead (23 teeth). The enamel irrespective of group appeared normal. However, in a majority of the specimens the enamel surface appeared hypomineralized, which was confirmed in SEM. No morphological changes connected to lead in blood could be found. The hypomineralized surface zone could possibly be attributed to an acid oral environment.


New technique for repair of rectal injury.
Injury to the rectum is a potentially serious complication of pelvic surgery. The management of rectal injury is controversial. We present a technique of using flaps of endopelvic fascia to reinforce the repair and isolate the injury site. We have utilized this approach in 4 men undergoing retropubic prostatectomy without complications.


Clinical evaluation of hyposensitization in allergic rhinitis: comparison of the results obtained with three different extracts. Material from a 3-year study.
Three different immunotherapy regimens were given during 4 years to 60 randomized patients. One can conclude from the symptom and medication scores that a tyrosine-bound mixture is less active. The results obtained with mixed grass and with highly purified timothy pollen are comparable, but in favour of the latter.


Dynamic role of epithelium-derived cytokines in asthma.
Asthma is an inflammatory disorder of the airways, characterized by infiltration of mast cells, eosinophils, and Th2-type CD4+ T cells in the airway wall. Airway epithelium constitutes the first line of interaction with our atmospheric environment. The protective barrier function of the airway epithelium is likely impaired in asthma. Furthermore, recent studies suggest critical immunogenic and immunomodulatory functions of airway epithelium. In particular, a triad of cytokines, including IL-25, IL-33 and TSLP, is produced and released by airway epithelial cells in response to various environmental and microbial stimuli or by cellular damage. These cytokines induce and promote Th2-type airway inflammation and cause remodeling and pathological changes in the airway walls, suggesting their pivotal roles in the pathophysiology of asthma. Thus, the airway epithelium can no longer be regarded as a mere structural barrier, but must be considered an active player in the pathogenesis of asthma and other allergic disorders.


Female meiotic drive in plants: mechanisms and dynamics.
Female meiosis is fundamentally asymmetric, creating an arena for genetic elements to compete for inclusion in the egg to maximize their transmission. Centromeres, as mediators of chromosomal segregation, are prime candidates to evolve via 'female meiotic drive'. According to the centromere-drive model, the asymmetry of female meiosis ignites a coevolutionary arms race between selfish centromeres and kinetochore proteins, the by-product of which is accelerated sequence divergence. Here, I describe and compare plant models that have been instrumental in uncovering the mechanistic basis of female meiotic drive (maize) and the dynamics of active selfish centromeres in nature (monkeyflowers). Then, I speculate on the mechanistic basis of drive in monkeyflowers, discuss how centromere strength influences chromosomal segregation in plants, and describe new insights into the evolution of plant centromeres.


The postribosomal particle of rabbit liver contains protein-synthesis factors and serum albumin mRNA.
As demonstrated by indirect immunoprecipitation and polyacrylamide gel electrophoresis, an 85S particle separated by sucrose density-gradient centrifugation from the postribosomal pellet of rabbit liver, is able to synthesize serum albumin if supplemented with both ribosomal subunits and sources of energy. It is retained on heparin bound to Sepharose 4B, contains translatable mRNA and apparently all protein factors required for translation. This particle may represent a highly organized protein synthesizing machinery, the combination of which with ribosomes results in formation of new protein molecules.


Thermal and Nonlinear Optical Properties of Sudan III.
We report the experimental and theoretical study of the diffraction patterns (DPs) and thermal properties of Sudan III. DPs are used in the calculation of the Sudan III nonlinear refractive index (NLRI), [Formula: see text]. As high as [Formula: see text]= 7.69 ×10-6 cm2/W is obtained. The study of the Sudan III thermal conductivity, TC, shows the reduction of the TC against the increase of the Sudan III temperature. The property, all-optical switching (AOS), is studied in details, both static and dynamic ones, using two, cw, visible, single mode laser beams of wavelengths 473 and 635 nm.


Social media's role in otolaryngology-head and neck surgery: informing clinicians, empowering patients.
With the increasing availability of the Internet in the United States, patients are more frequently seeking medical information online. Oftentimes, the medical information that patients find on traditional websites is unreliable. It is a physician's duty to ensure that patients are being educated properly. Providing sound medical information through social media websites is one way in which physicians may accomplish this goal, while also improving clinic reputation, patient volume, and doctor-patient communication.


Nursing assessment of the patient with primary HIV infection: key to improving clinical recognition.
David is a 29-year-old Hispanic male who presents complaining of fatigue, headache, muscle aches, a sore throat, and nausea. Physical assessment demonstrates an erythematous maculopapular rash on the trunk and symmetric adenopathy. His temperature is 37.6 degrees C; other vital signs are within normal limits. Laboratory findings include a white blood cell count of 4.5/microL and a platelet count of 98,000/mm3. Blood chemistry is unremarkable. David states that his symptoms began one week ago.


Surgical treatment of carpal boss by simple resection: Results in 25 cases at a mean of 8 years' follow-up.
Carpal boss is a symptomatic bony protrusion on the dorsal surface of the wrist at the base of the 2nd and/or 3rd metacarpal. The goal of this study was to assess the reliability and safety of simply resecting the exostosis. From 1994 to 2014, 29 cases of carpal boss were treated by simple resection. Twenty-five of these patients were subsequently assessed by telephone questionnaire at a mean of 8 years' follow-up (range 1.1 to 20 years). There were no cases of recurrence; however, 1 patient reported carpometacarpal instability requiring fusion, 5 years after surgery. Eight of the 24 patients without fusion (33%) reported moderate episodic pain (visual analog scale [VAS] pain: mean, 2.3/10, range 1 to 4). Range of motion improved in 8 cases (33%), was unchanged in 11 (46%) and decreased in 5 (21%). Twenty patients (83%) had no functional impairment; 4 reported impairment during unusual hand movements. Fifteen patients considered themselves cured (60%), 9 considered their status improved (36%) and one - the patient who required fusion - considered his status unchanged. Patients were very satisfied with the procedure in 15 cases (60%) and satisfied in 10 (40%). In all cases, features of dysplasia were present and associated with secondary osteoarthritis limited to the area of impingement. The single failure was most likely due to excessive bone resection. Simple exostosis resection is sufficient to effectively treat carpal boss. Fusion should be reserved for the rare cases of secondary metacarpal instability.


Synthesis of some new biologically active bis-(thiadiazolotriazines) and bis-(thiadiazolotriazinyl) alkanes.
4-Amino-3-mercapto-1,2,4-triazin-5(4H)-ones (1) were condensed with dicarboxylic acids 2 to yield bis-(4-oxo-4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-7-yl)alkanes (3b-d,f-h,j-l,n-p) and bis-thiadiazolotriazines (3a,e,i,m). All the newly synthesised compounds were characterised by analytical, IR, NMR and mass spectral studies. Some of the newly synthesised compounds were screened for their antibacterial and antifungal properties. Among the tested compounds, compound 7,7'-(1,4-butanediyl)-his-(3-t-butyl-4-oxo-4H-1,3,4-thia-diazolo[2,3-c]-1,2,4-triazine (3p) exhibited highest degree of antifungal activity.


Detection and biological characteristic of FLT3 gene mutations in children with acute leukemia.
FLT3 ITD and D835 mutations occur in high frequency in AML and to a lower rate in ALL patients with poor prognosis. ITD and D835 mutations were studied in 100 diagnosed acute leukemia patients including 27 AML and 73 ALL with various FAB classifications by PCR and PCR-RFLP, respectively. Subsequently, PCR products of positive samples were confirmed by sequencing analyses. ITD mutations occurred in 10% of all pediatric acute leukemia, including AML and ALL. 25.9% of AML patients harbor a mutation in the ITD in various subtypes. The frequency of ITD mutations was 4% in ALL. Various insertions of nucleotides in ITD were observed, similar to those described in the literature previously. These preliminary data suggest that flt3-ITD mutations may play an important role in leukemogenesis in a proportion of children, particularly in the case of AML.


Orosomucoid: a promising biomarker for the assessment of exercise-induced fatigue triggered by basic combat training.
Orosomucoid (ORM) is a positive acute phase protein verified to be upregulated in various forms of exercise-induced fatigued (EIF) rodents. However, its association with EIF among human beings remained unknown. This study aimed to explore the association between serum ORM and EIF triggered by military basic combat training (BCT). The degree of EIF were measured by Borg's Rating of Perceived Exertion Scale (Borg-RPE-Scale®) as RPE score after BCT. Fifty-three male recruits were classified into three groups according to the RPE score: (1) group 1 (slight fatigue group): RPE score after BCT < 13; (2) group 2 (moderate fatigue group): RPE score after BCT = 13 or 14; (3) group 3 (severe fatigue group): RPE score after BCT > 14. The levels of blood ORM, lactate (LAC), cortisol and C-reactive protein (CRP) were determined before and after BCT. The diagnostic value of ORM was evaluated by receiver operating characteristic (ROC) curve analysis and logistic regression. After BCT, the level of LAC, CRP, and cortisol increased among all groups, but the changes had no significant between-group difference (all p > 0.05). The level of ORM had a specific significant increase in group 3 (p = 0.039), and the changes of ORM (ΔORM) had significant difference among groups (p = 0.033). ROC curve analysis showed that the estimated area under ROC curve for ΔORM was 0.724 (p = 0.009) with the recommended optimal cut-off value as 0.2565 mg/mL. Logistic analysis showed that recruits with ΔORM ≥ 0.2565 mg/mL had higher odds for suffering from severe EIF, 5.625 times (95% CI 1.542-20.523, p = 0.009) as large as those with ΔORM < 0.2565 mg/mL. ORM might be a promising biomarker of severe EIF triggered by BCT among male recruits. Its potential optimal cut-off value regarding ΔORM was recommended to be 0.2565 mg/mL.


Pregnancy-associated plasma protein A (PAPP-A) in non-pregnant subjects.
A newly developed enzyme immunoassay technique was applied to the measurement of pregnancy-associated plasma protein A (PAPP-A) in the serum of women in the proliferative and luteal phases of the cycle, in hysterectomized and postmenopausal women and in the serum and seminal plasma of males. PAPP-A was detected in some individuals in all the categories of women and in seminal plasma but not in male serum. It is surmised that there must be a source of PAPP-A other than the placenta and that PAPP-A may be a maternal protein whose biosynthesis is stimulated by pregnancy rather than a product peculiar to the trophoblast.


A palaeo-hydrogeological model for arsenic contamination in southern and south-east Asia.
An argument is presented in which areas of natural arsenic contamination of modern groundwaters throughout Asia have a common origin. Arsenic originally accumulated in oceanic ferro-manganoan sediments of the eastern Palaeo-Tethys. This was further concentrated through oceanic crustal extinction in what later became the south-east Chinese accreted mineralised terrain. Proto-Himalayan uplift of this area created the palaeo-drainage systems of the Ganges - Brahmaputra, Irrawaddy, Mekong, and Red Rivers, with consequent headwater erosion of arsenic-rich sediments. Their downstream deposition as immature and easily redistributed Neogene sandstones, silts, and iron-rich clays has created secondary and tertiary reservoirs of adsorbed and authigenic arsenic, from which the current arsenic-rich groundwaters have evolved. Considering river basins within the above palaeo-hydrogeological framework provides a basis for assessing the risk of arsenic in groundwater basins of south and south-eastern Asia.


Human recombinant interferon alpha inhibits naloxone binding to rat brain membranes.
Regulation of certain central nervous system (CNS) functions by the immune system may involve interferons (IFNs) acting through opioid receptors. Human recombinant interferon alpha (hrIFN alpha), as well as natural IFN alpha, have been reported to modulate a variety of physiological CNS functions both in vivo and in vitro. If the mechanism is via opioid receptors then IFN alpha should inhibit the binding of certain opioid radioligands to brain membranes. This study reports the inhibitory effect of hrIFN alpha on the binding of 3H-naloxone to rat brain membranes in vitro. The inhibitory effect at 37 degrees C is hrIFN alpha concentration dependent over the range of 500 to 6000 antiviral units per ml (U/ml) with 500 micrograms of membrane protein. The presence of NaCl (100mM) increases specific binding of naloxone and attenuates the inhibitory effect of hrIFN alpha. The inhibitory effect of hrIFN alpha is sensitive to temperature with maximum inhibition observed at 37 degrees C, and less as incubation temperature is reduced. These data suggest that IFN alpha may modulate certain physiologic functions via opioid pathways in the brain.


Ventricular septal defect associated with aortic regurgitation.
The effectiveness of aortic valvuloplasty and the indications for aortic valve replacement were examined in 76 patients with ventricular septal defect associated with aortic regurgitation. Results of this study indicate aortic regurgitation is associated with rapid deterioration and that aortic valvuloplasty should be performed as soon as aortic regurgitation is detected. The data also suggest that aortoplasty is indicated if aortic valvuloplasty alone is inadequate for coaptation of the aortic cusps with thickening.


A new turn-off fluorescence probe based on graphene quantum dots for detection of Au(III) ion.
In this work, a new turn-off fluorescence probe based on the graphene quantum dots (GQDs) was designed for detection and quantification of Au(III) ion. GQDs were prepared by two simple carbonization methods using glucose (g-GQDs) and citric acid (c-GQDs) as carbon sources. The effect of some metal ions on the fluorescence intensity of the prepared GQDs was studied. It was found that the fluorescence of both GQDs is significantly quenched by Au(III) ions but the sensitivity and analytical performances are different for two prepared GQDs. Using g-GQDs, a new analytical method was developed for the determination of Au(III) in the concentration range of 1.0-80 μM, with a detection limit of 0.5 μM. The developed method was applied to the determination of Au(III) in water and plasma samples with satisfactory results.


IL-6/NOS2 inflammatory signals regulate MMP-9 and MMP-2 activity and disease outcome in nasopharyngeal carcinoma patients.
The role of nitric oxide (NO)(·) in the development of the metastatic properties of nasopharyngeal carcinoma (NPC) is not fully understood. Previous studies proposed that interleukin-6 (IL-6) would act as regulator of matrix metalloprotease activation in NPC. Recently, we showed that (NO)(·) was a critical mediator of tumor growth in patients. The aim of this study was to determine the implication of IL-6 in the progression of NPC pathology via metalloprotease (MMP) activation and their possible correlation with (NO)(·) production. We observed a significant increase in IL-6 and nitrite (NO2 (-)) synthesis in patients (n = 17) as well as a strong expression of IL-6 and nitric oxide synthase 2 (NOS2) in the analyzed tumors (n = 8). In patients' plasma, a negative correlation associated IL-6 with circulating nitrites (r = -0.33). A negative correlation associated the H-scores of these signals in the tumors (r = -0.47). In patients' plasma, nitrite synthesis was positively associated with MMP-9 activation (r = 0.45), pro-MMP-2 expression (r = 0.37), and negatively correlated with MMP-2 activation (r = -0.51). High nitrite levels was associated with better recurrence-free survival (RFS) (p = 0.02). Overall, our results suggest that the IL-6/NOS2 inflammatory signals are involved in the regulation of MMP-9- and MMP-2-dependent metastatic activity and that high circulating nitrite levels in NPC patients may constitute a prognostic predictor for survival.