Open questions on bioequivalence: an updated reappraisal.
During the last thirteen years, the author has investigated a relevant number of bioequivalence trials, for the approval of generics, which in the Mediterranean area show an increasing business trend. In his activity the author has faced several problems, most of them not considered in operating guidelines, defined "open questions on bioequivalence". They deal with the most appropriate procedures to adopt in case of studies on drugs with long half-lives, of ethics problems, high data dispersion, endogenous substances, presence of active metabolite(s), prevalent metabolites and reversible metabolism, very low plasma concentrations, multiple peak phenomenon, titre differences, polymorphic metabolism, stereogenic atoms. The relevance of a pilot trial, mainly for modified-release formulations, and the problem of frauds are discussed as well. These open questions are discussed in the present review taking into account EU and US FDA guidelines, current literature and personal experience. In most cases suitable approaches are suggested. Appropriate procedures should be planned and defined in the study protocol and extensively discussed in the final report. An appropriate approach to the "open questions" is a requisite to achieve a clearly defined bioequivalence/bioinequi-valence conclusion.


Non-Functional Adrenal Gland Ganglioneuroma Masquerading as Chronic Calculus Cholecystitis.
Adrenal ganglioneuromas in young adults are rare and ill-understood. We report an incidentally detected adrenal gland tumor diagnosed as ganglioneuroma (mature type) in 33 years old man who presented with vomiting and epigastric pain for 2 months. Histopathology examination revealed a well-encapsulated benign tumor of mature ganglion cells and Schwann-like cells arranged in fascicles, staining strongly with NSE and s-100 proteins, with adjacent unremarkable adrenal cortex and medulla.


Computational Selection of High-Performing Covalent Organic Frameworks for Adsorption and Membrane-Based CO2/H2 Separation.
Covalent organic frameworks (COFs) have high potential in gas separation technologies because of their porous structures, large surface areas, and good stabilities. The number of synthesized COFs already reached several hundreds, but only a handful of materials were tested as adsorbents and/or membranes. We used a high-throughput computational screening approach to uncover adsorption-based and membrane-based CO2/H2 separation potentials of 288 COFs, representing the highest number of experimentally synthesized COFs studied to date for precombustion CO2 capture. Grand canonical Monte Carlo (GCMC) simulations were performed to assess CO2/H2 mixture separation performances of COFs for five different cyclic adsorption processes: pressure swing adsorption, vacuum swing adsorption, temperature swing adsorption (TSA), pressure-temperature swing adsorption (PTSA), and vacuum-temperature swing adsorption (VTSA). The results showed that many COFs outperform traditional zeolites in terms of CO2 selectivities and working capacities and PTSA is the best process leading to the highest adsorbent performance scores. Combining GCMC and molecular dynamics (MD) simulations, CO2 and H2 permeabilities and selectivities of COF membranes were calculated. The majority of COF membranes surpass Robeson's upper bound because of their higher H2 permeabilities compared to polymers, indicating that the usage of COFs has enormous potential to replace current materials in membrane-based H2/CO2 separation processes. Performance analysis based on the structural properties showed that COFs with narrow pores [the largest cavity diameter (LCD) < 15 Å] and low porosities (ϕ < 0.75) are the top adsorbents for selective separation of CO2 from H2, whereas materials with large pores (LCD > 20 Å) and high porosities (ϕ > 0.85) are generally the best COF membranes for selective separation of H2 from CO2. These results will help to speed up the engineering of new COFs with desired structural properties to achieve high-performance CO2/H2 separations.


A prospective evaluation of cognitive decline in early Huntington's disease: functional and radiographic correlates.
We examined prospectively the relationship between progressive disability in Huntington's disease (HD) and concomitant alterations in neuropsychological functioning and brain imaging indices in a cohort of 60 patients who were enrolled and followed for 30 to 42 months in a controlled clinical trial. Standardized measures of functional capacity and neuropsychological performance were collected, and CT was performed, at regular intervals every 6 to 12 months. Psychomotor skills showed the most significant and consistent decline among the cognitive functions assessed. Memory disturbances were already present at the time of enrollment, but memory did not deteriorate until patients reached advanced stages. Other cognitive operations, such as visual construction and semantic knowledge, manifested small and variable changes over time. CT indices of striatal atrophy correlated only with changes in psychomotor function, while the CT index of frontal atrophy weakly predicted memory and semantic knowledge scores at 42 months. These results confirmed earlier cross-sectional findings and extended our knowledge of the evolution of cognitive dysfunction in HD.


Effects of recombinant human erythropoietin (EPOCH) on the coagulation and fibrinolytic systems and platelet function in pre-dialysis patients with chronic renal failure.
The purpose of this study was to investigate whether or not the systems of coagulation and fibrinolysis are activated after human recombinant erythropoietin therapy in patients with end-stage renal failure and renal anemia. Six thousand IU of human recombinant erythropoietin (EPOCH) were administered intravenously to 11 patients once a week for 8 weeks. Coagulation, fibrinolysis and platelet as well as renal functions were investigated before and after the EPOCH therapy. Platelet count did not increase in spite of improvement in anemia. No changes in prothrombin time, activated partial thromboplastin time, concentrations of fibrinogen, fibrinopeptide A, thrombin antithrombin III complex, fibrin/fibrinogen degradation products (FDP), FDP-E, FDP-D dimer, plasmin alpha 2-plasmin inhibitor complex were observed. Platelet factor 4 and beta-thromboglobulin also were unchanged. Reciprocal changes in serum creatinine concentrations over the duration of therapy were compared before and after therapy. There was no significant difference between the reciprocal changes in serum creatinine concentrations before and after therapy. The increases in hemoglobin did not correlate with the changes in coagulation, fibrinolysis and the other parameters, except for the change in prothrombin time. These results indicate that coagulation, fibrinolysis and platelet systems in end-stage renal failure patients were not affected by EPOCH administration, in spite of increase in hemoglobin.


Bioabsorbable synthetic plug in the treatment of anal fistulas.
Management of anal fistulas is challenging, because surgeons must aim to obtain complete healing while sparing the sphincter and avoiding fecal incontinence. The optimal treatment method remains unknown. This study assessed the safety and effectiveness of the use of a new synthetic fistula plug made of bioabsorbable polymers in the treatment of cryptoglandular anal fistulas. This study is a retrospective review of a database of patient records. : Patients were treated at a general hospital in Italy. Forty-eight patients (39 men and 9 women; mean age, 49.9 years) with 49 fistulas were treated with the synthetic plug between November 2009 and March 2012. Types of fistula were as follows: 24 superficial transsphincteric, 18 medium transsphincteric, 5 deep transsphincteric, and 1 medium intersphincteric. The fistula tract was cleaned by using curettage, and a synthetic plug was sized to fit the tract and inserted. A draining seton was used preoperatively in 1 patient. The outcome measures were complete closure of the fistula, with no discharge/residual fistula (verified by endoanal ultrasonography), perineal pain level (assessed with a visual analog scale), and fecal continence. Follow-up was conducted at 1 week and 1, 3, 6, and 12 months postoperatively. The overall healing rate was 69.3% (34/49 fistulas, 33/48 patients). Eight patients (24.2%) had healing by 3 months after surgery, 21 patients (63.6%) had healed by 6 months, and 4 patients (12.1%) had healed by 12 months. By 3 months, no patient had perineal pain or fecal incontinence. No plug became dislodged, and no patient had the onset of anal stenosis, bleeding, local infection, or any other complication. The number of patients and the retrospective nonrandomized nature of the investigation are limitations of this study. In patients with cryptoglandular anal fistulas, the use of a bioabsorbable synthetic plug provided a high rate of healing without causing fecal incontinence or other major adverse effects. Larger and randomized studies of this treatment are warranted.


Stereoselective synthesis of trifluoromethylated vicinal ethylenediamines with alpha-amino N-tert-butanesulfinimines and TMSCF3.
Isolable alpha-amino N-tert-butanesulfinimines were prepared through the condensation of Reetz's alpha-amino aldehydes (prepared from alpha-amino acids) with Ellman's (R)-N-tert-butanesufinamide without any racemization, and these were trifluoromethylated with TMSCF3 and TMAF (tetramethylammonium fluoride) to the corresponding vicinal ethylenediamines derivatives. Imines derived from l-amino acids gave exclusively one diastereomer with a very high yield.


Characteristics of long-term live-donor pediatric renal transplant survivors: a single-center experience.
To study the characteristics and the predictors of survival observed in our pediatric live-donor renal transplant recipients with an allograft that functioned for more than 10 yr. One hundred fifteen children underwent renal transplantation between 1976 and 1995. Of these, 30 had functioning allografts for more than 10 yr (range, 11-18). The patients included 18 males and 12 females, with a mean age at transplantation of 13 yr (range, 5-18). Characteristics of the patients, data on graft survival, and determinants of outcome were obtained by reviewing all medical charts. At most recent follow-up (January 2005), the mean daily dose of azathioprine was 1.2 mg/kg (range, 1-2) and that of prednisone was 0.16 mg/kg (range, 0.1-0.2). Mean creatinine clearance was 72 mL/min per 1.73 m(2) (range, 45-112). Acute rejection occurred in 14 (47%) patients. Seven patients had one episode, five had two episodes, and two had three episodes of acute rejection. Three patients (10%) developed malignancy. A substantial proportion of patients (44%) were short, with a height standard deviation score (SDS) less than -1.88, which is below the third percentile for age and gender. One quarter of the patients, more commonly the females, were obese. Other complications included osteoporosis in 16 (53%) patients, avascular bone necrosis in four (13%), post-transplantation diabetes mellitus in three (10%), and hypertension in 18 (60%). Twelve (40%) patients were married and 27% had children post-transplantation. The independent determinants of long-term graft survival were acute rejection and post-transplant hypertension. Despite good renal function, long-term pediatric renal transplant survivors are at risk of significant morbidity. The determinants of long-term graft survival are acute rejection and post-transplant hypertension.


Type-specific detection of echovirus 30 isolates using degenerate reverse transcriptase PCR primers.
Following an approach used to specifically identify polioviruses and enterovirus 71, we have developed reverse transcriptase (RT) PCR primers containing mixed-base residues or deoxyinosine at positions of codon degeneracy. These primers permit specific RT-PCR amplification of echovirus 30 (E30) sequences by targeting sites that encode conserved amino acid motifs within the major capsid protein, VP1. All 221 E30 strains tested, isolated in 16 countries over a 44-year period, yielded the predicted 158-bp PCR product. No specific products were obtained by PCR assays containing templates from any of the other 63 EV serotypes. Inosine-containing degenerate primers may be widely applicable to the identification of echovirus serotypes by PCR.


Cytokines induce MMP-3-regulated proliferation of embryonic stem cell-derived odontoblast-like cells.
Matrix metalloproteinase (MMP)-3 expression increases after pulpectomy and accelerates angiogenesis in rat dental pulp by an uncharacterised mechanism. Odontoblasts, a major component of dental pulp, could represent a therapeutic target. We investigated whether MMP-3 activity is induced by cytokines and/or is associated with cell proliferation and apoptosis in embryonic stem cell-derived odontoblast-like cells. We used reverse transcriptase polymerase chain reaction, western blotting, an MMP-3 activity assay, a BrdU-cell proliferation enzyme-linked immunosorbent assay and DNA fragmentation analysis to evaluate siRNA-mediated downregulation of MMP-3 expression and activity, and any changes in the proliferative and apoptotic responses associated with this reduced expression. Pro-inflammatory cytokines (interleukin-1β, tumour necrosis factor-α and interferon-γ, at relatively low concentrations) induced MMP-3 mRNA and protein expression, and increased MMP-3 activity and cell proliferation, but not apoptosis. MMP-3 silencing produced a potent and significant suppression of cytokine-induced MMP-3 expression and activity, decreased cell proliferation and increased apoptosis. These effects were rescued by application of exogenous MMP-3. Our results suggest that pro-inflammatory cytokines induce MMP-3-regulated cell proliferation and anti-apoptosis effects in odontoblast-like cells derived from embryonic stem cells, in addition to their well-documented destructive role in inflammation.


Circulating intercellular adhesion molecule-1 as an early predictor of hepatic failure in patients with septic shock.
To investigate whether endotoxin, interleukin-6, and circulating adhesion molecules, measured sequentially in blood, can predict mortality and organ dysfunction in sepsis. Inception cohort study with follow-up for 28 days. Surgical intensive care unit at a university hospital. A total of 14 consecutive patients were enrolled in the study within the first 24 hrs after onset of septic shock. Seven healthy subjects were studied as controls. Patients were analyzed for mortality and development of organ dysfunction. At the end of the 28-day follow-up period, seven of the patients were still alive (survivors) but the other seven (nonsurvivors) had died. At the time of enrollment in the study (day 0), the Acute Physiology and Chronic Health Evaluation II score was 28.4 in survivors (n = 7) and 28.7 in nonsurvivors (n = 7). In contrast, circulating intercellular adhesion molecule-1 (ICAM-1) was significantly higher in nonsurvivors than in survivors. Circulating ICAM-1 predicted mortality in patients with septic shock with a sensitivity and a specificity of 71.4% each. Endotoxin, interleukin-6, circulating L-selectin, P-selectin, E-selectin, and platelet endothelial cell adhesion molecule-1, however, did not distinguish between survivors and nonsurvivors. In addition, circulating ICAM-1 at day 0 showed a significant correlation with the highest serum bilirubin observed during the entire study period (r2 = 0.963). Because only circulating ICAM-1 was higher in nonsurvivors than in survivors at day 0, circulating ICAM-1 may serve as an early prognostic marker for outcome in septic shock. In addition, measurement of circulating ICAM-1 facilitates identification of those patients with the highest risk of developing liver dysfunction.


Effect of pelvic inflammatory disease on fertility.
Genital infections, in both men and women, may cause permanent functional damage to the reproductive tract resulting in infertility. In men, post-infection infertility is uncommon, whereas in women sequelae after pelvic inflammatory disease (PID) are the most common cause of acquired infertility. In a prospective cohort study of women who all sought pregnancy after laparoscopically verified acute (non-tuberculous) salpingitis, 141/1309 (10.8%) were infertile because of proven post-PID tubal occlusion. In 448 control women, the corresponding figures were 4/448 (0.9%). Of independent and significant importance for post-PID infertility were the numbers of PID episodes (0/1/2 or= 3: RRs 1.0/7.0/16.2/28.3), and in women with only one PID episode, the severity of infection (mild/moderate/severe; RRs 1/1.8/5.6), delayed care (3 days/3 or more days; RR 1/2.8), use of contraceptives (none/pills/IUDs/other; RRs 1/0.3/0.5/0.8). Similar influences of the same variables were also demonstrated for subfertility, i.e. ectopic pregnancy, and time between index laparoscopy and pregnancy in those women who conceived after PID.


ANG II-mediated inhibition of neuronal delayed rectifier K+ current: role of protein kinase C-alpha.
It was previously determined that ANG II and phorbol esters inhibit Kv current in neurons cultured from newborn rat hypothalamus and brain stem in a protein kinase C (PKC)- and Ca2+-dependent manner. Here, we have further defined this signaling pathway by investigating the roles of "physiological" activators of PKC and different PKC isozymes. The cell-permeable PKC activators, diacylglycerol (DAG) analogs 1,2-dioctanoyl-sn-glycerol (1 micromol/l, n = 7) and 1-oleoyl-2-acetyl-sn-glycerol (1 micromol/l, n = 6), mimicked the effect of ANG II and inhibited Kv current. These effects were abolished by the PKC inhibitor chelerythrine (1 micromol/l, n = 5) or by chelation of internal Ca2+ (n = 8). PKC antisense (AS) oligodeoxynucleotides (2 micromol/l) against Ca2+-dependent PKC isoforms were applied to the neurons to manipulate the endogenous levels of PKC. PKC-alpha-AS (n = 4) treatment abolished the inhibitory effects of ANG II and 1-oleoyl-2-acetyl-sn-glycerol on Kv current, whereas PKC-beta-AS (n = 4) and PKC-gamma-AS (n = 4) did not. These results suggest that the angiotensin type 1 receptor-mediated effects of ANG II on neuronal Kv current involve activation of PKC-alpha.


Stimulation frequency history alters length-force characteristics of fully recruited rat muscle.
Effects of stimulation frequency history on length-force characteristics were determined for rat medial gastrocnemius muscle (GM). The peripheral nerve was stimulated supramaximally according to two stimulation protocols. First, a complete set of length-force data were obtained by stimulating the nerve with a decreasing stimulation frequency (DSF) staircase composed of five successive pulse trains (200 ms each) of 100-, 50-, 40-, 30- and 15-Hz stimulation. Then length-force data were obtained using constant stimulation frequency (CSF; during the isometric contraction inter-stimulus interval was constant). The acquisition order of a complete set of length-force data was: first 15-Hz, then 30-, 40-, 50- and finally 100-Hz stimulation. For all DSF conditions, both optimum muscle length as well as active slack length were shifted significantly (P < 0.05) to lower muscle length with respect to CSF. Muscle length range between active slack and optimum length for all DSF conditions was increased significantly with respect to CSF. DSF thus caused a marked shift of the length-force relationship to lower muscle length compared to the CSF-dependent length-force relationship. As a result of this shift, muscle force enhancement (potentiation) was non-linearly related to muscle length; force enhancement decreased exponentially with increasing muscle length. In addition, DSF-dependent length-force characteristics are not scaled and shifted versions of those for CSF. Possible factors affecting these length-force characteristics are higher intracellular calcium concentration, myosin light chain phosphorylation, fatigue during sustained contractions, interaction between aponeurosis and fibre length, distribution of fibre mean sarcomere length with respect to muscle length, and muscle length changes during unfused tetanic contractions. It is concluded that length-force characteristics of rat GM are dependent on both short-term stimulation frequency history as well as stimulation frequency per se.


Genetic correlates of olanzapine-induced weight gain in schizophrenia subjects from north India: role of metabolic pathway genes.
Olanzapine is an efficacious drug often used as a first-line medication in the treatment for schizophrenia. However, weight gain is a notable adverse drug reaction of this medication in a proportion of patients and a major cause of noncompliance. Several hypotheses, including a contribution from hormonal, physiological and environmental factors, have been postulated. In this study, we aimed to analyze a possible association of genetic polymorphisms at four important candidate genes involved in appetite regulation and antipsychotic-induced metabolic syndrome with olanzapine-induced weight gain. A total of 154 schizophrenia subjects were recruited in a systematic, 6-week, open-label trial of olanzapine. We investigated the contribution of 14 polymorphisms from four genes, namely, leptin, lipoprotein lipase, tri-acyl-glycerol lipase and citrate lyase using a binary logistic regression analysis towards olanzapine-induced weight gain. rs 4731426 C/G SNP, a variant in the leptin gene, was moderately associated with median weight gain (Delta weight(m); [p = 0.05; OR: 2.2; 95% CI: 0.99-4.90]) and significantly associated with extreme weight gain (Delta weight(e) [p = 0.019; OR: 11.43; 95% CI: 1.49-87.55]) when average drug dose was included in a regression model. Using in silico analysis, we found that this associated intronic SNP in the leptin gene alters the binding of zinc finger 5, a transcription factor. The leptin gene may be a promising candidate for olanzapine-induced weight gain. As the associations are modest, replicate studies are warranted. This approach may facilitate rationalized drug regimens.


Bioinspired Quercitrin Nanocoatings: A Fluorescence-Based Method for Their Surface Quantification, and Their Effect on Stem Cell Adhesion and Differentiation to the Osteoblastic Lineage.
Polyphenol-based coatings have several potential applications in medical devices, such as cardiovascular stents, contrast agents, drug delivery systems, or bone implants, due to the multiple bioactive functionalities of these compounds. In a previous study, we fabricated titanium surfaces functionalized with flavonoids through covalent chemistry, and observed their osteogenic, anti-inflammatory, and antifibrotic properties in vitro. In this work, we report a fluorescence-based method for the quantification of the amount of flavonoid grafted onto the surfaces, using 2-aminoethyl diphenylborinate, a boronic ester that spontaneously forms a fluorescent complex with flavonoids. The method is sensitive, simple, rapid, and easy to perform with routine equipment, and could be applied to determine the surface coverage of other plant-derived polyphenol-based coatings. Besides, we evaluated an approach based on reductive amination to covalently graft the flavonoid quercitrin to Ti substrates, and optimized the grafting conditions. Depending on the reaction conditions, the amount of quercitrin grafted was between 64 ± 10 and 842 ± 361 nmol on 6.2 mm Ti coins. Finally, we evaluated the in vitro behavior of bone-marrow-derived human mesenchymal stem cells cultured on the quercitrin nanocoated Ti surfaces. The surfaces functionalized with quercitrin showed a faster stem cell adhesion than control surfaces, probably due to the presence of the catechol groups of quercitrin on the surfaces. A rapid cell adhesion is crucial for the successful performance of an implant. Furthermore, quercitrin-nanocoated surfaces enhanced the mineralization of the cells after 21 days of cell culture. These results indicate that quercitrin nanocoatings could promote the rapid osteointegration of bone implants.


Microcomputer stabilization of a Fabry-Perot interferometer.
Fabry-Perot interferometers typically require some form of active stabilization system for long-term operation. A stabilization system based on a microcomputer is described which is able to maintain the finesse of a plane parallel Fabry-Perot interferometer for long periods of time. The microcomputer takes the place of the multichannel analyzer, ramp generator, and stabilizer of a conventionally stabilized system. Sample data illustrating the operation of the system on the Brillouin spectrum of fused silica, with and without computer corrections, are included.


Simultaneous determination of nicotinamide, pyridoxine hydrochloride, thiamine mononitrate and riboflavin in multivitamin with minerals tablets by reversed-phase ion-pair high performance liquid chromatography.
A reversed-phase ion-pair high performance liquid chromatographic method (HPLC) has been developed and validated for the routine analysis of nicotinamide, pyridoxine hydrochloride, thiamine mononitrate and riboflavin in multivitamin with minerals tablets. HPLC separation of the vitamins was performed on a Hypersil C(18) column and detected by ultraviolet absorbance at 280 nm. The use of methanol-aqueous 0.5% acetic acid solution (18:82, v/v; containing 2.5 mM sodium hexanesulfonate, pH = 2.8) as the mobile phase at a flow-rate of 1.2 mL/min enables the baseline separation of the four analytes free from interferences with isocratic elution at 30 degrees C. The analysis time was 17 min per injection. The method was linear in the ranges of 5-90, 2.5-90, 5-95 and 25-450 micro g/mL for thiamine mononitrate, riboflavin, pyridoxine hydrochloride and nicotinamide, respectively. The average coefficients of variation of within- and between-day assays were 2.2 and 3.6% for thiamine mononitrate, 1.8 and 2.4% for riboflavin, 1.3 and 1.7% for pyridoxine hydrochloride and 1.0 and 1.5% for nicotinamide, respectively. The average recoveries of thiamine mononitrate, riboflavin, pyridoxine hydrochloride and nicotinamide were 97.0, 97.2, 98.9 and 100.4% for the tablets, respectively. The method has been successfully applied to the simultaneous determination of nicotinamide, pyridoxine hydrochloride, thiamine mononitrate and riboflavin in multivitamin with minerals tablets.


Characterization and differential nuclear localization of Nopp140 and a novel Nopp140-like protein in trypanosomes.
Trypanosomatids possess two homologues of Nopp140: a canonical Nopp140 and a Nopp140-like protein (TbNoLP) in which a GAR domain replaces the C-terminal SRP40 domain. Both are phosphorylated and coimmunoprecipitate with RNA polymerase I. Each paralogue has a distinct subnuclear localization, and depletion of TbNoLP produces an enlarged nucleolus in which TbNopp140-containing regions disperse. The restricted occurrence pattern of NoLP proteins reflects an intriguing convergence in evolution, suggestive of a function in nucleoplasmic small nucleolar ribonucleoprotein shuttling.


Selection of acrosome-reacted human spermatozoa and their fusing ability by micro-injection into the perivitelline space of hamster eggs.
Previously we reported the selective binding of human acrosome-reacted spermatozoa to monoclonal antibody-coated paramagnetic beads. In the present paper, the fusing ability of spermatozoa that bound to the beads was estimated by micro-injecting them into the perivitelline space of hamster oocytes. Acrosome-reacted human spermatozoa were collected by monoclonal antibody-coated paramagnetic beads. Bead-bound spermatozoa were selected under a microscope and micro-injected into the perivitelline space of hamster oocytes. When the injection was begun 5 min after mixing spermatozoa with the beads, 6.6% of the injected spermatozoa fused with an oocyte. However, when the injection was begun 30 min after the mixing, no fusion occurred. Moreover, when spermatozoa were injected with the beads attached to their head, no fusion was observed. The fusing ability of spermatozoa thus prepared was compared with that of randomly chosen and injected spermatozoa. Using spermatozoa from 10 healthy volunteers, 22 independent experiments were performed. The overall fusion rate of injected, randomly selected spermatozoa was 2.8%, whilst that of bead-selected spermatozoa was 7.3%. Selection of spermatozoa by beads appeared to be beneficial to the fusion event.


New Aspects of Degradation in Silicone Rubber under UVA and UVB Irradiation: A Gas Chromatography-Mass Spectrometry Study.
In this paper, gas chromatography-mass spectrometry (GC-MS) and positron annihilation lifetime spectroscopy (PALS) were used to probe the changes of oligomers and the polydimethylsiloxane (PDMS) network in silicone rubber, after different durations of UVA/UVB irradiation. At the early stage (<300 h) of UVA/UVB irradiation, the concentration of D4-D9 decreases. The o-Ps intensity of the extracted silicone rubber increases in the stage after UVB irradiation. These results indicate the crosslinking of oligomers into the PDMS network. After a long duration (>300 h) of UVB irradiation, D4 was generated and the lifetime of τ3 also increased, indicating the rupture of the Si-O bond in the PDMS network. These two aging processes were termed the post curing process and the chain session process. The new finding was that UVA could only induce the post curing process; UVB causes the rupture of the chemical bond in silicone rubber. Photons of UVB could break the C-H bond, and then trigger the backbiting decomposition of PDMS, breaking the Si-O bond, while the photons of UVA cannot. The fact that D4 was generated after UVB irradiation can be used to evaluate the UVB stability of silicone rubber in the future.


Extension of maternity allowances.
In June 1988, the right to daily allowances in San Marino in respect of temporary incapacity for work caused by pregnancy or childbirth was extended to women employed in agriculture and employees of the public administration.


Psychometric Validation of the Autism Impact Measure (AIM).
The Autism impact measure (AIM) is a caregiver-reported questionnaire assessing autism symptom frequency and impact in children, previously shown to have good test-retest reliability, convergent validity and structural validity. This study extended previous work by exploring the AIM's ability to discriminate between 'known-groups' of children, and estimating thresholds for clinically important responses. Data were collected online and electronically on computer and mobile devices; hence, it was also possible to confirm other psychometric properties of the AIM in this format. This study provides confirmatory and additional psychometric validation of the AIM. The AIM offers a valid, quick and inexpensive method for caregivers to report core symptoms of autism spectrum disorder (ASD) including communication deficits, difficulties with social interactions and repetitive behaviors.


Antenatal diagnosis of placental sulphatase deficiency.
A dynamic test for the antenatal diagnosis of placenta sulphatase deficiency was examined in ten patients, selected on the basis of low urinary oestrogen levels (i.e. below the 10th centile at between 30 and 40 weeks gestation). The test consisted of measurement of plasma oestradiol levels over a period of 120 min after an i.v. injection of dehydroepiandrosterone sulphate. The oestradiol response was vigorous in seven patients, absent in two and small, but significant, in one. The three patients with reduced oestradiol response were also found to have raised levels of urinary steroid monosulphates and thus were probably placental sulphatase deficient. The overall clinical importance of placental sulphatase deficiency and the value of the dehydroepiandrosterone sulphate loading test in antenatal diagnosis are discussed.


System-wide and Superemitter Policy Options for the Abatement of Methane Emissions from the U.S. Natural Gas System.
This work assesses trade-offs between system-wide and superemitter policy options for reducing methane emissions from compressor stations in the U.S. transmission and storage system. Leveraging recently collected national emissions and activity data sets, we developed a new process-based emissions model implemented in a Monte Carlo simulation framework to estimate emissions for each component and facility in the system. We find that approximately 83% of emissions, given the existing suite of technologies, have the potential to be abated, with only a few emission categories comprising a majority of emissions. We then formulate optimization models to determine optimal abatement strategies. Most emissions across the system (approximately 80%) are efficient to abate, resulting in net benefits ranging from $160M to $1.2B annually across the system. The private cost burden is minimal under standard and tax instruments, and if firms market the abated natural gas, private net benefits may be generated. Superemitter policies, namely, those that target the highest emitting facilities, may reduce the private cost burden and achieve high emission reductions, especially if emissions across facilities are highly skewed. However, detection across all facilities is necessary regardless of the policy option and there are nontrivial net benefits resulting from abatement of relatively low-emitting sources.


Perinatal Treponema pallidum: evidence based guidelines to reduce mother to child transmission.
Universal antenatal screening for T. pallidum is standard in Irish maternity units. The prevalence of adult syphilis has increased in Ireland. We audited the neonatal management of infants exposed to T. pallidum in utero. A cross sectional retrospective analysis of all pregnancies with confirmed positive serology for T. pallidum from January 2005 to December 2010 was conducted at the National Maternity Hospital, Holles St. Data were analysed using SPSS 14.0. Ethical approval was obtained. There were 55,058 live births during the study period. Fifty-eight women had positive serology and 41 met inclusion criteria. Infant evaluation and follow up was decided by allocation to an evidence based algorithm. Twenty-one infants (51%) were accurately allocated and assessed, 5 (12%) had a partial assessment and the algorithm was incorrectly applied in 15 (36%) of cases. Failure to adhere to evidence based neonatal guidelines is common and undermines efficacy of the screening program.


Diagnostic ability of maximum blink interval together with Japanese version of Ocular Surface Disease Index score for dry eye disease.
Various symptoms of the dry eye disease (DED) interfere with the quality of life and reduce work productivity. Therefore, screening, prevention, and treatment of DED are important. We aimed to investigate the potential diagnostic ability of the maximum blink interval (MBI) (the length of time participants could keep their eyes open) with disease-specific questionnaire for DED. This cross-sectional study included 365 patients (252 with DED and 113 without DED) recruited between September 2017 and December 2019. Discriminant validity was assessed by comparing the non-DED and DED groups based on the MBI with a Japanese version of the Ocular Surface Disease Index (J-OSDI) and tear film breakup time (TFBUT) with J-OSDI classifications. The MBI with J-OSDI showed good discriminant validity by known-group comparisons. The positive and predictive values of MBI with J-OSDI were 96.0% (190/198 individuals) and 37.1% (62/167 individuals), respectively. The area under the receiver operating characteristic curve (AUC) of MBI with J-OSDI was 0.938 (95% confidence interval 0.904-0.971), the sensitivity was 75.4% (190/252 individuals), and the specificity was 92.9% (105/113 individuals), which are similar to the diagnostic ability of TFBUT with J-OSDI (AUC 0.954). In conclusion, MBI with J-OSDI may be a simple, non-invasive screening test for DED.


A Review of Samidorphan: A Novel Opioid Antagonist.
Opioid modulators have been explored as a treatment option for psychiatric disorders, but their use has been limited due to their abuse potential. Samidorphan (SAM), a μ-opioid receptor antagonist, has gained interest due to its favorable pharmacokinetic and pharmacodynamic profile. In this review article, six electronic databases including PubMed, PsycINFO, PsycARTICLES, Scopus, Web of Science, and CINAHL were searched to find relevant human studies with a focus on different clinical aspects of SAM. SAM was used in combination with buprenorphine (BUP) to counteract the abuse potential while still maintaining effectiveness in the treatment of depression. The BUP/SAM 2 mg/2mg combination improved depression in patients with major depressive disorder (MDD). SAM's ability to mitigate the weight gain associated with olanzapine (OLZ) has also been explored. Initial studies have shown promising results in some parameters of alcohol-use disorder, while no significant benefit in the treatment of binge-eating disorder has been reported. Somnolence and gastrointestinal side effects were the most commonly observed side effects of SAM.


Effect of Counterion Valence on Conformational Behavior of Spherical Polyelectrolyte Brushes Confined between Two Parallel Walls.
We study the conformational behavior of spherical polyelectrolyte brushes in the presence of monovalent and trivalent counterions in a confined environment. The confinement is exerted by two parallel walls on the brushes. The enhancement of the confinement induces the extension of grafted chains. For the monovalent case, the increase of the charge fraction leads to extended brush conformation for different slit width (distance between two walls) but collapsed brush in the presence of trivalent counterions is observed. The confinement does not affect electrostatic correlation between trivalent counterions and charged monomers. However, it was found that narrow slit width contributes to stronger electrostatic correlation for the monovalent case. This is because more monovalent counterions are inside the brush at strong confinement, but almost all trivalent counterions are trapped into the brush independently of the slit width. The diffusion of counterions under the confinement is related to the electrostatic correlation. Our simulations also reveal that the brush thickness depends on the slit width nonlinearly.


Paradoxical Association Between Baseline Apolipoprotein B and Prognosis in Coronary Artery Disease: A 36,460 Chinese Cohort Study.
Apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) were identified targets for blood lipid management among coronary artery disease (CAD) patients. However, previous studies reported an inverse correlation between baseline LDL-C concentration and clinical outcomes. This study aims to explore the definite association between baseline ApoB and long-term prognosis. A total of 36,460 CAD patients admitted to Guangdong Provincial People's Hospital were enrolled and categorized into two groups: high ApoB (≥65 mg/dL) group and low ApoB (<65 mg/dL) group. The association between baseline ApoB and long-term all-cause mortality was evaluated by the Kaplan-Meier method, Cox regression analyses and restricted cubic splines. The overall mortality was 12.49% (n = 4,554) over a median follow-up period of 5.01 years. Patients with low baseline ApoB levels were paradoxically more likely to get a worse prognosis. There was no obvious difference in risk of long-term all-cause mortality when only adjusted for age, gender, and comorbidity (aHR: 1.07, 95% CI: 0.99-1.16). When CONUT and total bilirubin were adjusted, the risk of long-term all-cause mortality would reduce in the low-ApoB (<65 mg/dL) group (aHR: 0.86, 95% CI: 0.78-0.96). In the fully covariable-adjusted model, patients in the ApoB <65 mg/d group had a 10.00% lower risk of long-term all-cause mortality comparing to patients with ApoB ≥65 mg/dL (aHR: 0.90; 95% CI:0.81-0.99). This study found a paradoxical association between baseline ApoB and long-term all-cause mortality. Malnutrition and bilirubin mainly mediate the ApoB paradox. Increased ApoB concentration remained linearly associated with an increased risk of long-term all-cause mortality.


Separation strategies for untargeted metabolomics.
Metabolomics has rapidly become a profiling technique of choice for biomarker elucidation and molecular diagnostics in addition to studies focused on understanding disease pathogenesis. Key to the success of metabolomics in these areas has been the techniques to separate and analyze the chemically diverse group of compounds comprising the metabolome by using global and untargeted approaches. Untargeted metabolomic efforts have the goal of examining as many metabolites as possible simultaneously and most frequently use an LC/MS-based approach. Here, the importance of LC in an untargeted metabolomic workflow is outlined and separation strategies for optimization are reviewed within the context of these criteria.


Gene duplication and divergence affecting drug content in Cannabis sativa.
Cannabis sativa is an economically important source of durable fibers, nutritious seeds, and psychoactive drugs but few economic plants are so poorly understood genetically. Marijuana and hemp were crossed to evaluate competing models of cannabinoid inheritance and to explain the predominance of tetrahydrocannabinolic acid (THCA) in marijuana compared with cannabidiolic acid (CBDA) in hemp. Individuals in the resulting F2 population were assessed for differential expression of cannabinoid synthase genes and were used in linkage mapping. Genetic markers associated with divergent cannabinoid phenotypes were identified. Although phenotypic segregation and a major quantitative trait locus (QTL) for the THCA/CBDA ratio were consistent with a simple model of codominant alleles at a single locus, the diversity of THCA and CBDA synthase sequences observed in the mapping population, the position of enzyme coding loci on the map, and patterns of expression suggest multiple linked loci. Phylogenetic analysis further suggests a history of duplication and divergence affecting drug content. Marijuana is distinguished from hemp by a nonfunctional CBDA synthase that appears to have been positively selected to enhance psychoactivity. An unlinked QTL for cannabinoid quantity may also have played a role in the recent escalation of drug potency.


Evaluation of polysaccharides intended for ophthalmic use in ocular dosage forms.
Different water-soluble polysaccharides were evaluated for their intended use in ocular dosage forms. The physicochemical characteristics and the viscosity of the solutions prepared with several iso-osmotic vehicles were measured. The influence of ions present in lacrimal fluid, mucin and cyclodextrin on the rheological behaviour was examined. Scleroglucan and xanthan gum exhibit viscoelastic and mucoadhesive properties useful for ocular dosage form formulations.


Effects of aging and musical experience on the representation of tonal hierarchies.
Two experiments explored the representation of the tonal hierarchy in Western music among older (aged 60 to 80) and younger (aged 15 to 22) musicians and nonmusicians. A probe tone technique was used: 4 notes from the major triad were presented, followed by 1 note chosen from the 12 notes of the chromatic scale. Whereas musicians had a better sense of the tonal hierarchy than nonmusicians, older adults were no worse than younger adults in differentiating the notes according to musical principles. However, older adults were more prone than younger adults to classify the notes by frequency proximity (pitch height) when proximity was made more salient, as were nonmusicians compared with musicians. With notes having ambiguous pitch height, pitch height effects disappeared among older adults but not nonmusicians. Older adults seem to have internalized tonal structure, but they sometimes fail to inhibit less musically relevant information.


Purpose plus: supporting youth purpose, control, and academic achievement.
Research in the past decade suggests that a persistent achievement gap between students from low-income minority backgrounds and higher-income white backgrounds may be rooted in theories of student motivation and youth purpose. Yet limited research exists regarding the role of purpose on positive youth development as it pertains to academic achievement. Using a sample of 209 high school students, this study examines the effectiveness of an intervention designed to promote purpose development and internal control over academic success in high school students from a low-socioeconomic-status community. Findings reveal that a short-term intervention was effective in significantly increasing internal control over academic success and purpose in life for students participating in the intervention group. In addition, analysis of academic achievement for students who experienced positive gains in internal control and purpose demonstrates significant gains in academic achievement as measured by grade point average. Implications are made for further study of internal control and life purpose as a means of academic intervention in the effort to address the achievement gap.


[A study of the simulation model of the lower urinary tract for urodynamics--(the first report)--theoretical evaluation of hydrodynamic model].
From the view point of urodynamics, the lower urinary tract might be able to be simulated by a hydrodynamic model, consisting of a spherical balloon corresponding to the bladder and a circular tube to the urethra. In this hydrodynamic model, the diameter of the tube corresponding to the posterior urethra was assumed to become smaller with increase of the prostatic pressure according to the development of BPH. On this assumption, Bernoulli's equation might be adopted. Because of the turbulent flow in the tube, the velocity of flow was expressed as a function of the invariants, which indicated the pressure in the balloon, the respective lengths and diameters of narrow tube and wide tube, coefficients due to pipe friction, pipe fitting and pipe enlargement. The findings suggested that the smaller the diameter of the narrow tube, the smaller the flow volume showed with the development of BPH. In conclusion the urodynamics in the lower urinary tract could be simulated quantitatively by this model. The study may lead to the development of the urodynamic simulation model for the lower urinary tract.


Mature mediastinal bronchogenic cyst with left pericardial defect: A case report.
Mediastinal bronchogenic cysts and pericardial defects are both rare. It is extremely rare that both occur simultaneously. To the best of our knowledge, this is the first case of a coexistent bronchogenic cyst and pericardial defect reported in China. We performed a literature review and found a relationship between bronchogenic cysts and pericardial defects, which further revealed the correlation between the bronchus and pericardium during embryonic development. A 14-year-old boy attended a local hospital for ankylosing spondylitis. Chest radiography showed an enhanced circular-density shadow near the left mediastinum. The patient had no chest symptoms and the physical examination was normal. Because of the mediastinal occupation, the patient visited our department of chest surgery for further treatment. During surgery, a left pericardial defect was observed. The bronchogenic cyst was removed by thoracoscopic surgery, but the pericardial defect remained untreated, and a satisfactory outcome was achieved after the operation. The patient was diagnosed with a mediastinal tumor. The pathological diagnosis of the tumor was a bronchogenic cyst. This case further reveals the correlation between the bronchus and pericardium during embryonic development.


Determination by capillary electrophoresis of total and available niacin in different development stage of raw and processed legumes: comparison with high-performance liquid chromatography.
The available and total niacin evolution during maturation of yellow pea lupine (Lupinus luteus L., cv. Juno), pea (Pisum sativum L., cv. Ergo), faba bean (Vicia faba sp. minor Harz, cv. Tibo) and in germinated and high-pressure heated peas (Pisum sativum L., cv. Esla) have been determined by capillary electrophoresis (CE). The results have been compared with those obtained by high-performance liquid chromatography (HPLC). The values obtained by CE were similar to those obtained by HPLC. Maturation of seeds significantly reduced the available and total niacin content in legumes. The available/total niacin ratio during seed maturation depends on the type of legume. In faba beans and peas, a reduction was observed which was more pronounced in the case of peas. For lupine seeds, the ripening produced an increase (34%) in the available/total niacin ratio 50 days after flowering (DAF). Pea germination produced an overall increase in available and total niacin content although the available/total niacin ratio decreased. High pressure heating of pea yielded an increase in the available niacin content and available/total niacin ratio but the total niacin content did not change.


The sound insulation and directivity of the sound radiation from double glazed windows.
The sound insulation and directivity of the radiated sound from double glazed windows have been measured by different researchers. Previously, airborne sound insulation models have been used to predict the associated measurement results with limited success. In this paper, the importance of accounting for the structure borne sound transmission between two glazing elements via the window frame on the prediction results is demonstrated. The decreased stiffness of the wall cavity as the depth is increased is the reason why sound transmission via the window frame needs to be considered. The reciprocity argument provided by Davy for the prediction of the directivity of sound radiating into a room is validated and it is shown that once the structure borne transmission is considered, an additional weighting term is not needed to compensate for the extra wall collisions which the sound experiences when radiated at grazing incidence.


Effects of rigid contact lens edge lift changes on tear pump efficiency.
The effects of rigid contact lens axial edge lift changes on corneal oxygenation and tear exchange with the blink were studied for lenses of five axial edge lifts (0.05 to 0.13 mm in 0.02-mm steps). The overall and optic zone diameters were maintained at 8.8 and 7.4 mm, respectively, and all other parameters were held constant. Oxygen uptake rates were measured for the normal open eye after 5 min of static (without blinking) and dynamic (with blinking once every 5 s) contact lens wear. As expected, no significant differences were found in the oxygen uptake rates associated with the static wear of the contact lenses; however, under dynamic conditions, increasing edge lift was associated with a reduction in oxygen demand. The differences between data obtained under static and dynamic conditions increased with increasing axial edge lift, and subjects with small palpebral aperture sizes seemed to benefit more from increasing axial edge lift.


The nature of the hydrated proton H(aq)+ in organic solvents.
The nature of H(H2O)n(+) cations for n = 3-8 with weakly basic carborane counterions has been studied by IR spectroscopy in benzene and dichloroethane solution. Contrary to general expectation, neither Eigen-type H3O x 3 H2O(+) nor Zundel-type H5O2(+) x 4 H2O ions are present. Rather, the core species is the H7O3(+) ion.


The PI3K/AKT pathway in the pathogenesis of prostate cancer.
Despite recent advances in our understanding of the biological behavior of prostate cancer (PCa), PCa is becoming the most common malignancy in men worldwide. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in prostate carcinogenesis. Inflammatory cytokines (CCR9, IL-6, and TLR3) regulate PI3K/AKT signaling during apoptosis of PCa cells, and PI3K/AKT signaling participates with androgen-, 1alpha,25(OH)2-vitamin D3-, and prostaglandin-associated mechanisms and is regulated by ErbB, EGFR, and the HER family during cell growth. During metastasis of PCa cells, the PI3K/AKT/NF-kappaB/BMP-2-Smad axis, PTEN/PI3K/AKT pathway, and PI3K/AKT/mTOR signaling regulates tumor cell metastasis and invasion. The present review focuses on the PI3K/AKT signal pathway and discusses the role of the PI3K/AKT signal pathway in PCa tumorigenesis.


The influence of occupational and social factors on obesity and body fat distribution in middle-aged men.
The principal aim of the present study was to analyse possible associations between psychosocial and occupational factors with body mass index (BMI) and the waist-to-hip circumference ratio (WHR). A cohort study of data derived from questionnaires. 1040 men from a population sample of 1302 men born 1944. Occupational, social and leisure time conditions, smoking and alcohol habits as well as height, weight and waist-to-hip circumferences. In multivariate analyses, the BMI, when adjusted for the WHR, smoking and alcohol, was marginally associated with shift work and, negatively, with influence on the work situation. Such men were often married or cohabited, had a low educational level, felt little time pressure and watched TV frequently. In contrast men with elevated WHR, when adjusted for BMI, alcohol and smoking, seemed to be more often out of work, and to be less satisfied with work management. They were frequently divorced and lived under relatively poorer housing conditions, indicating a low socio-economic status, exercised seldom and had little leisure time activities. It was concluded that obesity (BMI) and centralisation of body fat stores (WHR) are differently associated to occupational and social factors as well as leisure time activities.


The effect of silver thickness on the enhancement of polymer based SERS substrates.
We investigated silver-covered polymer based nanogratings as substrates for surface-enhanced Raman spectroscopy (SERS), in particular with respect to the thickness of the plasmonically active silver film. In order to obtain accurate geometrical input data for the simulation process, we inspected cross sections of the gratings prepared by breaking at cryogenic temperature. We noticed a strong dependence of the simulation results on geometrical variations of the structures. Measurements revealed that an increasing silver film thickness on top of the nanogratings leads to a blue shift of the plasmonic resonance, as predicted by numerical simulations, as well as to an increased field enhancement for an excitation at 488 nm. We found a clear deviation of the experimental data compared to the simulated results for very thin silver films due to an island-like growth at a silver thickness below 20 nm. In order to investigate the SERS activity. we carried out measurements with crystal violet as a model analyte at an excitation wavelength of 488 nm. The SERS enhancement increases up to a silver thickness of about 30 nm, whereas it remains nearly constant for thicker silver films.


Sexually Dimorphic Epigenetic Regulation of Brain-Derived Neurotrophic Factor in Fetal Brain in the Valproic Acid Model of Autism Spectrum Disorder.
Prenatal exposure to the antiepileptic, mood-stabilizing drug, valproic acid (VPA), increases the incidence of autism spectrum disorders (ASDs); in utero administration of VPA to pregnant rodents induces ASD-like behaviors such as repetitive, stereotyped activity, and decreased socialization. In both cases, males are more affected than females. We previously reported that VPA, administered to pregnant mice at gestational day 12.5, rapidly induces a transient, 6-fold increase in BDNF (brain-derived neurotrophic factor) protein and mRNA in the fetal brain. Here, we investigate sex differences in the induction of Bdnf expression by VPA as well as the underlying epigenetic mechanisms. We found no sex differences in the VPA stimulation of total brain Bdnf mRNA as indicated by probing for the BDNF protein coding sequence (exon 9); however, stimulation of individual transcripts containing two of the nine 5'-untranslated exons (5'UTEs) in Bdnf (exons 1 and 4) by VPA was greater in female fetal brains. These Bdnf transcripts have been associated with different cell types or subcellular compartments within neurons. Since VPA is a histone deacetylase inhibitor, covalent histone modifications at Bdnf 5'UTEs in the fetal brain were analyzed by chromatin immunoprecipitation. VPA increased the acetylation of multiple H3 and H4 lysine residues in the vicinity of exons 1, 2, 4, and 6; minimal differences between the sexes were observed. H3 lysine 4 trimethylation (H3K4me3) at those exons was also stimulated by VPA. Moreover, the VPA-induced increase in H3K4me3 at exons 1, 4, and 6 was significantly greater in females than in males, i.e., sexually dimorphic stimulation of H3K4me3 by VPA correlated with Bdnf transcripts containing exons 1 and 4, but not 6. Neither H3K27me3 nor cytosine methylation at any of the 117 CpGs in the vicinity of the transcription start sites of exons 1, 4, and 6 was affected by VPA. Thus, of the 6 epigenetic marks analyzed, only H3K4me3 can account for the sexually dimorphic expression of Bdnf transcripts induced by VPA in the fetal brain. Preferential expression of exon 1- and exon 4-Bdnf transcripts in females may contribute to sex differences in ASDs by protecting females from the adverse effects of genetic variants or environmental factors such as VPA on the developing brain.


Using behavioral skills training and video rehearsal to teach blackjack skills.
A behavioral skills training procedure that consisted of video instructions, video rehearsal, and video testing was used to teach 4 recreational gamblers a specific skill in playing blackjack (sometimes called card counting). A multiple baseline design was used to evaluate intervention effects on card-counting accuracy and chips won or lost across participants. Before training, no participant counted cards accurately. Each participant completed all phases of the training protocol, counting cards fluently with 100% accuracy during changing speed criterion training exercises. Generalization probes were conducted while participants played blackjack in a mock casino following each training phase. Afterwards, all 4 participants were able to count cards while they played blackjack. In conjunction with count accuracy, total winnings were tracked to determine the monetary advantages associated with counting cards. After losing money during baseline, 3 of 4 participants won a substantial amount of money playing blackjack after the intervention.


Molecular diagnosis of deletions in the human multigene complex of growth and placental lactogen hormones.
The type IA of the isolated deficiencies (ID) of growth (HGH) and placental lactogen (HPL) hormones are frequently the consequence of deletions in their respective genes. To facilitate the diagnosis of these cases, we developed a rapid method for detecting deletions of the genes involved based on the polymerase chain reaction (PCR) technique. This method consist of the simultaneous amplification via consensus primers of the 5 genes which conform the hGH-hPL multigene family, followed by the identification of each of them in the amplification product by gene-specific patterns of restriction enzyme cuts evidenced by agarose gel electrophoresis. We demonstrate the effectiveness of our method by identifying patients with deletions in gene members of the hGH-hPL family.


The effect of strength and endurance training on SSTR2 and SSTR5 in patients with colorectal cancer.
The roots of apoptosis caused by the use of certain drugs in patients with colorectal cancer and certain drugs could be induced the change in genes SSTR2 and SSTR5. SSTRs play a role in colorectal cancer and it's also known that exercise training has similar effects to certain drugs. Therefore, this study aims to evaluate the effects of a combined training program on hormonal and physiological changes in patients with colorectal cancer. Twenty patients with colorectal cancer were included in this study and divided into two groups as experimental (n=10) and control (n=10). The experimental group performed an exercise training program 5 days a week for 14 weeks. Blood samples were taken from the patients before and after the training program, and analyzed for somatostatin and its receptors. When the pretest effect excluded as statistical, there were no significant differences in SSRT2 (P>0.05) and SSRT5 (P>0.05) between the experimental and control groups. The hypothesis for this study was "SSTR2 and SSTR5 will improve after combined training program" however, in accordance with the results it was rejected. It seems that the determined training program for these patients need to be extended and performed for at least 3 months in a gradual incremental structure so that it could affect their health indicators significantly.


Small bowel lymphoma: clinical update and challenges for the gastroenterologist.
The diagnosis of small bowel lymphoma (SBL) can be challenging, as they are very rare and also have a varied presentation. In this review, we aim to provide a broad overview of the types of SBL and also about the various modalities used for their diagnosis. We also discuss the overview of treatment strategies for a gastroenterologist. Small bowel capsule endoscopy (SBCE) and devise-assisted enteroscopy (DAE) has revolutionized the way we investigate the small bowel. DAE also makes it possible to obtain histological samples for further characterization of SBL. This has led to a significant improvement in diagnosis and management of the disease in conjunction with cross-sectional imagining. The diagnosis and management of small bowel lymphoma remains challenging despite the development of newer techniques such as SBCE and DAE. The current available diagnostic modalities have limitations; in the absence of a gold standard, the current investigative modalities compliment each other in reaching the final diagnosis.


Infection initiated by the RNA pregenome of a DNA virus.
We describe experiments demonstrating that after transfection into permissive cells, the RNA pregenome of an avian hepadnavirus, the duck hepatitis B virus, is infectious. Using a Sindbis virus expression vector, we showed that cytoplasmic synthesis of the pregenome resulted in hepadnaviral DNA synthesis. Moreover, complete infectious virus was produced from cells transfected with hepadnaviral pregenomic RNA. We conclude that the pregenome of hepadnaviruses can express all the proteins required for DNA synthesis as well as serve as a template for reverse transcription and that DNA resulting from pregenome expression can be utilized to establish a productive infection in pregenome-transfected cells.


Circular RNA 0001273 in exosomes derived from human umbilical cord mesenchymal stem cells (UMSCs) in myocardial infarction.
To investigate whether human umbilical cord mesenchymal stem cells (UMSCs) derived exosomes (exosome) can repair the heart after myocardial infarction (MI) by delivering circ-0001273 and its mechanism. Through the Sprague Dawley (SD) rat MI model was established, at the same time, we designed si-circ-0001273. Phosphate-buffered saline (PBS), exosome and si-circ-0001273-exosome were transplanted into ischemic hearts of rat, respectively. Through the echocardiography, hematoxylin-eosin staining (HE) method to detect the rat heart recovery. Meanwhile, H9c2 was treated with hypoxic serum-free serum to construct an in vitro apoptosis model to further explore the effect of circ-0001273 on myocardial cell apoptosis. Compared with the exosome-treated group, the left ventricular ejection fraction (EF) and shortened fraction (FS) of the rat heart was remarkably reduced and the cardiac structure was more disordered in the si-circ-0001273-exosome-treated group. Meanwhile, in vitro TUNEL staining and flow cytometry detection, results showed that compared with the exosome co-culture group, the incidence of H9C2 cell apoptosis in the si-circ-0001273-exosome co-culture group was obviously increased. Circ-0001273 can remarkably inhibit the occurrence of myocardial cell apoptosis in ischemic environment, promote MI repair, and provide a good reference for clinical treatment.


Inhibition of macrophage chemotaxis by supernatant fluid from malignant cell lines.
The chemotactic locomotion of peritoneal macrophages in vitro was measured in the presence of supernatant fluid from 27 different tumour cell lines. All the tumour-derived cells tested caused profound depression of macrophage chemotaxis towards the chemo-attractant casein. Conversely, supernates from rapidly dividing non-malignant cells uniformly failed to depress macrophage migration. This confirms the results of a previous investigation and provides further evidence that malignant tumours depress the functions of the reticuloendothelial system of the host animal in vivo.


Genome scan detects quantitative trait loci affecting female fertility traits in Danish and Swedish Holstein cattle.
Data from the joint Nordic breeding value prediction for Danish and Swedish Holstein grandsire families were used to locate quantitative trait loci (QTL) for female fertility traits in Danish and Swedish Holstein cattle. Up to 36 Holstein grandsires with over 2,000 sons were genotyped for 416 microsatellite markers. Single trait breeding values were used for 12 traits relating to female fertility and female reproductive disorders. Data were analyzed by least squares regression analysis within and across families. Twenty-six QTL were detected on 17 different chromosomes. The best evidence was found for QTL segregating on Bos taurus chromosome (BTA)1, BTA7, BTA10, and BTA26. On each of these chromosomes, several QTL were detected affecting more than one of the fertility traits investigated in this study. Evidence for segregation of additional QTL on BTA2, BTA9, and BTA24 was found.


Generation of assay positive controls for detection of isotype anti-drug antibodies for immunogenicity monitoring.
Development of drug-related surrogate positive controls for isotype anti-drug antibodies assay remains challenging. Efforts on antibody engineering or chemical crosslinking have been made. However, multiple epitope recognition, purity and stability are often of concern. To tackle these challenges, we used LC-SPDP/SMPB crosslinking to conjugate polyclonal anti-drug IgG and human immunoglobulin isotype (hIgE, hIgA, hIgM or hIgG4) with optimized conditions. The final product was a hybrid of anti-drug IgG cross-linked to human isotype immunoglobulin through stable thioether bond. The characteristics of the hybrids and their performance as assay positive controls were further evaluated. The results demonstrate that LC-SPDP/SMPB chemical crosslinking method is suitable for generating stable hybrids to be used as assay positive controls in isotype anti-drug antibodies assay.


Genomic Analysis Uncovers Immune Microenvironment Characteristics and Drug Sensitivity of Ferroptosis in Breast Cancer Brain Metastasis.
Background: The role of ferroptosis in breast cancer brain metastasis (BCBM) is unclear. This study aimed to explore the ferroptosis-related genes (FRG) relations with the tumor microenvironment, as well as evaluate their values in predicting survival and drug sensitivity in patients with BCBM. Materials and Methods: Genes expression and clinical data were downloaded from Gene Expression Omnibus (GEO). Univariate and multivariate Cox regression analyses were performed to explore the independent prognostic factors. Consensus cluster principal component analysis (PCA) was used to establish the ferroptosis score. Immunological signatures were analyzed by the single-sample gene set enrichment analysis (ssGSEA). Drug sensitivity was evaluated through the estimated half-maximal inhibitory concentration (IC50). Finally, results were validated in external cohorts. Results: Fourteen significantly different FRG were identified between breast cancer (BC) and BCBM tissues. Survival analysis demonstrated HMOX1, PEBP1, KEAP1, and LPCAT3 were significantly associated with overall survival (OS) and relapse-free survival (RFS) (all p < 0.05). High ferroptosis score was correlated with iron ion homeostasis, iron metabolism, higher stromal cells and immune cells scores. Patients with high- and low-ferroptosis scores were characterized by different drug sensitivities. Following external validations, the ferroptosis had distinct expression profiles between the BC and BCBM, and could serve as biomarkers for OS and drug response. Conclusion: Our findings suggested that ferroptosis may be involved in the process of BCBM, and ferroptosis could serve as prognostic biomarkers. Evaluation of ferroptosis may deepen our understanding about the tumor microenvironment, and could help clinicians to make individualized therapy.


Circular RNA cMTO1 Promotes PTEN Expression Through Sponging miR-181b-5p in Liver Fibrosis.
Circular RNAs (circRNAs) are considered as key regulators of cancer biology. Recently, cMTO1 (a circRNA derived from MTO1 gene, hsa_circ_0007874) has been demonstrated to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the roles of cMTO1 in liver fibrosis are largely unknown. Expressions and roles of cMTO1 were examined in vivo and in vitro during liver fibrosis. The interaction between microRNA-181b-5p (miR-181b-5p) and cMTO1 was analyzed by luciferase activity assays and pull down assays. cMTO1 was shown to be reduced in the liver from patients with cirrhosis. In addition, cMTO1 was down-regulated in the mouse fibrotic livers as well as activated hepatic stellate cells (HSCs). Restoring of cMTO1 led to a reduction in HSC proliferation. Results of immunofluorescence analysis showed that cMTO1 suppressed the expressions of α-SMA and type I collagen. cMTO1 was found to be expressed in the cytoplasm of HSCs. Further studies confirmed that cMTO1 and miR-181b-5p were co-located in the cytoplasm. Interestingly, there was an interaction between cMTO1 and miR-181b-5p. Results of luciferase reporter assays and pull down assays confirmed that miR-181b-5p could bind to cMTO1. cMTO1-inhibited HSC activation was blocked down by miR-181b-5p or PTEN. Meanwhile, PTEN was a target of miR-181b-5p. cMTO1 inhibits HSC activation, at least in part, through miR-181b-5p-mediated PTEN expression. Our results also suggest that cMTO1 may be a novel therapeutic target in liver fibrosis.


The kinetics of Ins(1,4)P2 dephosphorylation by Ins(1,4)P2 1-phosphatase in bovine brain.
Ins(1,4)P2 1-phosphatase catalyses the dephosphorylation of Ins(1,4)P2 to Ins(4)P. This enzyme was purified 3000-fold to a specific activity of 10-20 mumol/min/mg protein. Ins(1,4,5)P3 (0.04-1 microM) was not a substrate of the enzyme under conditions where 50% of Ins(1,4)P2 was dephosphorylated. All kinetics of Ins(1,4)P2 1-phosphatase displayed Michaelis-Menten behaviour. Both reaction products, Ins(4)P and phosphate inhibited the enzyme: Ins(4)P was a non-competitive inhibitor (Ki = 59 microM) and phosphate was competitive (Ki = 0.53 mM) with respect to Ins(1,4)P2 as substrate. In contrast, Li+ inhibition was uncompetitive (Ki at 1 mM LiCl was 2.7 mM).


Hypertension in diabetes: is there a place for age-adjusted centile cut-offs in those aged <50 years?
Conventional cut-offs for hypertension are arbitrary, and vascular complications can occur below these values, particularly in diabetes. To evaluate systolic blood pressure (SBP) distribution in diabetes and control populations, comparing hypertension prevalence using either conventional cut-offs (140 and 160 mmHg) or age-adjusted centile (75(th) and 90(th)) cut-offs derived from the control population. We compared 2521 individuals with diabetes to 5809 controls, after excluding those on anti-hypertensives and with established vascular disease in both groups. Diabetic individuals were older (mean +/- SD 56 +/- 16 vs. 43 +/- 16years, diabetes vs. controls), and had higher BMI (29 +/- 5 vs. 24 +/- 4 kg /cm(2)) and SBP (145 +/- 23 vs. 131 +/- 18 mmHg, all p < 0.001). These factors were adjusted for in subsequent analysis. SBP rose with age and was also significantly higher in the diabetes group. In diabetes, conventional cut-offs indicated less hypertension in those aged < 50 years, compared to age-adjusted centile cut-offs. In age bands 18-29, 30-39, 40-49, 50-59, 60-69 and >70 years of the diabetes group, 24%, 33%, 43%, 62%, 70% and 74%, respectively exceeded 140 mmHg, compared to 35%, 44%, 43%, 45%, 40% and 27% exceeding the control-derived 75(th) centile value. The use of control-derived age-adjusted cut-offs may provide an alternative approach to define hypertension in diabetes that may be of particular relevance to younger patients, although this would require validation against outcomes.


Limitations of 131I-MIBG scintigraphy in locating pheochromocytomas.
131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy for the location of pheochromocytomas has proved to be a major advance in patient management. In combination with computerized tomographic scanning, nearly all pheochromocytomas can be located before surgery and invasive investigations are now indicated only in exceptional cases. However, there are still lessons to be learned concerning the optimal administration and interpretation of 131I-MIBG scintigraphy. With careful attention to detail and an awareness of isotope distribution, false positive studies should be extremely rare. While the incidence of false negative studies is uncommon, these certainly occur. A patient with sporadic bilateral adrenal medullary hyperplasia, bilateral pheochromocytomas, and additional benign pheochromocytomas arising in paraganglia tissue anterior to the abdominal aorta is presented. The right adrenal pheochromocytoma was not identified on 131I-MIBG imaging. We conclude that even with current locating techniques, the traditional surgical approach to pheochromocytoma should not be abandoned. This involves transabdominal exploration of both adrenal glands and careful examination of all possible sites of extra-adrenal pheochromocytomas.


Blood Pressure Monitoring and Perinatal Outcomes in Normotensive Women with Gestational Diabetes Mellitus.
Alterations in ambulatory blood pressure detected by monitoring (ABPM) have been associated with perinatal complications in hypertensive pregnant women. To establish the relationships between the blood pressure (BP) profiles detected by ABPM and adverse perinatal outcomes in normotensive women with gestational diabetes mellitus (GDM). A prospective study of normotensive women in whom 24 h ABPM was performed at 28-32 weeks of pregnancy. The obstetric and perinatal outcomes were evaluated. Two hundred patients were included. Thirty-seven women with GDM and obesity had significantly higher mean systolic BP (SBP) and nocturnal SBP and diastolic BP (DBP) compared to women with only GDM (n = 86). Nocturnal SBP (OR = 1.077; p = 0.015) and obesity (OR = 1.131; p = 0.035) were risk factors for the development of hypertensive disorders of pregnancy (HDPs). Mothers of newborns with neonatal complications (n = 27) had higher nocturnal SBP (103.8 vs. 100 mmHg; p = 0.047) and DBP (62.7 vs. 59.4; p = 0.016). Women who delivered preterm (n = 10) had higher BP and a non-dipper pattern (p = 0.005). Nocturnal SBP was a predictor of HDPs in normotensive women with obesity or GDM. Alterations in ABPM in these patients were associated with poor obstetric and perinatal outcomes.


Causes and mechanisms in acute pancreatitis.
Acute pancreatitis (AP) presents clinically with either mild or severe clinical course. There are no effective specific drugs for treatment of AP today. Basic knowledge about pathophysiological processes is the key for the development of novel therapeutic principles. This article provides a review on the pathophysiological mechanisms involved in the early phase of AP.


Dalbavancin exposure in vitro selects for dalbavancin-non-susceptible and vancomycin-intermediate strains of methicillin-resistant Staphylococcus aureus.
Dalbavancin is a lipoglycopeptide active against methicillin-resistant Staphylococcus aureus (MRSA). Its long half-life (8.5-16 days) allows for once-weekly or single-dose treatments but could prolong the mutant selection window, promoting resistance and cross-resistance to related antimicrobials such as vancomycin. The objective of this study was to evaluate the capacity of post-distributional pharmacokinetic exposures of dalbavancin to select for resistance and cross-resistance in MRSA. We simulated average, post-distributional exposures of single-dose (1500 mg) dalbavancin (fCmax 9.9 μg/mL, β-elimination t1/2 204 h) in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for 28 days (672 h) against five MRSA strains and one methicillin-susceptible strain (MSSA). Samples were collected at least daily, and surviving colonies were enumerated and screened for resistance on drug-free and dalbavancin-supplemented medium respectively. Isolates from resistance screening plates were subjected to whole-genome sequencing (WGS) and susceptibly testing against dalbavancin, vancomycin, daptomycin, and six β-lactams with varying penicillin-binding protein (PBP) affinities. Dalbavancin was bactericidal against most strains for days 1-4 before regrowth of less susceptible subpopulations occurred. Isolates with eight-fold increases in dalbavancin MIC were detected as early as day 4 but increased 64-128-fold in all models by day 28. Vancomycin and daptomycin MICs increased 4-16-fold, exceeding the susceptibly breakpoints for both antibiotics; β-lactam MICs generally decreased by two-to eight-fold, suggesting a dalbavancin-β-lactam seesaw effect, but increased by eight-fold or more in certain isolates. Resistant isolates carried mutations in a variety of genes, most commonly walKR, apt, stp1, and atl. In our in vitro system, post-distributional dalbavancin exposures selected for stable mutants with reduced susceptibility to dalbavancin, vancomycin, and daptomycin, and generally increased susceptibility to β-lactams in all strains of MRSA tested. The clinical significance of these findings remains unclear, but created an opportunity to genotype a unique collection of dalbavancin-resistant strains for the first time. Mutations involved genes previously associated with vancomycin intermediate susceptibility and daptomycin non-susceptibility, most commonly walKR-associated genes.


Cyclooxygenase activity contributes to the monoaminergic damage caused by serial exposure to stress and methamphetamine.
Methamphetamine (Meth) is a widely abused psychostimulant that causes long-term dopamine (DA) and serotonin (5-HT) depletions. Stress and Meth abuse are comorbid events in society and stress exacerbates Meth-induced monoaminergic terminal damage. Stress is also known to produce neuroinflammation. This study examined the role of the neuroinflammatory mediator, cyclooxygenase (COX), in the depletions of monoamines caused by serial exposure to chronic unpredictable stress (CUS) and Meth. CUS produced an increase in COX-2 protein expression and enhanced Meth-induced monoaminergic depletions in the striatum and hippocampus. The enhanced DA and 5-HT depletions in the striatum, but not the hippocampus, were prevented by pretreatment with COX inhibitor, ketoprofen, during stress or during Meth; however, ketoprofen did not attenuate the monoaminergic damage caused by Meth alone. The COX-dependent enhancement by stress of Meth-induced monoaminergic depletions was independent of hyperthermia, as ketoprofen did not attenuate Meth-induced hyperthermia. In addition, the EP1 receptor antagonist, SC-51089, did not attenuate DA or 5-HT depletions caused by stress and Meth. These findings illustrate that COX activity, but not activation of the EP1 receptor, is responsible for the potentiation of Meth-induced damage to striatal monoamine terminals by stress and suggests the use of anti-inflammatory drugs for mitigating the neurotoxic effects associated with the combination of stress and Meth.


MECHANISMS IN ENDOCRINOLOGY: Update on treatments for patients with genetic obesity.
Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For some clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: (i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome and (ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin-melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients' early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity.


Synthesis of alpha-amylase by Aspergillus oryzae in solid-state fermentation.
Spent Brewing Grains (SBG) was evaluated for its efficacy to be used as sole carbon source for the synthesis of alpha-amylase in solid-state fermentation using a fungal strain of Aspergillus oryzae NRRL 6270. Enzyme production was superior when the culture grew on mesophilic temperatures and best yields were at 25 degrees C. At 30 degrees C, yields were almost comparable. Maximum production of alpha-amylase [6870 U/g dry substrate (gds)] was obtained when SSF was carried out at 30 degrees C for 96 h using SBG medium, which had initial moisture of 70% and was inoculated using a spore suspension containing 1 x 10(7) spores/ml. Supplementation of SBG with external carbon sources such as mono-, di and polysaccharides caused repression in enzyme synthesis by the fungal culture.


Vaginal leiomyoma.
Leiomyomas are common benign tumors in the uterus. However, vaginal leiomyomas remain an uncommon entity with only about 300 reported cases. Here, we report a case of a 38-year-old multigravida who presented with lower abdominal pain and vaginal bleeding. A physical examination and ultrasonography were performed, and a diagnosis of cervical fibroid was made. Pervaginal removal of the tumor was performed and subsequent histopathology revealed a vaginal leiomyoma. Although a rare tumor, vaginal leiomyomas may present with a variety of clinical features and may be mistaken preoperatively for cervical fibroid. Removal of tumor by vaginal route, wherever possible, with subsequent histopathological examination appears to be the optimum management plan.


Effects of Musical Tempo on Musicians' and Non-musicians' Emotional Experience When Listening to Music.
Tempo is an important musical element that affects human's emotional processes when listening to music. However, it remains unclear how tempo and training affect individuals' emotional experience of music. To explore the neural underpinnings of the effects of tempo on music-evoked emotion, music with fast, medium, and slow tempi were collected to compare differences in emotional responses using functional magnetic resonance imaging (fMRI) of neural activity between musicians and non-musicians. Behaviorally, musicians perceived higher valence in fast music than did non-musicians. The main effects of musicians and non-musicians and tempo were significant, and a near significant interaction between group and tempo was found. In the arousal dimension, the mean score of medium-tempo music was the highest among the three kinds; in the valence dimension, the mean scores decreased in order from fast music, medium music, to slow music. Functional analyses revealed that the neural activation of musicians was stronger than those of non-musicians in the left inferior parietal lobe (IPL). A comparison of tempi showed a stronger activation from fast music than slow music in the bilateral superior temporal gyrus (STG), which provided corresponding neural evidence for the highest valence reported by participants for fast music. Medium music showed stronger activation than slow music in the right Heschl's gyrus (HG), right middle temporal gyrus (MTG), right posterior cingulate cortex (PCC), right precuneus, right IPL, and left STG. Importantly, this study confirmed and explained the connection between music tempo and emotional experiences, and their interaction with individuals' musical training.


Using health status measures with the seriously mentally ill in health services research.
Changes in the delivery of mental health care have prompted interest in using generic health status measures to test the effect of system change on those receiving treatment. Of special concern are those with serious and persistent mental illness who may be neglected when cost containment efforts reduce the availability of treatment services. This population may be affected by these changes, which might go undetected if investigators use scales that measure only pathology and not the full spectrum of well-being. The purpose of this study was to test the feasibility of using self-report health status measures with this population, to describe the psychometric properties of the scales, and to report the health status scores of a random sample of the Medicaid psychiatrically disabled population. We found that the four health status scales had adequate psychometric properties, that score variability was high, the distributions normal, and that patterns of association with more traditional clinical measures were of the expected size and direction. One scale, General Health Perceptions, had reliability and item-to-score correlation below acceptable levels.


Transportation noise and blood pressure in a population-based sample of adults.
There is some evidence for an association between traffic noise and ischemic heart disease; however, associations with blood pressure have been inconsistent, and little is known about health effects of railway noise. We aimed to investigate the effects of railway and traffic noise exposure on blood pressure; a secondary aim was to address potentially susceptible subpopulations. We performed adjusted linear regression analyses using data from 6,450 participants of the second survey of the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA 2) to estimate the associations of daytime and nighttime railway and traffic noise (A-weighted decibels) with systolic blood pressure (SBP) and diastolic blood pressure (DBP; millimeters of mercury). Noise data were provided by the Federal Office for the Environment. Stratified analyses by self-reported hypertension, cardiovascular disease (CVD), and diabetes were performed. Mean noise exposure during the day and night was 51 dB(A) and 39 dB(A) for traffic noise, respectively, and 19 dB(A) and 17 dB(A) for railway noise. Adjusted regression models yielded significant effect estimates for a 10 dB(A) increase in railway noise during the night [SBP β = 0.84; 95% confidence interval (CI): 0.22, 1.46; DBP β = 0.44; 95% CI: 0.06, 0.81] and day (SBP β = 0.60; 95% CI: 0.07, 1.13). Additional adjustment for nitrogen dioxide left effect estimates almost unchanged. Stronger associations were estimated for participants with chronic disease. Significant associations with traffic noise were seen only among participants with diabetes. We found evidence of an adverse effect of railway noise on blood pressure in this cohort population. Traffic noise was associated with higher blood pressure only in diabetics, possibly due to low exposure levels. The study results imply more severe health effects by transportation noise in vulnerable populations, such as adults with hypertension, diabetes, or CVD.


[Gene mutation analysis of a collodion baby].
To determine the mutations pattern of the genes of a collodion baby. Collodion baby is a genetic heterogeneous disease caused by mutations of several genes. Since the most common mutations were observed in TGM1 gene, this gene was chosen for mutation screening. The screening was carried out by PCR and direct sequencing. The allele specific primers were designed for a missense mutation and allele-specific (AS) PCR was carried out in 50 normal individuals for population study. Three novel alterations were detected in TGM1 gene of the proband, a missense mutation c.463C > T (p.Arg155Trp) in exon 3, a nonsense mutation c.578G > A (p.Trp193X) in exon 4, and a single nucleotide deletion (c.694delG) also in exon 4 of TGM1 gene. This infant's father was heterozygote of c.694delG mutation, while his mother carried the two mutations (c.463C > T and c.578G > A) on the same chromosome. The missense mutation was not detected in his father and in any of the control individuals by AS-PCR. Three novel mutations were identified in TGM1 gene in a Chinese collodion baby. A double mutation (c.463C > T and c.578G > A) located on the maternal allele while the c.694delG deletion on the paternal allele.


[Comparison of the mechanisms of intralesional steroid, interferon or verapamil injection in the treatment of proliferative scars].
To investigate the effects of intralesional steroid, interferon alpha-2b or verapamil injection on proliferation, apoptosis and TGF-beta1 expression in keloid and hypertrophic scar in vivo. 6 patients with keloids and 6 patients with hypertrophic scar were treated with intralesional injection of triamcinolone acetonide (40 mg/ml) or IFN alpha-2b (15 x 10(5) U/ml) or verapamil (2.5 mg/ml). Samples were collected on the 7th day after intralesional injection. Samples of untreated keloid and hypertrophic scar and normal skin were used as control. Expression of PCNA and TGF-beta1 was detected in situ by immunohistochemical staining, and apoptosis was detected in situ by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL). 1) Triamcinolone acetonide could prohibit proliferative scars through inhibiting cell proliferation and TGF-beta1 expression, as well as inducing apoptosis. 2) IFN alpha-2b could prohibit proliferative scars through inhibiting cell proliferation and TGF-beta1 expression, but not inducing apoptosis; 3) Verapamil could also prohibit proliferative scars through inhibiting proliferation and TGF-beta1 expression in fibroblasts, as well as inducing apoptosis. While the effect of inducing apoptosis was stronger than that of triamcinolone acetonide, the effect of inhibiting TGF-beta1 expression was weaker than those of triamcinolone acetonide and IFN alpha-2b. Although intraleional injection of steroid, interferon alpha-2b or verapamil were all effective in the treatment of keloid and hypertrophic scar, their mechanisms are not similar.


Cardiac troponin T and cardiac enzymes after external transthoracic cardioversion of ventricular arrhythmias in patients with coronary artery disease.
Serum levels of cardiac troponins after external cardioversion (ECV) for atrial fibrillation and atrial flutter are widely investigated, and no increases in cardiac troponin T (cTnT) levels have been reported. However, the effect of ECV on cardiac enzyme release may depend on the type of arrhythmias. Furthermore, ventricular tachycardia (VT) or ventricular fibrillation (VF) could cause release of cardiac enzymes after ECV due to underlying myocardial ischemia, myocardial dysfunction, or more pronounced hemodynamic deterioration during arrhythmia. The purpose of this study was to determine whether direct current (DC) shock may increase cardiac enzyme levels in patients with coronary artery disease undergoing ECV for VT or VF, so that diagnosis of acute myocardial infarction, which initially presents with VT or VF, can be excluded. We obtained measurement of cTnT, total creatine kinase (CK), and CK MB isoenzyme (CK-MB) activity before and after ECV in 27 patients (mean +/- SD age, 62 +/- 13 years) with induced VT or VF (22 patients) who required ECV during provocative electrophysiologic testing and who underwent ECV due to VT (5 patients) in the cardiology department. Blood samples were drawn before, and 4 h, 8 h, and 24 h after ECV. The total energy used was 630 +/- 375 J (range, 200 to 1,280 J). CK levels rose to the upper limit of reference range in seven patients (26%), and CK-MB activity was higher than the normal reference range in five patients (19%) after ECV. In contrast, cTnT concentrations remained within the normal range (< 0.1 micro g/L) in all patients. Peak CK and CK-MB activity levels strongly correlated with the total energy delivered. Elevation of cTnT level after an urgent DC shock strongly indicates the diagnosis of acute myocardial infarction presented with life-threatening arrhythmias, rather than myocardial damage caused by ECV.


Systematic review of rectal foreign bodies in older men: humanistic care and a novel challenge for society.
In recent years, rectal foreign bodies have become a common proctological emergency in the male population, especially older Chinese men, often requiring surgical intervention due to associated complications. This review aimed to describe the epidemiology and clinical characteristics of rectal foreign bodies in older men and examine the possible challenges presented by the condition to clinicians and society. A comprehensive search was conducted in English-language databases and Chinese databases from January 2000 to December 2020. Studies concerning rectal foreign bodies were considered for this review if they reported the reason for a foreign body being in the rectum and related treatment measures. Contemporaneous rectal foreign bodies case data from General Surgery Department of Tangdu Hospital were also analyzed. According to differences in ethnicity, the older male patients were divided into a Chinese group and a non-Chinese group, and the parameters of the two groups were analyzed using statistical methods. A total of 159 studies were retrieved in an initial database search using "rectal foreign body" as the search term. These included 86 Chinese studies and 73 English-language studies. Collectively, these studies included 582 older male patients, 276 of whom were Chinese, and 307 who were non-Chinese. According to their source, the rectal foreign bodies were classified into 3 categories. The most common reason for a foreign body in the rectum was insertion for erotic purposes, with everyday articles accounting for most foreign body types. Sexual articles were mainly found to have been used in the pursuit of pleasure. There were no significant differences in foreign body sources, sizes, types, treatment selections, and outcomes between the two groups. Emergency hospital visits by older men with rectal foreign bodies due to erotic and sexual needs and practices are increasing. Although the sources, sizes, and types of foreign bodies were different, and patients recovered well after active and appropriate clinical treatment, the sexual needs of older men are a social issue that requires attention. Acknowledging and dealing with sexual issues is a multidimensional task that requires a collaborative effort to ensure a more humanistic approach to older patients.


6 beta-Propynyl-substituted steroids: mechanism-based enzyme-activated irreversible inhibitors of aromatase.
The synthesis and aromatase inhibitory profile of 6 alpha and 6 beta-propargyl androstenedione and estrenedione are described. The targeted compounds 1 and 2 were prepared by addition of the propargyl Gringard to the 5 alpha,6 alpha-epoxy bisketal 6 or the 5 alpha,6 alpha-epoxy diacetate 7 followed by dehydration of the 6 beta-propargyl 5 alpha-hydroxy diones 10 and 11 using thionyl chloride. Treatment of the 6 beta-propargyl analogs 1 and 2 with hydrochloric acid gave the corresponding 6 alpha-propargyl isomers 3 and 4. Inhibitory activity of the synthesized compounds was assessed using a human placental microsomal preparation as the enzyme source and [1 beta-3H]-4-androstenedione as substrate. Under initial velocity assay condition of low product formation, the inhibitors demonstrated potent inhibition of aromatase, with apparent KiS ranging from 10 to 66 nM, with the Km for androstenedione being 55 nM. 6 alpha-Propargylandrost-4-ene-3,17-dione and 6 alpha-propargylestr-4-ene-3,17-dione were found to be potent competitive inhibitors of aromatase (Ki 37 and 66 nM, respectively). On the other hand the 6 beta-propargylandrost-4-ene-3,17-dione (6 beta-PAD) and 6 beta-propargylestr-4-ene-3,17-dione (6 beta-PED) were found to bind to aromatase with an apparent Ki of 10 and 48 nM, respectively, as well as cause rapid time-dependent, first-order inactivation of aromatase in the presence of NADPH, whereas no inactivation was observed in the absence of NADPH. Substrate protects the enzyme from inactivation, but beta-mercaptoethanol does not, suggesting that the 6 beta-propargyl analogs 6 beta-PAD and 6 beta-PED are mechanism-based inactivators of aromatase. Energy-minimization calculations and molecular modeling studies indicate three global minima for each of the 6 beta-propargyl analogs in which one of the conformers is proposed to be responsible for the inactivation of aromatase.