Comparative insight into surfactants mediated amyloidogenesis of lysozyme.
Electrostatic and hydrophobic interactions have an important role in the protein aggregation. In this study, we have investigated the effect of charge and hydrophobicity of oppositely charged surfactants i.e., anionic (AOT and SDS) and cationic (CTAB and DTAB) on hen egg white lysozyme at pH 9.0 and 13.0, respectively. We have employed various methods such as turbidity measurements, Rayleigh light scattering, ThT, Congo red and ANS dye binding assays, far-UV CD, atomic force microscopy, transmission electron and fluorescence microscopy. At lower molar ratio, both anionic and cationic surfactants promote amyloid fibril formation in lysozyme at pH 9.0 and 13.0, respectively. The aggregation was proportionally increased with respect to protein concentration and hydrophobicity of surfactant. The morphology of aggregates at both the pH was fibrillar in structure, as visualized by dye binding and microscopic imaging techniques. Initially, the interaction between surfactants and lysozyme was electrostatic and then hydrophobic as investigated by ITC. This study demonstrates the crucial role of charge and hydrophobicity during amyloid fibril formation.


More than meets the eye: context effects in word identification.
The influence of semantic context on word identification was examined using masked target displays. Related prime words enhanced a signal detection measure of sensitivity in making lexical decisions and in determining whether a probe word matched the target word. When line drawings were used as primes, a similar benefit was obtained with the probe task. Although these results suggest that contextual information affects perceptual encoding, this conclusion is questioned on the grounds that sensitivity in these tasks may be determined by independent contributions of perceptual and contextual information. The plausibility of this view is supported by a simulation of the experiments using a connectionist model in which perceptual and semantic information make independent contributions to word identification. The model also predicts results with two other analytic methods that have been used to argue for priming effects on perceptual encoding.


Synthesis and magnetic properties of Co-Sn-O nanorings.
A novel Co-Sn-O nanoring structure was synthesized via a simple hydrothermal route; the difference in diffusion rates of ions was considered to be the main reason for the formation of such a ring structure.


Digital volar amelanotic malignant melanoma in a child.
Malignant melanoma in childhood is rare. An unusual case of amelanotic melanoma of the volar thumb in a fourteen-year-old boy which posed problems of recognition and management is presented.


Neuroprotective evaluation of novel substituted 1,3,4-oxadiazole and aroylhydrazone derivatives.
The paper reports on the facile and convenient synthesis of a series of novel 2,5-substituted 1,3,4-oxadiazoles 3a-f and that of aroylhydrazone-based molecular hybrids 5a-g from readily available starting materials. The structure of the compounds was confirmed by IR, 1H NMR, 13C NMR and HRESI-MS spectral data. The toxicological potential of the compounds was evaluated by monitoring the synaptosomal viability and the levels of reduced glutathione in rat brain synaptosomes, isolated by Percoll gradient. The neuroprotective effects were assessed in vitro in a model of 6-hydroxydopamine-induced neurotoxicity. Administered alone, at a concentration of 40 µM, most of the 1,3,4-oxadiazole derivatives and all of the hydrazone derivatives exhibited weak statistically significant neurotoxic effects, compared to the control. Two of the compounds from the novel oxadiazoles 3a and 3d did not have any toxicity. In a model of 6-OHDA-induced oxidative stress, again 3a and 3d and all aroylhydrazone derivatives 5a-g revealed statistically significant neuroprotective effect by preserving the synaptosomal viability and the level of reduced glutathione, against the toxic agent. Some of the compounds may have neuroprotective effects due to possible stabilization of the synaptosomal membrane and/or because of the preserved reduced glutathione. Additionally, all the compounds display a good predicted ADME profile.


C-reactive Protein, Infection, and Outcome After Acute Ischemic Stroke: A Registry and Systematic Review.
A number of studies have explored the prognostic role of CRP in patients with acute ischemic stroke, however, the results have been inconclusive. The aim of our study was to investigate the impact of infection on the association between CRP and 3-month functional outcome by performing a registry study and systematic review. Patients admitted within 24 hours of acute ischemic stroke onset and had CRP measured within 24 hours after admission were included. Patients admitted between June 2016 and December 2018 in Chengdu Stoke Registry were enrolled. The PubMed database was searched up to July 2019 to identify eligible studies. Poor outcome was defined as modified Rankin Scale scores at 3-month more than 3. Totally, 368 patients in the registry and 18 studies involving 15238 patients in the systematic review were included. A statistically significant association between CRP values on admission and 3-month poor outcome in patients without infection was found, both in our registry (CRP per 1-mg/L increment, OR 1.04, 95% CI 1.01 to 1.07, p=0.008) and meta-analysis (CRP per 1-mg/dL increment, OR 1.66 [95% CI 1.37 to 2.01, p<0.001]). In patients with infection, CRP was not associated with a 3-month poor outcome according to registry data (OR 1.00, 95% CI 0.99 to 1.01, p=0.663) and meta-analysis (OR 1.01, 95% CI 0.99 to 1.01, p=0.128). High CRP value was independently associated with a 3-month poor outcome after stroke in patients without infection. Further studies are required to examine the value of infection on CRP measures and long-term functional outcomes.


Pharmacokinetics, biological effects, and distribution of (1-->3)-beta-D-glucan in blood and organs in rabbits.
The pharmacokinetics, biological effects and distribution in blood and organs of 125I-labeled (1-->3)-beta-D-glucan purified from Candida albicans were analyzed in rabbits during the 24-h period following an intravenous administration.The intravascular half-life of (1-->3)-beta- D-glucan was 1.8 min in the low-dose group (9.3 mug/kg) and 1.4 min in the high-dose group (222 mug/kg), and the mean (+/-SD) total body clearance was 1.12 +/- 0.30 and 1.17 +/- 0.16 ml/min, respectively. The rabbits remained well and (1-->3)-beta-D-glucan failed to alter blood cell counts. Less than 3% of the (125)I-(1-->3)-beta-D-glucan was initially associated with the cellular compartment, and this value decreased further during the 2-h period following administration (P = 0.0001). Over 97% of (125)I-(1-->3)-beta-D-glucan was associated with cell-free plasma, and the majority in plasma appeared to be present in the unbound form (not associated with lipoproteins or plasma proteins). The liver contained more than 80% of the (125)I-(1-->3)-beta-D-glucan detected in the six major organs analyzed.


The coming of age of a young subspecialty: paediatric hepatology.
Paediatric hepatology dates from the 1970s and it is the youngest of the organ-specific subspecialties. As then there have been impressive achievements in the fields of anatomical, metabolic, immunological and neoplastic diseases, and the advent of modern molecular biology has resulted in a marked increase in exact diagnoses. Liver transplants provided enormous stimulus for the discipline. Due to changing morbidity patterns, the discipline faces new challenges, such as environment- and lifestyle-induced liver diseases, but different forms of chronic viral hepatitis are diminishing. High levels of competence require good clinical research, optimal results and a high degree of centralisation.


Antihypertensive effect of diltiazem in a slow-release formulation for mild to moderate essential hypertension.
The antihypertensive efficacy and frequency of adverse reactions following administration of diltiazem in a new slow-release formulation were compared with placebo in 34 patients with mild to moderate essential hypertension in a randomized, double-blind, crossover study. After 6 weeks of treatment with diltiazem (240 or 360 mg/day), average supine blood pressure (BP) decreased from 165 +/- 21/101 +/- 5 mm Hg at baseline to 152 +/- 16/93 +/- 4 mm Hg compared with 160 +/- 19/100 +/- 7 mm Hg with placebo (p less than 0.01/p less than 0.001). Standing BP decreased from 162 +/- 20/107 +/- 6 mm Hg at baseline to 150 +/- 14/101 +/- 5 mm Hg compared to 159 +/- 18/107 +/- 8 mm Hg with placebo (p less than 0.01/p less than 0.001). The supine heart rate after diltiazem was 65 +/- 7 beats/min and after placebo 69 +/- 9 beats/min (p less than 0.01). There were no hematologic side effects. Only minor differences between diltiazem and placebo were observed in some of the biochemical laboratory values. Four patients were withdrawn due to side effects during treatment with diltiazem and 2 with placebo. Diltiazem in a slow-release formulation given twice a day lowered blood pressure significantly as monotherapy in patients with mild to moderate hypertension and was well tolerated.


Osteoconductive properties of methylpyrrolidinone chitosan in an animal model.
Bone defects were surgically produced in the tibiae of rabbits and medicated with freeze-dried methylpyrrolidinone chitosan. Histological observations 60 d after surgery showed a considerable presence of neoformed bone tissue, as opposed to controls, originating from the pre-existing bone as well as from the periosteum. The cationic nature and the chelating ability of the methylpyrrolidinone chitosan apparently favoured mineralization. Endosteal-periosteal and bone marrow osteoblast-like precursors, stimulated by growth factors entrapped in the coagulum-polysaccharide mixture, gave rise to intramembranous bone formation. The ultrastructural examination evidenced that bone osteoid was followed by mineralization of the tissue.


Quantitative measurements of aortic valve coaptation by three-dimensional transesophageal echocardiography in patients with aortic regurgitation without primary leaflet disease.
Aortic regurgitation (AR) without primary leaflet disease (functional AR) is known to occur as a result of loss of coaptation due to sinotubular junction (STJ) dilatation. However, the characteristics of change in the aortic valve coaptation length (AVCL) in 3 cusps in patients with functional AR are, as yet, unclear. The aim of this study was to measure the AVCL in 3 cusps in patients with functional AR by three-dimensional transesophageal echocardiograph (3D TEE). Thirteen patients with functional AR with or without aortic dilatation (trivial to mild AR [group A] and moderate to severe AR [group B]) and 7 controls without AR (group N) were examined. We measured the AVCL between the left coronary cusp (LCC) and right coronary cusp (RCC), the LCC and non coronary cusp (NCC), the RCC and NCC, and we also measured the cusp projection area, STJ arc length, leaflet tip-Valsalva wall distance and inter-commissural distance in each cusp by 3D TEE. The average AVCL was significantly shorter in group B than in groups N and A (P < 0.001). Particularly, in group B, there was a significant difference in AVCL in the 3 cusps (P = 0.043). Moreover, although there were no significant differences in the size of cusps in groups N and A, there was disproportion in the size of those cusps in group B with the largest in RCC. Cusp enlargement was not uniform and was greatest in the RCC, and the loss of coaptation between the 3 cusps was also not uniform, with predominant reduction in the coaptation between the RCC and the other 2 cusps.


Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner.
To determine the effects of low-intensity exercise on chronic muscle pain and potential activation of the endogenous opioid system. Randomized placebo-controlled trial. Animal laboratory. Sixty-three male Sprague-Dawley rats. Rats performed a low-intensity exercise protocol for 5 consecutive days after the induction of chronic muscle pain. In a separate experiment, naloxone or saline was administered systemically before 5 low-intensity exercise sessions. Mechanical hyperalgesia was measured using von Frey filaments to determine the mechanical withdrawal threshold. Low-intensity exercise increased mechanical withdrawal threshold in the chronic muscle pain model. Naloxone attenuated the antihyperalgesic effects of low-intensity exercise. Low-intensity exercise reversed mechanical hyperalgesia in the chronic muscle pain model through activation of the endogenous opioid system.


Prognostic Value of Time in Blood Pressure Target Range Among Patients With Heart Failure.
Blood pressure (BP) is a continuous and dynamic measure. However, standard BP control metrics may not reflect the variability in BP over time. This study assessed the prognostic value of time in BP target range among hypertensive patients with heart failure (HF). The authors performed a post hoc analysis of data from the TOPCAT (Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist) trial and the BEST (Beta-Blocker Evaluation of Survival Trial). Time in target range (TTR) for each patient was calculated using linear interpolation across the study period with the target range of systolic BP between 120 and 130 mm Hg. A total of 4,789 hypertensive patients (n = 1,654 from BEST and n = 3,135 from TOPCAT) were included. The cumulative incidences of primary endpoint (ie, cardiovascular death or HF hospitalization) were highest among the top quartile of TTR with a dose-dependent manner across quartiles (Ptrend <0.005). The top quartile of TTR was significantly associated with a lower risk of primary outcome using adjusted Cox regression model (HR: 0.71; 95% CI: 0.60-0.82), cardiovascular mortality (HR: 0.68; 95% CI: 0.55-0.84), HF hospitalization (HR: 0.70; 95% CI: 0.58-0.85), all-cause mortality (HR: 0.69; 95% CI: 0.58-0.83), and any hospitalization (HR: 0.76; 95% CI: 0.67-0.85). Further analyses using restricted cubic spline indicated a linear relationship between TTR and primary outcome. Similar patterns were observed in the individual trial. Sensitivity analyses generated consistent results while redefining target range as 110 to 130 mm Hg for systolic BP or 70 to 80 mm Hg for diastolic BP. TTR could independently predict major adverse cardiovascular events in hypertensive patients with HF.


Sex-specific disturbances of the glutamate/GABA balance in the hippocampus of adult rats subjected to adolescent cannabinoid exposure.
Adolescence is a period of active synaptic remodelling and plasticity and as such, a developmental phase of particular vulnerability to the effects of environmental insults. The endogenous cannabinoid system regulates central nervous system development and cannabinoid exposure during adolescence has been linked to several alterations to hippocampal-dependent processes such as cognition and emotion, which rely on intact glutamatergic and GABAergic systems. Here we show that K(+)-induced γ-amino butyric acid (GABA) release increases in the CA1 hippocampal field of Wistar rats of both sexes that were treated chronically with the cannabinoid agonist CP 55,940 (CP55940) during adolescence. GABA(B) receptors levels also increased in cannabinoid-exposed rats. In addition, CP55940-treated females exhibit reduced GABA transporter gene expression (GAT-1), increased GABA(A) receptor expression, as well as decreased K(+)-induced glutamate release and NMDA receptor levels. CP55940 administration did not affect the glial (EAAT2) or neuronal (EAAT3) glutamate transporter gene expression in either males or females, and nor were any changes in the mGlu5 receptor protein levels observed. Taken together, these results show that while the exacerbated GABA release induced by early cannabinoid exposure may be compensated by an increment in GABA(B) receptors, which normally function as inhibitory autoreceptors, adolescent cannabinoid exposure in the females disturbs the normal balance between glutamate and GABA transmission. These observations may provide important insight into the neuronal basis of the well-documented alterations in cognitive and emotional processes induced by adolescent cannabinoid exposure.


Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study.
To evaluate the relationship between use of methotrexate in rheumatoid arthritis patients and development of hematologic malignancies. We retrospectively analyzed all patients registered at the Mayo Clinic from 1976 through 1992 with rheumatoid arthritis (n = 16,263) cross-indexed with patients registered during the same period with a hematologic malignancy (n = 21,270). Adult patients were selected who had rheumatoid arthritis, were treated with a disease-modifying antirheumatic drug, and subsequently developed a hematologic malignancy. Thirty-nine patients met the selection criteria. Twelve of them had been given methotrexate. The characteristics of those who received methotrexate, including the type of hematologic malignancy, did not differ from those of patients who received other disease-modifying antirheumatic drugs. Hematologic malignancies are uncommon in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, including methotrexate. There does not appear to be a relationship between the peak or cumulative dose or the duration of methotrexate therapy and the subsequent development of hematologic malignancy. The histologic types of hematologic malignancy seen in the methotrexate-treated patients did not differ from those of patients treated with other disease-modifying antirheumatic drugs.


Depression Screening, Diagnosis, and Treatment Across the Lifespan.
This article focuses on six basic components of more effective depression care, emphasizing systems of team-based and collaborative care for diagnosis, monitoring, and follow-up. It also emphasizes the principles of stepped care and proactive and timely intensification of treatment, and discusses various augmentation strategies that all primary care providers could more readily employ.


Monitoring bcr-abl by polymerase chain reaction in the treatment of chronic myeloid leukemia.
The elucidation of the molecular biology of chronic myeloid leukemia (CML) has provided a paradigm for understanding leukemogenesis, targeted drug development, and disease monitoring at the molecular level. Minimal residual disease (MRD) monitoring by fluorescence in situ hybridization and polymerase chain reaction (PCR) has become an important tool in predicting relapse after allogeneic transplant, allowing for early intervention strategies such as donor lymphocyte infusion. MRD monitoring is important for assessment of disease status in patients who obtain a complete cytogenetic remission, and this approach is likely to play an important role in following patients to determine who will relapse on imatinib mesylate therapy. This review focuses primarily on MRD monitoring by PCR.


SPAM-sub partual analgesia with meptazinol: a prospective cohort study comparing intramuscular with intravenous administration.
Safe and effective analgesia sub partu is one of the central issues in optimizing vaginal delivery birth experiences. Meptazinol is a common opiate approved for treating labor pain in the first stage of labor. According to the manufacturer, manual meptazinol can be applied intramuscularly or intravenously. The aim of this study was to compare the two application methods in terms of efficacy in pain relief, occurrence of side effects and treatment satisfaction. 132 patients with singleton term pregnancies and intended vaginal delivery, receiving meptazinol during first stage of labor were included in this prospective cohort study from 05/2020 to 01/2021. We evaluated effectiveness in pain relief and treatment satisfaction using numeric rating scales (NRS) and documented the occurrence of adverse effects. Chi-square test or Fisher exact test were used to compare categorical data and Mann-Whitney U test to compare continuous data between the two treatment groups. Statistical analysis was done by SPSS 27.0. A p value < 0.05 was considered to indicate statistical significance (two tailed). Meptazinol decreased labor pain significantly from a NRS of 8 (IQR 8-10) to 6 (IQR 4.75-8) in both treatment groups with no difference in effectiveness between the groups. Frequency of effective pain reduction of a decrease of 2 or more on the NRS did not differ between groups (39.4% vs 54.5%, p = 0.116), as the occurrence of adverse effects. 12% of the newborns were admitted to NICU, the median NApH was 7.195. Meptazinol significantly reduces labor pain regardless of the method of application: intramuscular or intravenous. According to our data, no preferable route could be identified. The comparably poorer perinatal outcome in our study cohort hinders us to confirm that meptazinol is safe and can be recommended without restrictions.


Changes by two-dimensional echocardiography in the myocardial appearance of patients with end-stage renal disease.
A retrospective study of the clinical and biochemical data of all patients with end-stage renal disease who underwent 2-dimensional echocardiography at Tulane Medical Center between 1982 and 1986 was performed. Complete echocardiographic data were available for comparison in 53 patients. Highly reflective echoes were judged to be present in the myocardium of 81% of the patients. This characteristic is described as a "glistening speckled appearance." Patients with this characteristic had significantly greater left ventricular mass index (p = 0.0021).


Abolition by dextran sulfate of the heparin-accelerated antithrombin III/thrombin reaction.
Dextran sulfate did not inhibit the amidolytic activity of thrombin on Boc-Val-Pro-Arg-4-methylcoumaryl-7-amide, but abolished inhibition of the enzyme with antithrombin III (AT III) in the presence of heparin. Dextran sulfate did not bind to AT III and had less affinity than immobilized heparin for the protein. Dextran sulfate bound strongly to thrombin and had higher affinity than immobilized heparin for the enzyme. These findings indicate that binding of dextran sulfate to a site other than the active site of thrombin to prevent the approach of AT III in the presence of heparin.


British Association of Paediatric Urologists consensus statement on the management of the neuropathic bladder.
A large number of children with spina bifida develop a neuropathic bladder and this group of patients still forms the largest group of children who require urological management. Although there are published guidelines on the management of the neuropathic bladder, they are not specific to children. It is unsurprising, therefore, that the initial investigation, assessment and management of children with spina bifida vary considerably. The 2014 British Association of Paediatric Urologists (BAPU) meeting was devoted to the management of the neuropathic bladder. The aim was to produce a consensus on the appropriate investigation and management of a child with a neuropathic bladder. A questionnaire was devised and the members were polled on their current practice. Six paediatric urology fellows presented an evidence-based literature review on different aspects of the neuropathic bladder. At the end of the session, the members of the organisation present were polled again using the same questions. The BAPU felt that the use of urodynamics in the neuropathic bladder should be selectively determined by clinical parameters. Regarding CIC, the group was evenly split between universal use or only when poor emptying was established. Oxybutinin was the first-line anticholinergic of choice. Most paediatric urologists routinely used Botox and were happy to use it repeatedly. The surgical intervention most frequently employed was determined to be an ileocystoplasty, with most surgeons deferring the need for surveillance cystoscopy until at least 10 years after surgery. It was felt that a consensus statement is not a guideline or a way to establish best practice; however, it serves as a way of surveying current practice and providing a benchmark for clinicians involved in the management of these patients.


'Natural Conduit' between two atria associated with atrial septal defect.
Herein, we present a case of 46 years old woman with an extracardiac venous connection between two atria associated with secundum type atrial septal defect (ASD). This interatrial tunnel was not recognized by both transthoracic and transesophageal echocardiographic examinations. Computed tomography suspected a blood flow from right inferior pulmonary vein to inferior caval vein. Consequently, the patient underwent cardiac catheterization. Angiography revealed a tunnel between left and right atrium. To our knowledge, this is the first report of a case with venous tunnel between two atria associated with secundum type ASD in the literature.


Modelling gluteus medius tendon degeneration and repair in a large animal model.
Gluteus medius tendon tears often occur in the context of chronic tendinopathy and remain a difficult clinical problem. Surgical repair is challenging as it is often delayed and performed in degenerative tendons. No animal model currently exists to mimic the delayed repair of tendinopathic gluteus medius tears. The aims of this study were to develop a chronic model of gluteus medius tendinopathy and tear and then compare this model to an acute gluteus medius tear and repair. Six gluteus medius muscles were dissected and examined in mature sheep to confirm anatomical similarity to the human counterpart. Ten separate adult sheep underwent tendon detachment, followed by relook and histological sampling at 6 and 16 weeks to assess the extent of tendon degeneration. Six adult sheep underwent tendon repair at 6 weeks and were later assessed for healing of the tendon and compared to a further four adult sheep who underwent an acute tendon detachment and repair procedure. The sheep gluteus medius muscle consisted of three compartments, the anterior, middle and posterior. All compartments inserted via the common tendon on the superolateral aspect of the greater trochanter. At both 6 and 16 weeks, there was significant tendinopathic changes on histology compared to controls as assessed by modified Movin's score (p = 0.018, p = 0.047) but no difference between the 6- and 16-week groups (p = 0.25). There were significant differences between delayed and acute repair in both histological appearance (p = 0.025) and biomechanical properties (p = 0.019), with acute repair superior in both. Tendon detachment for 6 weeks is sufficient to produce histological changes similar to chronic tendinopathy and repair of this degenerative tendon results in significantly poorer healing when compared to an acute repair model. Animal models for gluteus medius tears should use a delayed repair model to improve clinical validity.


Type 2 Diabetes Mellitus Remission Models Following Laparoscopic Gastric Bypass: a 4-Model Analysis in a Latino Population.
Bariatric surgery is indicated for major weight loss and for the control of associated comorbidities, particularly type 2 diabetes. Remission prediction scores have been proposed for this end, such as: DiaRem, Ad-DiaRem, ABCD, and DiaBetter. Nevertheless, they have not been evaluated all together in a specific population. Retrospective study with Mexican patients submitted to gastric bypass with at least 12 months follow-up. All patients had BMI > 30 kg/m2 and type 2 diabetes. The primary objective was to evaluate the remission prediction performance of scores. A baseline analysis (anthropometric, biochemical, and metabolic) and remission rates were obtained. Remission scores and cut-off values were assigned based on original descriptions. A ROC analysis was performed for sensibility and specificity. A total of 95 patients were included. Mean age 44 years, 85.6% female with mean BMI of 44.1 kg/m2, and mean HbA1C of 7.2%. At 12 months, complete remission was obtained in 76.8%. ROC curves were plotted showing that DiaRem had 75.3% sensitivity and 68.2% specificity (AUC 0.723 p = 0.001), Ad-DiaRem had 84.9% and 50% (AUC 0.702 p = 0.002), ABCD had 57.5% and 77.3% (AUC 0.0.690 p = 0.002), and DiaBetter had 72.6% and 77.3% (AUC 0.748 p < 0.001). In Mexican patients with obesity and type 2 Diabetes, submitted to gastric bypass, remission prediction could be assessed with any current model showing satisfactory sensibility and specificity. Among such models, DiaBetter obtained the best statistical performance in our population. Type 2 diabetes remission rate at 1 year is similar to any other race or ethnicity.


Methylprednisolone enhances the efficacy of ondansetron in acute and delayed cisplatin-induced emesis over at least three cycles. Ondansetron Study Group.
This double-blind multicentre study has been carried out in order to confirm the improvement of ondansetron's antiemetic efficacy when combined with a corticosteroid and to determine whether this increased efficacy is maintained over three chemotherapy courses. One hundred and two patients receiving their first course of cisplatin (50-120 mg m-2)-containing chemotherapy were randomised to receive one of the two following treatments: 8 mg OND i.v. injection and 120 mg MPD i.v. injection before chemotherapy, followed 8-12 h later by an 8 mg OND tablet and a 16 mg MPD tablet (oral treatment administered twice daily for 3-5 days): or 8 mg OND plus placebo i.v. injection before chemotherapy, followed by 8-12 h later by an 8 mg OND tablet and placebo p.o. (oral treatment administered twice daily for 3-5 days). The number of emetic episodes (EEs = vomits + retches) and the grade of nausea were recorded. Of the 101 patients studied (efficacy analysis), complete or major control (0-2 EEs) was experienced in 90.4% of patients in the first 24 h in the OND/MPD group compared with 71.4% of patients in the OND group during the first course. This difference in favour of OND/MPD was noted over the three courses and is statistically significant. In the control of delayed emesis (worst day between days 2 and 6) there is a trend in favour of the OND/MDP group during the first course [56.2% vs 43.2% for complete response (no emetic episodes)] which was statistically significant on courses 2 and 3. The global antiemetic control over the course was always in favour of OND/MPD, which leads to a better efficacy maintained over the three courses. Both treatments were well tolerated. The results of this study confirm the increased antimetic efficacy of ondansetron and methylprednisolone in combination in cisplatin-induced acute and delayed emesis which led to a better maintained efficacy over three repeated chemotherapy courses.


PAK paradox: Paramecium appears to have more K(+)-channel genes than humans.
K(+)-selective ion channels (K(+) channels) have been found in bacteria, archaea, eucarya, and viruses. In Paramecium and other ciliates, K(+) currents play an essential role in cilia-based motility. We have retrieved and sequenced seven closely related Paramecium K(+)-channel gene (PAK) sequences by using previously reported fragments. An additional eight unique K(+)-channel sequences were retrieved from an indexed library recently used in a pilot genome sequencing project. Alignments of these protein translations indicate that while these 15 genes have diverged at different times, they all maintain many characteristics associated with just one subclass of metazoan K(+) channels (CNG/ERG type). Our results indicate that most of the genes are expressed, because all predicted frameshifts and several gaps in the homolog alignments contain Paramecium intron sequences deleted from reverse transcription-PCR products. Some of the variations in the 15 genomic nucleotide sequences involve an absence of introns, even between very closely related sequences, suggesting a potential occurrence of reverse transcription in the past. Extrapolation from the available genome sequence indicates that Paramecium harbors as many as several hundred of this one type of K(+)-channel gene. This quantity is far more numerous than those of K(+)-channel genes of all types known in any metazoan (e.g., approximately 80 in humans, approximately 30 in flies, and approximately 15 in Arabidopsis). In an effort to understand this plurality, we discuss several possible reasons for their maintenance, including variations in expression levels in response to changes in the freshwater environment, like that seen with other major plasma membrane proteins in Paramecium.


The removal of UV-induced pyrimidine dimers from DNA of rat skin cells in vitro and in vivo in relation to aging.
Young and old rats were compared with respect to the capacity of their skin fibroblasts and epidermal keratinocytes to remove low levels of ultraviolet light (UV) induced UV-endonuclease sensitive sites (pyrimidime dimers) from their DNA, in vitro and in vivo, respectively. In vitro, over a 24-h time period, fibroblasts from both young and old rats were found to remove about 20% of the pyrimidine dimers originally induced by 4.6 J/m2 of UV-C. In vivo, after 2.6 kJ/m2 of UV-B hardly any UV lesions were found to be present in fibroblasts, as demonstrated by immunohistochemistry using an anti-thymine dimer antibody. As reported earlier (Mullaart et al., J. Invest. Dermatol., 90 (1988) 346-349) cultured epidermal keratinocytes do not differ from cultured fibroblasts in UV repair kinetics, whereas in vivo they remove at least 50% of the pyrimidine dimers induced by 4 kJ/m2 of UV-B within 3 h. We now show that epidermal keratinocytes from old rats are not deficient in their in vivo repair characteristics upon this low UV-B dose. However, since a considerable fraction of the pyrimidine dimers appeared to be persistent in fibroblasts and keratinocytes, demonstrated by both enzymatic and immunochemical assays, the possibility is discussed that long-term exposure of skin cells to UV may lead to an accumulation of DNA damage with age.


Immunohistochemical detection of antigens of distemper, adenovirus and parainfluenza viruses in domestic dogs with pneumonia.
The lungs of 35 dogs that died in Mexico from acute or subacute pneumonia were examined immunohistochemically for canine distemper virus (CDV), canine adenovirus (CAV) and canine parainfluenza virus (CpiV), to determine their frequency and occurrence and possible associations. CDV was identified in 27 (77%) cases, CAV in 20 (57%) and CpiV in 18 (51%). The most frequent dual association was that between CDV and CpiV (five cases; 14%). All three viruses, however, were identified in the same lung in 10 cases. Immunolabelling occurred in alveolar macrophages, monocytes, pneumocytes, epithelial cells and syncytial cells. It was concluded that immunohistochemistry is a useful diagnostic tool in canine respiratory disease to complement histopathological examination.


Functional Rhinoplasty.
Understanding nasal anatomy and physiology are the most important points for successful functional rhinoplasty. Anatomic structures playing major roles in nasal breathing functions include the septum, and internal and external nasal valves, so physical examination of these regions is essential. Planning for functional rhinoplasty involves the identification of the sites of nasal airway obstruction or old trauma, and addressing those regions during the operation with a number of different techniques that have been described.


Alcohol consumption and alcoholism in an urban population in central Sweden.
A representative selection of 2,283 individuals, 18-65 years old, in "former" Stockholm County, were examined by psychiatrists in 1970-71. The total of non-participants was 12%. The alcohol consumption pattern and the prevalence of the diagnosis alcoholism for the last 12 months are reported. Significantly more men than women confirmed "very high" and "high" consumption, respectively. The diagnosis alcoholism was given to 4.8% men and 1.4% women. Significantly more women in social class I than in II and III, as significantly more men in social class I than in II stated "very high" or "high" consumption. Social consequences of alcohol consumption, in the form of entries in the Penal Register of the National Board of Excise (Kontrollstyrelsens straffregister) for the years 1965-71, were, on the other hand, found significantly more frequently among men in social class III than in social classes I and II.


Activity and specificity studies of the new thermostable esterase EstDZ2.
In this paper, we study the activity and specificity of EstDZ2, a new thermostable carboxyl esterase of unknown function, which was isolated from a metagenome library from a Russian hot spring. The biocatalytic reaction employing EstDZ2 proved to be an efficient method for the hydrolysis of aryl p-, o- or m-substituted esters of butyric acid and esters of secondary alcohols. Docking studies revealed structural features of the enzyme that led to activity differences among the different substrates.


Fecal Incontinence and the Risk of Urinary Tract Infection in Patients Presenting for Urogynecological Consultation.
Urinary tract infection (UTI) is common in urogynecology patients. Patients with fecal incontinence (FI) often attribute their UTIs to FI, but this association has not been evaluated. The objectives of this study were to compare the prevalence of UTI in urogynecology patients with and without FI and to characterize factors associated with UTI and recurrent UTI. This retrospective cohort study included all new adult patients who presented to an academic female pelvic medicine and reconstructive surgery practice with FI from January 2014 through December 2017. Patients were age-matched to new adult patients with stage <2 pelvic organ prolapse without FI. All urine culture results from 1 year before and 1 year after the first visit were identified. Logistic regression identified factors associated with UTI. Among 399 patients, 106 (27%) had a culture-confirmed UTI in the year before or after their first urogynecology visit; the prevalence of UTI was 23% (45/198) in patients with FI and 30% (61/201) in those without FI (P = 0.09). The rate of recurrent UTI was 11.5% overall and did not differ among those with and without FI. In multivariate models, variables that were statistically significantly associated with UTI included age, diabetes mellitus, anterior vaginal wall prolapse, and sexual activity. Fecal incontinence was not associated with any or recurrent UTI. The prevalence of UTI and recurrent UTI was similar in urogynecology patients with and without FI. Variables that were associated with UTI risk included older age, sexual activity, diabetes mellitus, and anterior vaginal wall prolapse.


Draft Genome Sequence of a Washington Isolate of "Candidatus Phytoplasma pruni".
Illumina sequencing of a Prunus avium tree with X-disease symptoms was performed to obtain a draft genome of "Candidatus Phytoplasma pruni." The genome consists of 14 contigs covering 588,767 bp. This is the first metagenome to be sequenced from the current X-disease epidemic in stone fruit in the Pacific Northwest.


Pharmacokinetic Properties of Liraglutide as Adjunct to Insulin in Subjects with Type 1 Diabetes Mellitus.
The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D. Subjects (18-64 years; body mass index 20.0-28.0 kg/m2; glycated hemoglobin ≤9.5 %) were randomized 1:1:1 to 0.6, 1.2, or 1.8 mg liraglutide/placebo. Each group underwent two 4-week treatment periods (liraglutide then placebo or placebo then liraglutide) separated by a 2- to 3-week washout. Both trial drugs were administered subcutaneously, once daily, as adjunct to insulin. A stepwise hypoglycemic clamp was performed at the end of each treatment period (data reported previously). Pharmacokinetic endpoints were derived from liraglutide concentration-time curves after the final dose and exposure was compared with data from previous trials in healthy volunteers and subjects with T2D. The pharmacokinetic properties of liraglutide in T1D were comparable with those observed in healthy volunteers and subjects with T2D. Area under the steady-state concentration-time curve (AUC) and maximum plasma concentration data were consistent with dose proportionality of liraglutide. Comparison of dose-normalized liraglutide AUC suggested that exposure in T1D, when administered with insulin, is comparable with that observed in T2D. Liraglutide, administered as adjunct to insulin in subjects with T1D, shows comparable pharmacokinetics to those in subjects with T2D. ClinicalTrials.gov Identifier: NCT01536665.


Physostigmine reversal of postoperative somnolence.
The effects of physostigmine on reversal of post-operative somnolence following general anaesthesia were evaluated in 187 patients. Significant reversal of anaesthetic-induced post-operative somnolence was observed in those patients receiving physostigmine when compared to a control group. These results suggest that general anaesthesia with halothane may be included in those situations where central nervous system depression may be reversed by administration of physostigmine. Cholinergic side-effects observed with physostigmine administration were minimal.


Ethanol fermentation technologies from sugar and starch feedstocks.
This article critically reviews some ethanol fermentation technologies from sugar and starch feedstocks, particularly those key aspects that have been neglected or misunderstood. Compared with Saccharomyces cerevisiae, the ethanol yield and productivity of Zymomonas mobilis are higher, because less biomass is produced and a higher metabolic rate of glucose is maintained through its special Entner-Doudoroff pathway. However, due to its specific substrate spectrum as well as the undesirability of its biomass to be used as animal feed, this species cannot readily replace S. cerevisiae in ethanol production. The steady state kinetic models developed for continuous ethanol fermentations show some discrepancies, making them unsuitable for predicting and optimizing the industrial processes. The dynamic behavior of the continuous ethanol fermentation under high gravity or very high gravity conditions has been neglected, which needs to be addressed in order to further increase the final ethanol concentration and save the energy consumption. Ethanol is a typical primary metabolite whose production is tightly coupled with the growth of yeast cells, indicating yeast must be produced as a co-product. Technically, the immobilization of yeast cells by supporting materials, particularly by gel entrapments, is not desirable for ethanol production, because not only is the growth of the yeast cells restrained, but also the slowly growing yeast cells are difficult to be removed from the systems. Moreover, the additional cost from the consumption of the supporting materials, the potential contamination of some supporting materials to the quality of the co-product animal feed, and the difficulty in the microbial contamination control all make the immobilized yeast cells economically unacceptable. In contrast, the self-immobilization of yeast cells through their flocculation can effectively overcome these drawbacks.


Absorbable synthetic mesh (910-polyglactin) intestinal sling to reduce radiation-induced small bowel injury in patients with pelvic malignancies.
Absorbable synthetic mesh (910-polyglactin) was used to create an intestinal sling in six patients undergoing surgical staging of pelvic malignancies prior to radiation therapy. All patients had effective compartmentalization of small intestine out of the pelvis which persisted throughout the duration of radiation therapy. None of the patients developed complications related to the intestinal sling. This technique is well tolerated and has the potential to minimize chronic small intestinal complications caused by radiation therapy for pelvic malignancies.


Nurse-led care for the management of side effects of pelvic radiotherapy: what does it achieve?
To describe what a nurse-led clinic can achieve, focusing on gastrointestinal side effects after pelvic radiotherapy. This article illustrates how a structured approach for management and treatment of late gastrointestinal symptoms after pelvic radiotherapy can be used as a model for other nurse-led clinics. A large majority of cancer survivors treated for gynaecological, rectal and anal cancer suffer from physical symptoms from the bowels, the urinary bladder and the genitals. These long-term side effects lead to impairment of social functioning, sexual dysfunction and lowered quality of life. A structured model for the comprehensive management of cancer survivors can help care givers to offer patients treated with pelvic radiotherapy, methods that could help them to more fully restore physical health. Nurses play an important role in the rehabilitation of cancer patients, improving patients' quality of life and psychosocial well being, and they are in the best position to provide continuity during the tailoring of rehabilitation care.


Destruxin Ed1 a cyclopeptide from the fungus Metarhizium anisopliae.
A new destruxin Ed1 has been isolated from the entomopathogenic fungus Metarhizium anisopliae. Its structure was deduced from the NMR and mass spectral data.


Molecular basis of mucopolysaccharidosis type VII: replacement of Ala619 in beta-glucuronidase with Val.
We have identified a mutation causing beta-glucuronidase (beta Gl) deficiency in a 6-year-old girl with mucopolysaccharidosis type VII. Enzyme assay of lysates of a girl's lymphocytes or cultured fibroblasts showed little residual activity and a normal beta Gl-specific mRNA level, as revealed by Northern-blot analysis. Sequencing of the full-length mutated cDNA revealed a C----T transition, an event causing a single Ala619----Val change (we designated this variant beta GGifu). This change is detected by loss of the cleavage site for the enzyme Fnu4HI in the mutated cDNA. On the basis of the loss of Fnu4HI restriction site, the patient was shown to be a homozygote with the beta GGifu mutation and her parents and brother were heterozygotes. This mutation disrupts a functional domain consisting of a region of sequence highly conserved among human, rat and bacterial beta Gls, and it reduces the enzyme activity, as tested by transfection of COS cells with expression vectors harboring the mutated cDNA.


[Features of structural organization of mouse centrometric heterochromatin, detected during differential decondensation of chromosomes].
The centromeric heterochromatin (CH) of mouse metaphase and interphase chromosomes has been shown to be practically devoid of the chromonemal and chromomeric levels of DNP organization. CH decondensation into DNP-fibrils caused by decreasing Ca2+-ions concentration is accomplished without formation of chromonemata and chromomeres. The peripheral regions of CH, immediately contacting the inner surface of kinetochores, display the highest stability towards the factors inducing the artificial decondensation.


Secondary analysis of gut hormone data from children with and without in utero exposure to gestational diabetes: Differences in the associations among ghrelin, GLP-1, and insulin secretion.
Intrauterine exposure to gestational diabetes mellitus (GDM) increases risk for type 2 diabetes (T2D). Ghrelin and GLP-1 have opposite functions in nutritional homeostasis and are associated with insulin secretion, but it is not known if individuals exposed to GDM exhibit dysregulation in these associations. Test the hypothesis that children exposed to GDM in utero will exhibit dysregulation among ghrelin, GLP-1, and C-peptide (reflecting insulin secretion). Data from N = 43 children aged 5 to 10 years were included in this secondary analysis of ghrelin, GLP-1, and C-peptide response to a liquid meal test. Repeated measures mixed model analyses were used to measure associations among hormones. The association of ghrelin and GLP-1 was moderated by GDM group (P < .01), such that ghrelin was inversely associated with GLP-1 in children without GDM exposure, but not for those exposed to GDM. GLP-1 was positively associated with C-peptide in both groups, but the association was stronger in those exposed to GDM (estimate = 1.06 vs 1.01). Differences in the associations among ghrelin, GLP-1, and C-peptide displayed here suggest novel lines of research about whether the regulation of gut hormones and insulin secretion contribute to obesity and risk for T2D in children exposed to GDM.


T lymphocyte responses to flaviviruses - diverse cell populations affect tendency toward protection and disease.
Dengue virus (DENV), Yellow Fever virus, West Nile virus, Japanese encephalitis virus and Zika virus are medically important flaviviruses transmitted to humans by mosquitoes and circulate in overlapping geographic areas. Cross-reactive immune responses have been demonstrated among the flaviviruses, particularly the four DENV serotypes. The immunological imprint left by a flavivirus infection can therefore have profound effects on the responses to subsequent infections. In this review we summarize recent research focusing on T cell responses to DENV using clinical samples from prospective cohort studies in Asia. These data suggest that durability of different T cell populations after natural infection or vaccination is an important consideration for the outcome of subsequent flavivirus exposures and we argue for continued investigation in the context of longitudinal cohort studies.


Serological and histological studies on adult rabbits with recent, naturally acquired encephalitozoonosis.
Twenty adult rabbits were killed two to 12 weeks after antibodies to Encephalitozoon cuniculi were first detected in their sera. Specimens of urine were examined for E cuniculi and sections of kidneys and brains were examined both for organisms and lesions consistent with encephalitozoonosis. Organisms were observed in the kidneys from two weeks after the appearance of antibodies, and histological lesions in the kidneys were observed after five weeks. However, organisms were rarely seen in the brain and lesions in this organ were infrequent and, generally, not present until at least eight weeks after the first detectable antibody. The results indicate the course of natural infection of encephalitozoonosis in rabbits and show that serology is the most sensitive procedure for its early diagnosis.


Genetics of oocyte ageing.
Correlations between parental age, aneuploidy in germ cells and recent findings on aetiological factors in mammalian trisomy formation are reviewed. Data from observations in human oocytes, molecular studies on the origin of extra chromosomes in trisomies, experiments in a mouse model system, and transgenic approaches are shown. Errors in chromosome segregation are most frequent in meiosis I of oogenesis in mammals and predominantly predispose specific chromosomes and susceptible chiasmate configurations to maternal age-related nondisjunction. Studies on spindle structure, cell cycle and chromosome behaviour in oocytes of the CBA/Ca mouse used as a model for the maternal age-effect suggest that hormonal homeostasis and size of the follicle pool influence the quality, maturation competence and spindle size of the mammalian oocyte. Predisposition to errors in chromosome segregation are critically dependent on altered cell cycles. Compromised protein synthesis and mitochondrial function affect maturation kinetics and spindle formation, and cause untimely segregation of chromosomes (predivision), mimicking an aged phenotype. Altered cell cycles and untimely resolution of chiasmata but also nondisjunction of late segregating homologues caused by asynchrony in cytoplasmic and nuclear maturation appear to be causal to errors in chromosome segregation with advanced maternal age. Oocytes appear to lack checkpoints guarding against untimely chromosome segregation. Genes and exposures affecting pool size, hormonal homeostasis and interactions between oocytes and their somatic compartment and thus quality of follicles and oocytes have the potential to critically influence chromosome distribution in female meiosis and affect fertility in humans and other mammals.


Describing Anopheles arabiensis aquatic habitats in two riceland agro-ecosystems in Mwea, Kenya using a negative binomial regression model with a non-homogenous mean.
This research illustrates a geostatistical approach for modeling the spatial distribution patterns of Anopheles arabiensis Patton (Patton) aquatic habitats in two riceland environments. QuickBird 0.61 m data, encompassing the visible bands and the near-infra-red (NIR) band, were selected to synthesize images of An. arabiensis aquatic habitats. These bands and field sampled data were used to determine ecological parameters associated with riceland larval habitat development. SAS was used to calculate univariate statistics, correlations and Poisson regression models. Global autocorrelation statistics were generated in ArcGISfrom georeferenced Anopheles aquatic habitats in the study sites. The geographic distribution of Anopheles gambiae s.l. aquatic habitats in the study sites exhibited weak positive autocorrelation; similar numbers of log-larval count habitats tend to clustered in space. Individual rice land habitat data were further evaluated in terms of their covariations with spatial autocorrelation, by regressing them on candidate spatial filter eigenvectors. Each eigenvector generated from a geographically weighted matrix, for both study sites, revealed a distinctive spatial pattern. The spatial autocorrelation components suggest the presence of roughly 14-30% redundant information in the aquatic habitat larval count samples. Synthetic map pattern variables furnish a method of capturing spatial dependency effects in the mean response term in regression analyses of rice land An. arabiensis aquatic habitat data.


Doublecortin-expressing cells in the ischemic penumbra of a small-vessel stroke.
A cortical lesion was induced by disrupting the medium-size pial vessels, which led to a cone-shaped cortical lesion and turned into a fluid-filled cavity surrounded by a glial acidic fibrillary protein-positive (GFAP(+)) glia limitans 21 days after injury. Therefore, it mimics conditions of lacunar infarctions, one of the most frequent human stroke pathologies. Doublecortin (DCX)-positive cells were present in the neocortex and corpus callosum at the base of the lesion. The number of DCX-positive cells in the corpus callosum was significantly increased from day 5 to day 14 compared with the control group. In contrast, there were no DCX-positive cells in neocortex of control animals; the DCX-positive cells appeared in the neocortex after lesioning and were maintained until 14 days postlesioning. Some of the DCX-positive cells were also immunoreactive for beta III-tubulin, another marker of immature neurons. They did not stain positively for markers of glia cells. The presence of these DCX-positive cells near the lesion might indicate a migratory pathway for developing neuroblasts from the subventricular zone (SVZ) through the corpus callosum to the lesion. SVZ cells were labeled with a lipophilic molecule, 5- (and 6-) carboxyfluorescein diacetate succinimidyl ester (CFSE) stereotaxical injections. Although rostral migratory stream and olfactory bulb were intensely labeled, no CFSE-containing cells were found in the cortex beneath the lesion. These results do not support the idea that the DCX-positive cells were originating from neural precursors of the SVZ, but they might be generated from local progenitor cells.


Coverage losses of substance in the shoulder.
Losses of substance of the shoulder are less common than elsewhere in the upper limb. They arise essentially from tumors (sarcomas), infectious diseases (hidradenitis) or traumatic events, (burns). The objectives of reconstruction depend on whether the losses of substance are located on the curve of the shoulder or in the axillary area. There exist numerous regional solutions, including perforator, propeller, pedicled and free flaps. The donor region may be the thorax (latissimus dorsi, serratus anterior), the back (trapezium, scapular or subscapular flaps, occipito-cervico-thoracic flap), the anterior surface of the thorax (pectoralis major or minor, supraclavicular, perforators of the acromiothoracic artery, delto-pectoral flap) or arm (brachial lateral or medial). Multitissular reconstructions are also possible in regional and pedicled form, as well as microanastomosed flaps in exceptional conditions.


Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications.
DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiation of stem cells, are found to be frequent targets of hypermethylation in cancers. Here we performed comprehensive analysis across multiple cancer types and identified that the decrease in H3K4me1 levels coincides with DNA hypermethylation at the bivalent promoter CGIs during tumorigenesis. Removal of DNA hypermethylation leads to increment of H3K4me1 at promoter CGIs with preference for bivalent genes. Nevertheless, the alteration of H3K4me1 by overexpressing or knockout LSD1, the demethylase of H3K4, doesn't change the level or pattern of DNA methylation. Moreover, LSD1 was found to regulate the expression of a bivalent gene OVOL2 to promote tumorigenesis. Knockdown of OVOL2 in LSD1 knockout HCT116 cells restored the cancer cell phenotype. In summary, our work identified a universal indicator that can pre-mark DNA hypermethylation in cancer cells, and dissected the interplay between H3K4me1 and DNA hypermethylation in detail. Current study also reveals a novel mechanism underlying the oncogenic role of LSD1, providing clues for cancer therapies.


Port site infiltration of local anesthetic after laparoendoscopic single site surgery for benign adnexal disease.
To determine whether local bupivacaine injection into the incision site after gynecologic laparoendoscopic single site surgery (LESS) improves postoperative pain. This prospective cohort study included consecutive 158 patients who had LESS for benign adnexal disease from March 2013 to December 2015. Chronologically, 82 patients (March 2013 to August 2014) received no bupivacaine (group 1) and 76 (August 2014 to December 2015) received a bupivacaine block (group 2). For group 2, 10 mL 0.25% bupivacaine was injected into the 20 mm-incision site through all preperitoneal layers after LESS completion. Primary outcome is postoperative pain score using the visual analog scale (VAS). There was no difference in clinicopathological characteristics between the groups. Operating time (expressed as median [range], 92 [55-222] vs. 100 [50-185] minutes, P=0.137) and estimated blood loss (50 [30-1,500] vs. 125 [30-1,000] mL, P=0.482) were similar between the groups. Post-surgical VAS pain scores after 3 hours (3.5 [2-6] vs. 3.5 [2-5], P=0.478), 6 to 8 hours (3.5 [2-6] vs. 3 [1-8], P=0.478), and 16 to 24 hours (3 [2-4] vs. 3 [1-7], P=0.664) did not differ between groups. Bupivacaine injection into the trocar site did not improve postoperative pain after LESS. Randomized trials are needed to evaluate the benefits of local bupivacaine anesthetic for postoperative pain reduction.


The current landscape of intracranial aneurysms in Africa: management outcomes, challenges, and strategies-a narrative review.
Intracranial aneurysms (IAs) pose complex and potentially life-threatening challenges in Africa, where limited resources, restricted access to specialised healthcare facilities, and disparities in healthcare provision amplify the difficulties of management. Timely diagnosis and treatment are pivotal in preventing complications, including subarachnoid haemorrhage. Treatment options encompass observation, surgical clipping, endovascular coiling, and flow diversion. Positive outcomes observed in IA management in Africa include high survival rates, favourable functional outcomes, successful treatment techniques, and the absence of complications in some cases. However, negative outcomes such as postoperative complications, reduced quality of life, perioperative mortality, and the risk of recurrence persist. Challenges in IA management encompass limited access to diagnostic tools, a scarcity of specialised healthcare professionals, and an unequal distribution of services. Addressing these challenges requires interventions focused on improving access to diagnostic tools, expanding the number of trained professionals, and establishing specialised IA treatment centres. Collaboration, research, and capacity-building efforts hold significant importance in improving patient outcomes and reducing disparities in IA management across Africa.


Sensitive LC-MS/MS method for the temporal profiling of bile acids, fatty acids and branched-chain alpha-keto acids in maternal plasma during pregnancy and cord blood plasma at delivery.
There are significant changes to the maternal inflammatory profile across pregnancy. Recent studies suggest that perturbations in maternal gut microbial and dietary-derived plasma metabolites over the course of pregnancy mediate inflammation through a complex interplay of immunomodulatory effects. Despite this body of evidence, there is currently no analytical method that is suitable for the simultaneous profiling of these metabolites within human plasma. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the high-throughput analysis of these metabolites in human plasma without derivatization. Plasma samples were processed using liquid-liquid extraction method with varying proportions of methyl tert-butyl ether, methanol, and water in a 3:10:2.5 ratio to reduce matrix effects. LC-MS/MS detection was sufficiently sensitive to quantify these gut microbial and dietary-derived metabolites at physiological concentrations and linear calibration curves with r2 > 0.99 were obtained. Recovery was consistent across concentration levels. Stability experiments confirmed that up to 160 samples could be analyzed within a single batch. The method was validated and applied to analyse maternal plasma during the first and third trimester and cord blood plasma of 5 mothers. This study validated a straightforward and sensitive LC-MS/MS method for the simultaneous quantitation of gut microbial and dietary-derived metabolites in human plasma within 9 minutes without prior sample derivatization.


Silane to enhance the bond between polymethyl methacrylate and titanium.
The machined surface of wrought titanium frameworks used in implant-supported, fixed prostheses does not bond well with acrylic resin. Surface pretreatment has been suggested to enhance the retention of polymethyl methacrylate to machined titanium surfaces. This study evaluated a new bonding material (Rocatec) to determine its effect on the bond strength between titanium and polymethyl methacrylate. Twenty rod-shaped specimens of grade 2 titanium (7.6 x 0.3 cm in diameter) were divided into two groups of 10 samples. Group A received no pretreatment and group B was pretreated with 110 microns alumina air abrasive and the Rocatec material. Heat-cured denture base resin was processed around each titanium sample in a cylindrical shape approximately 0.9 x 1.5 cm. A Shell-Nielsen shear test was performed with a universal testing machine at a crosshead speed of 0.5 mm/minute to determine the bond strength in megapascals (MPa). Group B specimens (23.8 +/- 1.78 MPa) had a shear strength 68% greater than group A (16.1 +/- 1.61 MPa) (p 0.0001). The results of this study indicated that surface pretreatment of grade 2 titanium with 110 microns alumina air abrasive plus Rocatec bonding material significantly enhances the shear bond strength to PMMA.


Health risks associated with animals in different types of urban areas: present status and new ecological conditions due to urbanization.
For different reasons urban areas are colonized by numerous animal groups. From the aspect of the incidence of zoonoses the following animal groups are primarily significant: 1) food-producing animals; 2) pets; 3) synanthropic mammals; 4) synanthropic birds; 5) synanthropic arthropods. Certain species live in central parts of urban areas which the A. attempts to classify, and particularly in suburban areas which serve for recreation of town inhabitants. From the aspect of the occurrence of different animal species the A. points out the significance of various parts of urban agglomerations.


A novel disposable electrochemical sensor for determination of carbamazepine based on Fe doped SnO2 nanoparticles modified screen-printed carbon electrode.
An effective strategy to fabricate a novel disposable screen printing carbon electrode modified by iron doped tin dioxide nanoparticles for carbamazepine (CBZ) detection has been developed. Fe-SnO2 (Fe=0 to 5 wt.%) NPs were synthesized by a simple microwave irradiation method and assessed for their structural and morphological changes due to Fe doping into SnO2 matrix by X-ray diffraction and scanning and transmission electron microscopy. The electrochemical behaviour of carbamazepine at the Fe-SnO2 modified screen printed carbon electrode (SPCE) was investigated by cyclic voltammetry and square wave voltammetry. Electron transfer coefficient α (0.63) and electron transfer rate constant ks (0.69 s(-1)) values of the 5 wt.% Fe-SnO2 modified SPCE indicate that the diffusion controlled process takes place on the electrode surface. The fabricated sensor displayed a good electrooxidation response towards the detection of CBZ at a lower oxidation potential of 0.8 V in phosphate buffer solution at pH7.0. Under the optimal conditions, the sensor showed fast and sensitive current response to CBZ over a wide linear range of 0.5-100 μM with a low detection limit of 92 nM. Furthermore, the practical application of the modified electrode has been investigated by the determination of CBZ in pharmaceutical products using standard addition method.


Association of returning to work with better health in working-aged adults: a systematic review.
We systematically reviewed the literature on the impact of returning to work on health among working-aged adults. We searched 6 electronic databases in 2005. We selected longitudinal studies that documented a transition from unemployment to employment and included a comparison group. Two reviewers independently appraised the retrieved literature for potential relevance and methodological quality. Eighteen studies met our inclusion criteria, including 1 randomized controlled trial. Fifteen studies revealed a beneficial effect of returning to work on health, either demonstrating a significant improvement in health after reemployment or a significant decline in health attributed to continued unemployment. We also found evidence for health selection, suggesting that poor health interferes with people's ability to go back to work. Some evidence suggested that earlier reemployment may be associated with better health. Beneficial health effects of returning to work have been documented in a variety of populations, times, and settings. Return-to-work programs may improve not only financial situations but also health.


Pleomorphic mesothelioma: report of 10 cases.
Mesotheliomas with pleomorphic features are rare and only a few studies on this mesothelioma variant have been published. Little information regarding the immunoprofile of these tumors and none on their electron microscopic features was included in these studies. Herein are reported 10 cases of pleomorphic mesothelioma that were investigated using a large panel of immunohistochemical markers, 4 of which were also studied by electron microscopy. All of the patients were men and seven had a history of asbestos exposure. Nine of the cases originated in the pleura and one in the peritoneum. Histologically, the tumors were characterized by being composed of large, often discohesive, cells that varied in size and shape, had dense abundant eosinophilic cytoplasm, and single or multiple irregular nuclei, which often contained one or several large nucleoli. Mitotic activity was high and atypical mitoses frequent. Immunoreactivity for pan-keratin and keratin 7 was strong in all of the cases. Expression for calretinin, WT1, podoplanin, mesothelin and keratin 5/6 was also frequent, but variable. All cases were negative for MOC-31, carcinoembryonic antigen, CD15, TAG-72 and thyroid transcription factor-1. Electron microscopy often showed the presence of abundant long, slender microvilli on the cell membrane of the neoplastic cells. These findings demonstrate that, contrary to what has been suggested by some investigators, both immunohistochemistry and electron microscopy can be very helpful in assisting in the diagnosis of pleomorphic mesotheliomas. That the seven patients who underwent extrapleural pneumonectomy had extensive lymph node metastasis and that the median survival of those patients for whom follow-up information was available was only 8.2 months indicates that mesotheliomas with pleomorphic features are associated with highly aggressive clinical behavior. Therefore, when this subtype of epithelioid mesothelioma is present, it should be reported as it can significantly affect the prognosis and treatment of the patient.


Structural organization of avian retrovirus integrase in assembled intasomes mediating full-site integration.
Retrovirus preintegration complexes (PIC) purified from virus-infected cells are competent for efficient concerted integration of the linear viral DNA ends by integrase (IN) into target DNA (full-site integration). In this report, we have shown that the assembled complexes (intasomes) formed in vitro with linear 3.6-kbp DNA donors possessing 3'-OH-recessed attachment (att) site sequences and avian myeloblastosis virus IN (4 nm) were as competent for full-site integration as isolated retrovirus PIC. The att sites on DNA with 3'-OH-recessed ends were protected by IN in assembled intasomes from DNase I digestion up to approximately 20 bp from the terminus. Several DNA donors containing either normal blunt-ended att sites or different end mutations did not allow assembly of complexes that exhibit the approximately 20-bp DNase I footprint at 14 degrees C. At 50 and 100 mm NaCl, the approximately 20-bp DNase I footprints were produced with wild type (wt) U3 and gain-of-function att site donors for full-site integration as previously observed at 320 mm NaCl. Although the wt U5 att site donors were fully competent for full-site integration at 37 degrees C, the approximately 20-bp DNase I footprint was not observed under a variety of assembly conditions including low NaCl concentrations at 14 degrees C. Under suboptimal assembly conditions for intasomes using U3 att DNA, DNase I probing demonstrated an enhanced cleavage site 9 bp from the end of U3 suggesting that a transient structural intasome intermediate was identified. Using a single nucleotide change at position 7 from the end and a series of small size deletions of wt U3 att site sequences, we determined that sequences upstream of the 11th nucleotide position were not required by IN to produce the approximately 20-bp DNase I footprint and full-site integration. The results suggest the structural organization of IN at the att sites in reconstituted intasomes was similar to that observed in PIC.


Improved specificity of a new direct assay for urinary cortisol: application in corticoid treated patients.
Twenty four hours urinary free cortisol (UFC) excretion has been determined in 35 eucortisolic control patients, in seven of them before and after tetracosactide (Synacthen) stimulation and in 18 patients treated by anti-inflammatory steroids. Results of the new direct Immunotech RIA (DIm) were compared to those of the INCSTAR RIA kit with (ECA) or without methylene chloride extraction (DCA). In controls DIm UFC (106.2+/-45.8 nmol/24h) was significantly lower than DCA UFC (397+/-119 nmol/24h) and than ECA UFC (127+/-49 nmol/24h). After tetracosactide stimulation, median of DCA/DIm ratio decreased from 3.61 to 1.88 whereas ECA/DIm ratio did not change significantly (1.31 to 1.06). In treated patients most DCA and ECA results were over the upper limit of controls but only 5 DIm results were increased. DIm assay showed good specificity and practicability and may be used with benefit in the evaluation of the adrenal gland function.


Optimisation of region-specific reference gene selection and relative gene expression analysis methods for pre-clinical trials of Huntington's disease.
Transcriptional dysregulation is an early, key pathogenic mechanism in Huntington's disease (HD). Therefore, gene expression analyses have biomarker potential for measuring therapeutic efficacy in pre-clinical trials, particularly those aimed at correcting gene expression abnormalities. Housekeeping genes are commonly used as endogenous references in gene expression studies. However, a systematic study comparing the suitability of candidate reference genes for use in HD mouse models has not been performed. To remedy this situation, 12 housekeeping genes were examined to identify suitable reference genes for use in expression assays. We found that commonly used reference genes are dysregulated at later time points in the R6/2 mouse model of HD. Therefore, in order to reliably measure gene expression changes for use as pre-clinical trial biomarkers, we set out to identify suitable reference genes for use in R6/2 mice. The expression of potential reference genes was examined in striatum, cortex and cerebellum from 15 week old R6/2 and matched wild-type littermates. Expression levels of candidate reference genes varied according to genotype and brain region. GeNorm software was used to identify the three most stably expressed genes for each brain region. Relative quantification methods using the geometric mean of three reference genes for normalisation enables accurate determination of gene expression levels in wild-type and R6/2 mouse brain regions. Our study has identified a reproducible, reliable method by which we able to accurately determine the relative expression level of target genes in specific brain regions, thus increasing the potential of gene expression analysis as a biomarker in HD pre-clinical trials.


Prophylactic sacral protective dressings' effect on preventing pressure injury: A meta-analysis.
We performed a meta-analysis to evaluate the effect of prophylactic sacral protective dressings on preventing pressure injury. A systematic literature search up to July 2021 was performed, and 11 studies included 5150 community or hospital-based adult subjects requiring care at the start of the study; 2832 of them were using sacral protective dressings and 2318 were given standard care with no sacral protective dressings. They were reporting relationships between the effects of prophylactic sacral protective dressings on preventing pressure injury. We calculated the odds ratio (OR) with 95% confidence intervals (CIs) to assess the effects of prophylactic sacral protective dressings on preventing pressure injury using the dichotomous method with a random or fixed-effect model. Sacral protective dressings had a significantly lower incidence of pressure injuries (OR, 0.39; 95% CI, 0.28-0.53, P < .001) compared with standard care with no sacral protective dressings in community- or hospital-based adult subjects requiring care. Sacral protective dressings had a significantly lower incidence of pressure injuries compared with standard care with no sacral protective dressings in community- or hospital-based adult subjects requiring care. Further studies are needed to confirm these findings.


A Retrospective Analysis of the Relationship Between the Result of BRCA1/2 Genetic Testing and Surgical Method Selection in Japan.
We studied the extent of BRCA1/2 genetic testing to help select the surgical approach for patients with breast cancer in Japan remains unclear. The study subjects were female patients with primary unilateral invasive breast cancer considered as candidates for breast-conserving surgery who underwent preoperative BRCA1/2 genetic testing. A retrospective analysis was performed on the results of BRCA1/2 genetic testing and surgical method selection using national registration data from the Japanese Hereditary Breast and Ovarian Cancer Syndrome Consortium. Our study included 318 female patients. Among these patients, 23.7% of patients with BRCA1/2 mutations and 61.8% of patients without these variants underwent breast-conserving surgery (P < .01). Among the patients with BRCA1/2 mutations, those who chose breast-conserving surgery tended not to undergo risk-reducing salpingo-oophorectomy (P < .05). Among the patients with BRCA1/2 mutations who underwent mastectomy for the affected side, 31.8% received contralateral risk-reducing mastectomy. Patients diagnosed with breast cancer under the age of 50 years were more likely to have contralateral risk-reducing mastectomy than patients over the age 50 years (P < .05). Patients with BRCA1/2 mutations tend to choose mastectomy. However, it is speculated that the final surgical method selection is made in consideration of not only the test results but also with careful consideration of the patient, taking into account other factors including individual values for risk-reducing surgeries and the age of breast cancer onset.


Diversity of nifH genotypes in floating periphyton mats along a nutrient gradient in the Florida Everglades.
Periphyton mats are an important component of many wetland ecosystems, performing a range of vital ecosystem functions, including nitrogen fixation. The composition and integrity of these mats are affected by nutrient additions, which might result in changes in their function. The overall objective of this study was to investigate the distribution of nifH sequences in floating periphyton mats collected along a nutrient gradient in the Florida Everglades. Distribution of nifH clone libraries indicated nutrient enrichment selected primarily for sequences branching deeply within the heterocystous cyanobacteria and within a novel group of cyanobacteria; sequences from low-nutrient sites were broadly distributed, with no clear dominance of sequences associated with heterocystous and nonheterocystous cyanobacteria and alpha-, gamma-, and delta-proteobacteria. The dominance of heterocystous cyanobacteria in nutrient-enriched sites and the lack of clear dominance by heterocystous cyanobacteria is consistent with previously reported diurnal cycles of nitrogen fixation rates in these systems. Sequences clustering with those harbored by methanotrophs were also identified; sequences from nutrient-impacted and transition regions clustered with those characteristic of type II methanotrophs, and sequences from oligotrophic regions clustered with type I methanotrophs.


Proteomic analysis of liver in diet-induced Hyperlipidemic mice under Fructus Rosa roxburghii action.
Fructus Rosae Roxburghii (FRR) has been considered as edible and medicinal fruit possessing antiatherosclerotic effect, but the mechanism is still unclear. HLP is material basis for AS formation. Under FRR action, TC, TG, LDL, HDL and ASI in serum were regulated to control level. Differentially expressed proteins in liver were analyzed by using TMT labeling and LC-MS/MS for better understanding the effect and molecular mechanism of FRR on diet-induced hyperlipidemic mice. In total, 4460 proteins were quantified, of which 469 proteins showed dramatic changes between each group. According to molecular functions, 25 differentially co-expressed proteins were divided into five categories: substance metabolism, energy transformation and signal transduction, transcription and translation, immune defense. 15 key proteins involved lipids metabolism, which were identified as Cyp7a1, Cyp3a11, Tm7sf2, COAT2, CSAD, RBP3, Lpin1, Dhrs4, Aldh1b1, GK, Acot 4, TSC22D1, PGFS, EHs, GSTM1. This suggested that FRR could maintain metabolic homeostasis by regulating the metabolism of fatty acids, biosynthesis of BAs and steroids, and production of LPOs. 20 oxidative lipids further confirmed their importance regulating lipids metabolism. It's first time potential antiatherosclerotic mechanism of FRR regulating blood lipids was explored from protein level, which is of great significance to explore new drug targets for AS. SIGNIFICANCE: Under the action of FRR juice, the blood lipids in mice were regulated to control level. By TMT proteomic analysis, the effect and molecular mechanism of FRR on diet-induced hyperlipidemic mice were further explored. 25 differentially co-expressed proteins obtained in three diet groups might cooperatively regulate the lipids metabolism and hepatic function of mice, thus maintaining the metabolism homeostasis. By lipidomics analysis, 20 oxidative lipids further confirmed the importance of ω-3 and ω-6 PUFAs in regulating the lipids metabolism. These findings provide an improved understanding for the regulation of FRR on the blood lipids and explores potential metabolic targets for AS prevention.


Preparation of Fibrinogen-Depleted Human Platelet Lysate to Support Heparin-Free Expansion of Umbilical Cord-Derived Mesenchymal Stem Cells.
Human platelet lysate (hPL) has high levels of fibrinogen and coagulation factors, which can lead to gel and precipitate formation during storage and cell culture. Heparin derived from animals is commonly added to minimize these risks, but cannot completely eliminate them. Thus, this study proposes an alternative method to prepare fibrinogen-depleted hPL (Fd-hPL) that supports heparin-free expansion of mesenchymal stem cells (MSCs). hPL was added to heparin to prepare heparin-hPL (H-hPL), whilst Fd-hPL was prepared by adding calcium salt to hPL to remove the fibrin clot. The concentrations of calcium, fibrinogen, and growth factors in H-hPL and Fd-hPL were compared. The effects of H-hPL and Fd-hPL on umbilical cord-derived MSCs (UC-MSCs) were assessed. The results showed that Fd-hPL possessed a significantly higher calcium concentration and a lower fibrinogen level than H-hPL. The concentrations of BDNF, TGF-β1, and PDGF-BB showed no significant difference between H-hPL and Fd-hPL, but Fd-hPL had a lower VEGF concentration. Fd-hPL retained the characteristics of UC-MSCs, as it did not affect the cell viability, proliferation, multilineage differentiation potential, or surface marker expression. In conclusion, Fd-hPL effectively supported the in vitro expansion of MSCs without compromising their characteristics, positioning it as a potential substitute for FBS in MSC culture.


Modeling the global potential energy surface of the N + N2 reaction from ab initio data.
A new global potential energy surface for the N + N2 exchange reaction has been built from ab initio data. To overcome the difficulty of carrying out ab initio calculations for a large set of geometries the alternative strategy of fitting the minimum energy paths of the surface and their angular dependence using a modified LAGROBO functional form has been adopted. In this way we have been able to reproduce all the main features of the potential using a fairly small set of ab initio values.


The dynamics of deglutition during head rotation using dynamic 320-row area detector computed tomography.
We aimed to elucidate the dynamics of deglutition during head rotation by acquiring 320-row area detector computed tomography (320-ADCT) images and analyzing deglutition during head rotation. This study included 11 patients experiencing globus pharyngeus. A 320-ADCT was used to acquire images in two types of viscosity (thin and thick), with the head rotated to the left. We measured the movement time of deglutition-related organs (soft palate, epiglottis, upper esophageal sphincter [UES], and true vocal cords) and pharyngeal volume (bolus ratio at the start of UES opening [Bolus ratio], pharyngeal volume contraction ratio [PVCR], and pharyngeal volume before swallowing [PVBS]). A two-way analysis of variance was performed for statistical analysis, and all items were compared for significant differences in terms of head rotation and viscosity. EZR was used for all statistical analyses (p-value <.05). Head rotation significantly accelerated the onset of epiglottis inversion and UES opening compared with no head rotation. The duration of epiglottis inversion with the thin viscosity fluid was significantly longer. The bolus ratio increased significantly with thick viscosity. There was no significant difference in viscosity and head rotation in terms of PVCR. PVBS increased significantly with head rotation. The significantly earlier start of epiglottis inversion and UES opening due to head rotation could be caused by: (1) swallowing center; (2) pharyngeal volume; and (3) pharyngeal contraction force. Thus, we plan to further analyze swallowing with head rotation by combining swallowing CT with manometry and examine its relationship with pharyngeal contraction force. 3b.


Acute rheumatic fever in children in the Ankara area in 1990-1992 and comparison with a previous study in 1980-1989.
Two hundred and twenty-eight patients with acute rheumatic fever (ARF), who were admitted to Dr Sami Ulus Children's Hospital between January 1990 and November 1992, were evaluated. Compared with the 1980s, an increase in the frequency of the disease was observed. The majority of patients (56.5%) were between 9 and 12 years old and 36.8% were admitted in winter. One hundred patients had arthritis only, 59 carditis and 40 chorea; 5 had carditis and chorea and 24 had arthritis and carditis. Nineteen percent of patients had a history of a previous attack. Seven of 84 patients with carditis had congestive heart failure and 2 had pericarditis. Cardiomegaly was present in 36 patients. The mitral valve was affected in 77 patients, tricuspid valve in 1 patient and both miral and aortic valves in 6 patients. One patient died as a result of severe congestive cardiac failure. Twenty-one patients had a recurrent attack. We observed that ARF is still a significant cause of morbidity in our country. As the disease is preventable by the eradication of streptococcus, we conclude that more effort should be made in the early detection and treatment of streptococcal infections.


Spontaneous lateral pontine hemorrhage with associated trigeminal nerve root hematoma.
Spontaneous hemorrhage into the lateral part of the pons with sequelae compatible with survival has been documented previously. The author describes an unusual case with spontaneous hemorrhage into the lateral pons, with intraneural extension into the right trigeminal nerve root. Radiological features were of an expanding mass of the cerebellopontine angle. The patient was treated surgically with success.


Gender differences in the antinociceptive effect of tramadol, alone or in combination with gabapentin, in mice.
Gender difference in the antinociceptive effect of tramadol and gabapentin (alone or in combination) were investigated in mice. For investigation of acute antinociceptive effect, tramadol and gabapentin were administered to mice by intraperitoneal injection and per os, respectively, and antinociceptive activity was measured by the tail-flick test 30 min after drug administration. For investigation of the development of antinociceptive tolerance to analgesics, mice were injected with tramadol (60 mg/kg), alone or in combination with gabapentin (75 mg/kg), twice daily for seven consecutive days and the tail-flicks were tested on experimental days 1, 3, 5 and 7. Results showed there was a lower ED(50) value of tramadol antinociception in males than in females, indicating that females were less sensitive to the drug. Gabapentin produces a limited antinociception in both males and females. The combination of gabapentin and tramadol produced synergistic effect without gender difference. Repeated administration of tramadol produced antinociceptive tolerance in both genders. Gabapentin produced synergistic effect in tramadol-tolerant mice and repeated administration of gabapentin did not alter the synergistic effect in tramadol-tolerant mice. Because females show a higher overall prevalence of pain and less sensitivity to opioids, our finding may suggest a clinical significance of combined use of the two drugs.


Fast-Response Turn-on Fluorescent Probes Based on Thiolysis of NBD Amine for H2 S Bioimaging.
Hydrogen sulfide (H2 S) is an important endogenous signaling molecule with multiple biological functions. New selective fluorescent turn-on probes based on fast thiolyling of NBD (7-nitro-1,2,3-benzoxadiazole) amine were explored for sensing H2 S in aqueous buffer and in living cells. The syntheses of both probes are simple and quite straightforward. The probes are highly sensitive and selective toward H2 S over other biologically relevant species. The fluorescein-NBD-based probe showed 65-fold green fluorescent increase upon H2 S activation. The rhodamine-NBD-based probe reacted rapidly with H2 S (t1/2 ≈1 min) to give a 4.5-fold increase in red fluorescence. Moreover, both probes were successfully used for monitoring H2 S in living cells and in mice. Based on such probe-based tools, we could observe H2 O2 -induced H2 S biogenesis in a concentration-dependent and time-dependent fashion in living cells.


Psychological therapies for recipients of implantable cardioverter defibrillators.
Implantable Cardioverter Defibrillators (ICDs) are an increasingly common therapy for the treatment of ventricular arrhythmias. Whereas most ICD recipients adjust well to living with the implant, a substantial minority suffer anxiety, depression, and anger that appears to be related to the ICD. A large number of studies have reported on the incidence of psychopathology and common psychosocial problems among patients with ICDs, however very few psychological interventions with this cohort have been reported. In an extensive literature search we identified only a handful of studies that described outcomes of psychological interventions, and most of these were in pilot form. Only one randomized controlled study with a homogenous sample of ICD patients has been reported to date. Given the unique situation of patients with ICDs and the particular vulnerability of those who experience frequent shocks, the evaluation of interventions that may improve psychological adjustment within this group would appear a worthwhile endeavor.


Corticosteroid binder IB: a model of glucocorticoid receptor diversity.
Corticosteroid binder IB is a glucocorticoid receptor present in rat liver, kidney cortex and proximal colon. It is characterized by a lower molecular weight than the traditional and widely distributed glucocorticoid receptor II. The two receptors also differ in charge, affinity towards various steroids and potency of binding to DNA, nuclei and homodeoxypolymers. The in vivo and in vitro production of binder IB is not affected by protease inhibitors, nor can IB be produced by RNase digestion or proteolytic cleavage of binder II or its precursor molecule. The presumptive physiological role of corticosteroid binder IB and the implied biological significance of receptor diversity are discussed.


Pharmacokinetics and Safety of iGlarLixi in Healthy Chinese Participants: Results of a Phase 1 Randomized Study.
The Chinese Diabetes Society recommends basal insulin and glucagon-like peptide-1 receptor agonists as an add-on therapy to first-line oral antihyperglycemic drugs for people with type 2 diabetes (T2D). Fixed-ratio combination of insulin glargine 100 U/ml (iGlar) and lixisenatide (iGlarLixi) is known to improve glycemic control in adults with T2D. However, the pharmacokinetics of iGlarLixi has not been evaluated in Chinese participants. The present study evaluated pharmacokinetics and safety of two iGlarLixi (10 U/10 μg and 30 U/15 μg) doses following single subcutaneous administration in healthy Chinese participants. This was a Phase 1, single-center, open-label, parallel-group, randomized study in healthy Chinese adults who were randomized to receive a single dose of iGlarLixi with either 1:1 (10 U/10 μg) or 2:1 (30 U/15 μg) ratio of iGlar and lixisenatide. Primary objectives include assessment of pharmacokinetics of iGlar in iGlarLixi 30 U/15 μg group and the pharmacokinetics of lixisenatide in both the groups (iGlarLixi 10 U/10 μg and iGlarLixi 30 U/15 μg). Safety and tolerability were also assessed. In iGlarLixi 30 U/15 μg group, iGlar concentrations were low and quantifiable in three of ten participants, while its main metabolite (M1) was quantifiable in all participants, reflecting rapid conversion of iGlar to M1. Median INS-tmax was 14.00 h for iGlar and 13.00 h post-dose for M1. Absorption of lixisenatide was similar in both dose groups with median tmax of 3.25 and 2.00 h post-dose in both groups. The exposure increase was dose proportionate with a 1.5-fold increase in the lixisenatide dose. Adverse events observed were consistent with those previously reported with iGlar or lixisenatide. iGlarLixi administration resulted in early absorption of both iGlar and lixisenatide with a good tolerability profile in healthy Chinese participants. These results are consistent with the previously published data from other geographic regions. U1111-1194-9411.


The block of thyroglobulin synthesis, which occurs upon transformation of rat thyroid epithelial cells, is at the transcriptional level and it is associated with methylation of the 5' flanking region of the gene.
Transformation of rat thyroid epithelial cells by Kirsten murine sarcoma virus results in the block of certain thyroid differentiated functions, such as synthesis and secretion of thyroglobulin. Our studies, performed by a run-on assay, demonstrate that this block occurs at the transcriptional level. We also demonstrate the de novo methylation of two methylation-sensitive sites, located within the 5' end regulatory sequences of the thyroglobulin gene, in transformed cells, in the absence of any rearrangement of the gene. These two methylation-sensitive sites were methylated also in a rat thyroid cell line transformed by another retrovirus and in two normal cell lines which do not express the thyroglobulin gene.


Sjögren SER: National registry of the Spanish Society of Rheumatology of patients with primary Sjögren syndrome: Objectives and methodology.
To describe the objectives and methods of the Spanish Society of Rheumatology primary Sjögren syndrome (pSS) registry (SJOGREN-SER) METHODS: This is a multicenter descriptive transversal study of a cohort of pSS patients fulfilling European/American consensus criteria collected from Rheumatology clinics all over Spain. Patients were included by randomisation from an anonymised list provided by every department. Data were collected by reviewing clinical records and an interviewing the patients. Two hundred and ninety eight variables were investigated: epidemiological, clinical, serological characteristics, treatments and complications. Informed consent was obtained and local ethics committees approved the study. Variables were analysed by descriptive statistical methods, using means, medians, and rates, with their deviations and interquartile ranges (p25-p75). A total of 3 rheumatology departments participated in the registry. A total of 437 patients were included. And 95% of them were women, with a median age of 58. Median age at pSS 's diagnosis was 50 years. Dryness symptoms (95%) were the most frequent complaint and anti-Ro/SS-A were present in 94% of the cases. Only 27% of the patients fulfilled the new 2012 SICCA-ACR classification criteria. SJOGREN-SER has been designed in order to characterize a representative pSS Spanish cohort, in clinical daily practice, to analyze the magnitude and distribution of its manifestations, activity, accumulated damage and therapeutic management of the disease. This will allow broadening the knowledge of this disease and plan strategies of action in pSS.


Anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody positivity in 884 patients with burning mouth syndrome.
Burning mouth syndrome (BMS) is characterized by burning sensation of the oral mucosa in the absence of clinically apparent oral mucosal alterations. This study evaluated the anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity in 884 BMS patients. The blood hemoglobin (Hb) and serum iron, vitamin B12, folic acid, homocysteine, GPCA levels in 884 BMS patients were measured and compared with the corresponding levels in 442 age- and sex-matched healthy control subjects. We found that 175 (19.8%), 143 (16.2%), 42 (4.8%), 20 (2.3%), 170 (19.2%), and 109 (12.3%) BMS patients had blood Hb, serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity, respectively. Moreover, 884 BMS patients had significantly higher frequencies of blood Hb and serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity than 442 healthy control subjects (all P-values < 0.005). Of 175 anemic BMS patients, 95 had normocytic anemia, 27 had thalassemia trait-induced anemia, 21 had iron deficiency anemia, 15 had pernicious anemia, 15 had macrocytic anemia other than pernicious anemia, and 2 had microcytic anemia other than iron deficiency anemia and thalassemia trait-induced anemia. Burning sensation of oral mucosa (100.0%), dry mouth (48.1%), numbness of oral mucosa (30.7%), and dysfunction of taste (16.7%) were the four common symptoms in 884 BMS patients. BMS patients have significantly higher frequencies of blood Hb and serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity than healthy control subjects.