Intraoperative air leak test reduces the rate of postoperative anastomotic leak: analysis of 777 laparoscopic left-sided colon resections.
The evidence supporting the use of the air leak test (ALT) after laparoscopic left-sided colon resection (LLCR) to test the colorectal anastomosis (CA) integrity aiming at reducing the rate of postoperative CA leakage (CAL) is not conclusive. The aim of this study was to challenge the use of ALT after elective LLCR. It is a retrospective analysis of a prospectively collected database including all patients undergoing elective LLCR with primary CA and no proximal bowel diversion between January 1996 and June 2017. The decision to perform the ALT was based on the individual surgeon routine practice. A multivariate analysis was performed to identify independent risk factors for CAL. A total of 777 LLCR without proximal diversion were included in the analysis: the CA was tested in 398 patients (ALT group), while intraoperative ALT was not performed in 379 patients (No-ALT group). The two groups were similar in demographic characteristics, indication, and type of procedure. Intraoperative ALT was positive in 20 (5%) patients: a stoma was created in 14 (70%) patients, while 6 (30%) patients had a suture repair alone. Overall, postoperative CAL occurred in 32 patients (4.1%): the postoperative CAL rate was lower in ALT patients (2.5% vs. 5.8%, p = 0.025). A reoperation was needed in 87.5% of cases. No CAL occurred in the 20 patients with intraoperative positive ALT. Multivariate analysis showed that ASA score 3-4 (OR 5.39, 95% CI 2.53-11.51, p < 0.001) and male sex (OR 3.96, 95% CI 1.66-9.43, p = 0.002) were independent risk factors for postoperative CAL, while intraoperative ALT independently reduced the postoperative CAL rate (OR 0.40, 95% CI 0.18-0.88, p = 0.022). Intraoperative ALT allows to detect AL defects after LLCR that can be effectively managed intraoperatively, leading to a significant lower risk of postoperative CAL.


Studies on rat liver microsomal steroid metabolism using 18O-labelled testosterone and progesterone.
In order to investigate the possible involvement of oxygen functions in the rat liver microsomal metabolism of progesterone and testosterone these steroids were specifically labelled with 18O in their oxo-functions and incubated with NADPH supplemented 105,000 g sediments. Gas chromatography-mass spectrometry was used to identify the metabolites formed as well as to quantitate the losses of 18O-label. With 18O-labelled testosterone as substrate two of the major monohydroxylated metabolites, i.e. 2 beta- and 6 beta-hydroxytestosterone were shown to have lost about 25 and 50% of their 18O respectively. A complete retention of label was found in 7 alpha- and 16 alpha-hydroxytestosterone. None of the monohydroxylated progesterone metabolites, i.e. the 2 alpha-, 6 beta- and 16 alpha-hydroxyprogesterone had lost any 18O following incubation with 3,20-18O-labelled progesterone. Control incubation (30', 37 degrees C) with buffer and 18O-labelled progesterone and testosterone revealed no exchange of 18O. Thus the partial loss of 3-18O-label during 2 beta- and 6 beta-hydroxylation of testosterone may indicate a covalent interaction between the steroid 3-oxo-group and one or more cytochrome P-450 species in the rat liver microsomes. In view of the potentiating effect of a 3-imine group in spontaneous 6 beta-hydroxylation the present in vitro data suggest that a steroid protein-interaction may occur via a 3-imine group during 6 beta-hydroxylation of testosterone in rat liver microsomes. Analysis of 5 alpha-reduced metabolites of both progesterone and testosterone showed significant losses of 3-18O, but due to the ease with which 3-oxo-5 alpha-steroids exchange their 3-18O with aqueous media an enzymatically induced loss of 3-18O could not be safely established. The 20-oxido-reductase which converted progesterone did not induce a loss of 20- or 3-18O thus indicating that the oxofunctions were not covalently engaged in the enzymatic binding of the steroid.


The organization of GABAergic neurons in the mammalian superior colliculus.
GABA is an important inhibitory neurotransmitter in the mammalian superior colliculus. As in the lateral geniculate nucleus, GABA immunoreactive neurons in SC are almost all small and are distributed throughout the structure in all mammalian species studied to date. Unlike the LGN, GABA-labeled neurons in SC have a variety of morphologies. These cells have been best characterized in cat, where horizontal and two granule cell morphologies have been identified. Horizontal cells give rise to one class of presynaptic dendrite while granule C cells give rise to another class of spine-like presynaptic dendrite. Granule A cells may be the origin of some GABAergic axon terminals. GABA containing synaptic profiles form serial synapses, providing a possible substrate for disinhibition. The distribution of GABAA and GABAB receptor subtypes appears similar to that of GABA neurons, with the densest distribution found within the superficial gray layer. However, antibody immunocytochemistry of the beta 2 and beta 3 subunits of the GABAA receptor reveals that it is located at both synaptic and non-synaptic sites, and may be associated with membrane adjacent to terminals with either flattened or round vesicles. A few GABA containing neurons in SC colocalize the pentapeptide leucine enkephalin or the calcium binding protein calbindin. However, none appear to co-localize parvalbumin, a situation different from GABA containing interneurons in the LGN and visual cortex. The diversity of GABA neurons in SC rivals that found in visual cortex, although unlike visual cortex, the pattern of co-occurrence does not distinguish GABA cell types in SC. The superior colliculus also differs from both LGN and visual cortex in that GABA and calbindin immunoreactivity is not altered by either long-term occlusion and/or short-term enucleation in adult Rhesus monkeys. No consistent differences have been found in the optical density of GABA labeling in either cells or neuropil. To conclude, GABA neurons in the superior colliculus share some properties like those in LGN and others like those in visual cortex. In other properties, they differ from GABA neurons in both the LGN and visual cortex. The GABA systems in the superior colliculus are similar in all mammalian species studied, suggesting that they are phylogenetically conserved systems which are not amenable to plastic alterations, a situation different to that in the geniculostriate system.


Scale insect species names that have been combined with the genus name Dactylopius Costa (Hemiptera: Sternorrhyncha: Coccomorpha).
The genus Dactylopius is the only genus at present in the family Dactylopiidae. Since the name Dactylopius was proposed in 1829, however, numerous other species names belonging to different families of scale insects have been combined with it and these are also listed. The present status and the family placement are also given for each species.


The microsurgical treatment of lumbar disc protrusion. Follow-up of 60 cases.
The technique and results of microsurgical techniques for lumbar disc protrusions in 60 patients are presented. All patients were followed up for a minimum of 2.5 years, and 91% had good or excellent results. The only patient with a recurrent disc sequestration had a good result after a second operation.


Protection or police harassment? Impacts of punitive policing, discrimination, and racial profiling under end-demand laws among im/migrant sex workers in Metro Vancouver.
In 2014, Canada implemented end-demand sex work legislation which leaves the sale of sex under some circumstances legal. However, immigration policies based on discourses positioning sex work as exploitation and migration as trafficking continue to criminalize many im/migrant sex workers. Despite community reports of punitive policing, limited research has explored how police interactions with im/migrant sex workers have impacted labour conditions since this legislative shift. As part of a longstanding community-based Vancouver study, we drew on the conceptual framework of slow violence to analyze 20 in-depth interviews with sex workers born outside Canada. Despite rhetoric positioning im/migrant sex workers as victims deserving protection, participants described experiences of punitive, racialized, and stigmatizing police treatment. Fear of being 'outed' as a sex worker and living with precarious immigration status undermined participants' ability to seek police protections; yet when they did seek assistance after experiencing violence/theft, police were unsupportive or discriminatory. Our findings suggest that policies depicting im/migrant sex workers as victims act not to protect them, but to justify targeted repressive, racist policing that severely undermines women's occupational safety. Our results illustrate the harms of policies conflating sex work with trafficking; demonstrate the inherent opposition between legislative aims to protect those who sell sexual services and to abolish the sex industry; and interrogate who the state affirms as a deserving victim. The full decriminalization of sex work, removal of prohibitions on sex work among im/migrants, and community-led alternatives to the criminal justice system are urgently needed to uphold im/migrant sex workers' labour rights.


Studies of hormone-sensitive and -insensitive pools of phosphoinositides in cultured bovine zona fasciculata/reticularis cells. Evidence that acetylcholine and angiotensin II stimulate the breakdown of a common pool of phosphoinositides.
The effects of acetylcholine (ACh) and manganese pre-incubation on angiotensin II (AII)-stimulated incorporation of [3H]inositol into phosphoinositide, phosphoinositol and free inositol fractions of adrenocortical cells isolated from the bovine zona fasciculata/reticularis (zfr) were investigated. In cells pre-labelled for 6 hr with [3H]inositol, ACh and AII stimulated the incorporation of cytosolic [3H]inositol into a common hormone-sensitive pool of phosphoinositides, which was distinct from the non-hormone-sensitive pool labelled in the presence of manganese. Regression analysis of the cortisol versus [3H]inositol headgroup responses for both AII (10(-11)-10(-7) M) and ACh (10(-9)-10(-3) M) showed that the gradients of these responses were not significantly different. These data provide strong evidence that in cultured bovine zfr cells, ACh and AII stimulate the breakdown and resynthesis of a common pool of phosphoinositides.


Management of teeth with open apexes and necrotic pulps: representative cases.
This paper briefly reviews the pros and cons of five methods used to treat a tooth with a necrotic pulp and an open apex (incompletely developed root), and presents representative treatments of open apex cases. These treatments include customized cone, short-fill, periapical surgery, apexification, and one-visit apexification.


A study on the representation of mental disorders in Turkish newspapers.
Newspapers that address mental disorders affect health care positively or negatively and can affect the public's perspective with the way they explain mental disorders. To examine the representation of news about mental disorders published in Turkish newspapers. Using the document analysis method, 230 news about mental disorders published in the six most read newspapers in 2022 were examined. It has been concluded that the descriptive characteristics of individuals with mental disorders are often stated, schizophrenia and psychotic disorders are mentioned most, mental disorders are associated with delinquency and violent behaviour, these people are mostly represented by being detained as a result of the events, and negative concepts are frequently used in newspaper reports. Five sub-themes were determined under the main theme of "Negative Concepts": "Exaggerated Discourses", "Stigmatizing Discourses", "Discourses Targeting Mental Health", "Discourses That May Cause Negative Emotions", "Discourses Containing Misdescription". Newspaper items about mental disorders are represented as stigmatizing and misleading by using negative concepts. The sensitivity of media workers, the development of mental health policies and cooperation with mental health workers contribute to the recovery process of individuals with mental disorders.


The effect of pegylated interferon-alpha2b and ribavirin on posttraumatic stress disorder symptoms.
Patients with chronic psychiatric diagnoses have a prevalence of chronic hepatitis C (HCV) approximately 11 times higher than the general American population. Posttraumatic stress disorder (PTSD) is particularly common among HCV patients. The authors describe the effect of treatment with pegylated-interferon-alpha(2b) (IFN) and ribavirin for patients with HCV on their posttraumatic stress disorder (PTSD) symptoms. Sixteen patients with HCV and combat-related PTSD were followed for 24 weeks and assessed with self-report measures of PTSD, hostility, and depression. Depression and Resentment scores significantly increased in five patients treated with IFN and ribavirin, but no significant differences were found in PTSD scores when compared with 11 control patients. The results suggest that patients with PTSD and HCV can be safely treated with anti-viral therapies when they are given appropriate psychiatric care.


On symmetries, resonances and photonic crystals in morphogenesis.
Biological symmetries, theories of the morphogenetic field, resonant interactions and the role of photons in morphogenetic processes represented the main fields of interest of Lev Beloussov and his followers. This review article includes some results of our study on the important role of resonances and photonic crystals in genetic informatics. Mathematical formalisms of differential Riemannian geometry and tensor analysis are used for modeling inherited curved surfaces in biomorphology and for understanding conformal bio-symmetries connected with the networks of curvature lines of surfaces. Notions of a morpho-resonance field as one of variants of morphogenetic fields are discussed. The connection of the golden section with the Fibonacci matrix of growth used in morphogenetic models of phyllotaxis is shown. Photonic crystals are considered as important participants of organisation of molecular-genetic informatics.


[Truncal mechanochemical versus thermal endovenous ablation for varicose vein disease: a systematic review and meta-analysis].
To compare the outcomes of thermal and mechanochemical endovenous ablative techniques in patients with varicose veins. We searched the PubMed, EMBASE and Cochrane Library databases for studies devoted to mechanochemical and thermal endovenous ablative techniques from inception until July 2021. The primary outcome was anatomical success. Secondary endpoints were intraoperative pain syndrome, complications, modification of disease severity and quality of life. This meta-analysis enrolled 10 comparative studies and 1.252 participants after truncal ablations. The follow-up period ranged from 4 weeks to 36 months. With regard to overall anatomical success, 245 out of 267 (91.8%) patients after mechanochemical ablation and 249 out of 266 (93.6%) patients after thermal ablation had favorable results after a month (low-quality evidence; odds ratio [OR] 0.79; 95% CI 0.40-1.55). No statistical heterogeneity was identified (χ2=1.48; df=2; p=0.48; I2=0%). Further analysis identified different incidence of total occlusion after 12 months or later (OR 0.36; 95% CI 0.11-1.21; p=0.05; I2=68%). Mechanochemical ablation resulted less intraoperative pain. Mean difference was -1.3 (95% CI -2.53- -0.07; p=0.00001). MOCA was followed by fewer incidence of nerve injury, hematoma, deep vein thrombosis and phlebitis. There were more cases of skin pigmentation compared to thermal ablation (low-quality evidence, p>0.05). Subsequent assessment of disease severity identified significant between-group difference of means (-0.64 (95% CI -1.82-0.53; p=0.004) and -0.16 (95% CI -0.43-0.11; p=0.005) after 6 and 12 months, respectively). Further assessment of quality of life revealed no between-group differences. These data were characterized by moderate methodological quality. Mechanochemical ablation is as effective as standard TA within the first postoperative month. However, this approach is associated with lesser anatomical success after 12 months. In most studies, pain syndrome was less severe in case of mechanochemical ablation. These data suggest that mechanochemical ablation is a safe alternative for varicose veins. However, further large-scale trials are required to define the role of MOCA.


Adiponectin and human pregnancy.
Adiponectin is an adipose tissue-derived plasma protein that is involved in regulation of insulin resistance and glucose hemostasis. Human pregnancy is characterized by an increase in insulin resistance. Therefore, it is only natural that the role of adiponectin, a modulator of insulin resistance, is subject to investigation during gestation. Furthermore, conditions associated with increased insulin resistance, such as gestational diabetes and preeclampsia, may be influenced by this hormone. Adiponectin, a key modulator of insulin action and glucose metabolism, both known to regulate fetal growth, is a plausible candidate for regulation of intrauterine fetal development. In this review, we summarize the recent studies describing the relationship between adiponectin, pregnancy, and fetal growth.


Brain stem auditory evoked potentials: reduction of evaluation errors.
The commonly used method of BAER evaluation is measuring the latency to the extreme points of the components. Because of the influence of noise it is sometimes impossible to determine precisely the true top of the peak. It is possible to avoid this defect by estimating the latency to the middle of the peak front. In this research S.D.s for both methods of evaluation were calculated for all interpeak intervals. According to the obtained data the use of the middle of the front of the peak for the latency evaluation gave 24% reduction in S.D.s.


Research progress and perspective in metabolism and metabolomics of psoriasis.
Psoriasis is considered a systemic disease associated with metabolic abnormalities, and it is important to understand the mechanisms by which metabolism affects pathophysiological processes both holistically and systematically. Metabolites are closely related to disease phenotypes, especially in systemic diseases under multifactorial modulation. The emergence of metabolomics has provided information regarding metabolite changes in lesions and circulation and deepened our understanding of the association between metabolic reprogramming and psoriasis. Metabolomics has great potential for the development of effective biomarkers for clinical diagnosis, therapeutic monitoring, prediction of the efficacy of psoriasis management, and further discovery of new metabolism-based therapeutic targets.


Epidural hematoma of the newborn due to birth trauma.
Epidural hematoma due to birth trauma is unusual. The presentation is similar to subdural hematoma in the newborn, but the results of subdural puncture may be normal. The CT scan is diagnostic and early surgical evacuation may be lifesaving.


Gating the photochromism of an azobenzene by strong host-guest interactions in a divalent pseudo[2]rotaxane.
The ability of an E-configured azobenzene guest to undergo photoisomerisation is controlled by the presence of a complementary host. Addition of base/acid allowed for a weakening/strengthening of the interactions in the divalent pseudo[2]rotaxane complex and hence could switch on/off photochromic activity.


Respiration rates and population metabolism of woodland snails.
Experiments were done to measure the respiration rates of twenty species of terrestrial snail. Acclimatization phenomena were sought in two species, Discus rotundatus and Hygromia striolata, but not detected. The Q 10s between 5 and 15° C for the twenty species varied between 1.20 and 4.27, with a mean Q 10 of 2.21. Q 10 was higher in larger snail species. There was an increase in respiration with body weight for those species which grew to a large size, but the trend was not detectable in species with small adult weight. A double log plot of mean respiration rate of each species against the mean weight of each species gave a linear relationship.Mean monthly leaf litter temperature was measured in a beech woodland site in Wytham Woods, Berkshire. Litter temperature, in combination with snail population data and size class distribution, was used to calculate population metabolism of the snails on the site. Annual population metabolism amounted to 7.0934 kcals/m2/annum. The estimated annual production was 4.4386 kcals/m2. The P/R ratios varied between 0.143 and 1.861, P/B ratios varying from 1.0 to 34.3. From the data it is suggested that respiration alone will not give a good measure of the importance of different species in litter breakdown.


Association Between the Deletion Allele of Ins/Del Polymorphism (Rs145204276) in the Promoter Region of GAS5 with the Risk of Atherosclerosis.
LncRNA is a growth arrest-specific transcript 5 (GAS5) with tumor suppressor activities in some cancers, but its role in atherosclerosis is unclear. Bioinformatics algorithm analysis was utilized to search the target of GAS5 and miR-21, followed by luciferase assay to confirm these targets. Real-time PCR and western-blot were utilized to verify the connection among GAS5, miR-21 and Programmed cell death 4 (PDCD4). MTT assay and flow cytometry analysis were performed to explore the mechanism of GAS5 in the regulation of atherosclerosis. GAS5 directly targets miR-21 and functions as a competing endogenous RNA to suppress miR-21 expression. We also observed that rs145204276 polymorphism, including INS/INS and DEL/DEL, on GAS5 promoter increased transcription activity of GAS5, but the presence of rs145204276 DEL/DEL allele significantly promoted the transcription of GAS5 promoter compared with rs145204276 INS/INS allele. PDCD4 was predicted as a direct target gene of miR-21 with a binding site on PDCD4 3'UTR. It was further confirmed by luciferase assay that miR-21 significantly reduced the luciferase activity of wild-type PDCD4 3'UTR but not that of mutant PDCD4 3'UTR. In addition, high glucose significantly inhibited the growth rate of EC genotyped as DEL/DEL or INS/ INS, and apparently promoted the apoptotic rate of either DEL/DEL or INS/INS genotype ECs. Furthermore, the effect of high glucose was stronger in the INS/INS group, while the expression of GAS5 was dramatically upregulated with the presence of GAS5 DEL/DEL, while GAS5 positively regulated PDCD4 expression via inhibiting miR-21 expression. GAS5 siRNA and miR-21 mimics significantly decreased GAS5 and PDCD4 expressions, and the inhibitory effects of GAS5 siRNA or miR-21 mimics on GAS5 and PDCD4 expressions in the INS/INS group was stronger. Moreover, GAS5 siRNA and miR-21 mimics remarkably triggered cells proliferation and suppressed cell apoptosis, and the inhibition effects of GAS5 siRNA or miR-21 mimics on either cell viability and apoptosis in the INS/INS group was stronger. In this study, we enrolled 1,306 subjects with or without atherosclerosis and found that the INS/DEL or DEL/DEL genotypes significantly decreased the risk of atherosclerosis compared with the ins/ins genotype (adjusted odds ratio: 0.74 and 0.40, respectively). In summary, rs145204276 was associated with the risk of atherosclerosis by affecting the proliferation and apoptosis of endothelial cells via regulating the GAS5/miR-21/PDCD4 signaling pathway.


Human Tissue Kallikrein Activity in Angiographically Documented Chronic Stable Coronary Artery Disease.
Human tissue kallikrein (hK1) is a key enzyme in the kallikrein-kinin system (KKS). hK1-specific amidase activity is reduced in urine samples from hypertensive and heart failure (HF) patients. The pathophysiologic role of hK1 in coronary artery disease (CAD) remains unclear. To evaluate hK1-specific amidase activity in the urine of CAD patientsMethods:Sixty-five individuals (18-75 years) who underwent cardiac catheterism (CATH) were included. Random midstream urine samples were collected immediately before CATH. Patients were classified in two groups according to the presence of coronary lesions: CAD (43 patients) and non-CAD (22 patients). hK1 amidase activity was estimated using the chromogenic substrate D-Val-Leu-Arg-Nan. Creatinine was determined using Jaffé's method. Urinary hK1-specific amidase activity was expressed as µM/(min · mg creatinine) to correct for differences in urine flow rates. Urinary hK1-specific amidase activity levels were similar between CAD [0.146 µM/(min ·mg creatinine)] and non-CAD [0.189 µM/(min . mg creatinine)] patients (p = 0.803) and remained similar to values previously reported for hypertensive patients [0.210 µM/(min . mg creatinine)] and HF patients [0.104 µM/(min . mg creatinine)]. CAD severity and hypertension were not observed to significantly affect urinary hK1-specific amidase activity. CAD patients had low levels of urinary hK1-specific amidase activity, suggesting that renal KKS activity may be reduced in patients with this disease.


Profiling disease-selective drug targets: From proteomics to ligandomics.
Despite advancements in omics technologies, including proteomics and transcriptomics, identification of therapeutic targets remains challenging. Ligandomics recently emerged as a unique technology of functional proteomics for global profiling of cell-binding protein ligands. When applied to diseased versus healthy vasculatures, comparative ligandomics systematically maps novel disease-restricted ligands that allow selective targeting of pathological but not physiological pathways, providing high efficacy with intrinsic safety. In this review, we discuss the potential of cellular ligands as therapeutic targets and summarize the development of ligandomics. We further compare the advantages and limitations of different omics technologies for drug target discovery and discuss target selection criteria to improve drug R&D success rates.


New dynamic three-dimensional MRI technique for shoulder kinematic analysis.
To establish a new imaging technique using dynamic MRI three-dimensional (3D) volumetric acquisition in real-time, on six normal shoulders for the analysis of the 3D shoulder kinematics during continuous motion. At first, a standard static acquisition was performed. Then, fast images were obtained with a multi-slice 3D balanced gradient echo sequence to get a real time series during the initial phase of shoulder abduction. Subsequently, the images were reconstructed; registered and the translational patterns of the humeral head relative to the glenoid and the size of the subacromial space were calculated. Additionally, the intraobserver reproducibility was tested. The maximal abduction was on average 43° (30° to 60°) and the mean width of the subacromial space was 7.7 mm (SD: ±1.2 mm). Difference between extreme values and average values was low, respectively 2.5 mm on X-axis, 2 mm on Y-axis, 1.4 mm for the width of the subacromial space and 1.2° for the measure of the glenohumeral abduction. This study reported a dynamic MRI protocol for the monitoring of shoulder 3D kinematics during continuous movement. The results suggest that there is no superior shift of the humeral head during the first phase of abduction.


Elements in the C terminus of apolipoprotein [a] responsible for the binding to the tenth type III module of human fibronectin.
In previous studies, we showed that the C-terminal domain, F2, but not the N-terminal domain, F1, is responsible for the binding of apolipoprotein [a] (apo[a]) to human fibronectin (Fn). To pursue those observations, we prepared, by both elastase digestion and recombinant technology, subsets of F2 of a different length containing either kringle (K) V or the protease domain (PD). We also studied rhesus monkey apo[a], which is known to contain PD but not KV. In the case of Fn, we used both an intact product and its tenth type III module (10FN-III) expressed in Escherichia coli. The binding studies carried out on microtiter plates showed that the affinity of F2 for immobilized 10FN-III was approximately 6-fold higher than that for Fn (dissociation constants = 1.75 +/- 0.31 nM and 10.25 +/- 1.62 nM, respectively). The binding was also exhibited by rhesus apo[a] and by an F2 subset containing the PD linked to an upstream microdomain comprising KIV-8 to KIV-10 and KV, inactive by itself. Competition experiments on microtiter plates showed that both Fn and 10FN-III, when in solution, are incompetent to bind F2. Together, our results indicate that F2 binds to immobilized 10FN-III more efficiently than whole Fn and that the binding can be sustained by truncated forms of F2 that contain the catalytically inactive PD linked to an upstream four K microdomain.


Invasive group A streptococcal disease in pregnant women and young children: a systematic review and meta-analysis.
The incidence of invasive disease caused by group A streptococcus (GAS) has increased in multiple countries in the past 15 years. However, despite these reports, to the best of our knowledge, no systematic reviews and combined estimates of the incidence of invasive GAS have been done in key high-risk groups. To address this, we estimated the incidence of invasive GAS disease, including death and disability outcomes, among two high-risk groups-namely, pregnant women and children younger than 5 years. We did a systematic review and meta-analyses on invasive GAS outcomes, including incidence, case fatality risks, and neurodevelopmental impairment risk, among pregnant women, neonates (younger than 28 days), infants (younger than 1 year), and children (younger than 5 years) worldwide and by income region. We searched several databases for articles published from Jan 1, 2000, to June 3, 2020, for publications that reported invasive GAS outcomes, and we sought unpublished data from an investigator group of collaborators. We included studies with data on invasive GAS cases, defined as laboratory isolation of Streptococcus pyogenes from any normally sterile site, or isolation of S pyogenes from a non-sterile site in a patient with necrotising fasciitis or streptococcal toxic shock syndrome. For inclusion in pooled incidence estimates, studies had to report a population denominator, and for inclusion in pooled estimates of case fatality risk, studies had to report aggregate data on the outcome of interest and the total number of cases included as a denominator. We excluded studies focusing on groups at very high risk (eg, only preterm infants). We assessed heterogeneity with I2. Of the 950 published articles and 29 unpublished datasets identified, 20 studies (seven unpublished; 3829 cases of invasive GAS) from 12 countries provided sufficient data to be included in pooled estimates of outcomes. We did not identify studies reporting invasive GAS incidence among pregnant women in low-income and middle-income countries (LMICs) nor any reporting neurodevelopmental impairment after invasive GAS in LMICs. In nine studies from high-income countries (HICs) that reported invasive GAS in pregnancy and the post-partum period, invasive GAS incidence was 0·12 per 1000 livebirths (95% CI 0·11 to 0·14; I2=100%). Invasive GAS incidence was 0·04 per 1000 livebirths (0·03 to 0·05; I2=100%; 11 studies) for neonates, 0·13 per 1000 livebirths (0·10 to 0·16; I2=100%; ten studies) for infants, and 0·09 per 1000 person-years (95% CI 0·07 to 0·10; I2=100%; nine studies) for children worldwide; 0·12 per 1000 livebirths (95% CI 0·00 to 0·24; I2=100%; three studies) in neonates, 0·33 per 1000 livebirths (-0·22 to 0·88; I2=100%; two studies) in infants, and 0·22 per 1000 person-years (0·13 to 0·31; I2=100%; two studies) in children in LMICs; and 0·02 per 1000 livebirths (0·00 to 0·03; I2=100%; eight studies) in neonates, 0·08 per 1000 livebirths (0·05 to 0·11; I2=100%; eight studies) in infants, and 0·05 per 1000 person-years (0·03 to 0·06; I2=100%; seven studies) in children for HICs. Case fatality risks were high, particularly among neonates in LMICs (61% [95% CI 33 to 89]; I2=54%; two studies). We found a substantial burden of invasive GAS among young children. In LMICs, little data were available for neonates and children and no data were available for pregnant women. Incidences of invasive GAS are likely to be underestimates, particularly in LMICs, due to low GAS surveillance. It is essential to improve available data to inform development of prevention and management strategies for invasive GAS. Wellcome Trust.


The glider balloon: a useful device for the treatment of bifurcation lesions.
Final kissing balloon dilatation (FKBD) is a recommended final step in case of treatment of bifurcation lesions by two stents approaches. Furthermore, dilatation of the side branch (SB) may be necessary following main vessel (MV) stenting. Occasionally, recrossing the stent struts with a balloon is hampered because the tip hits a stent strut. The Glider (TriReme Medical, Pleasanton, CA) is a dedicated balloon designed for crossing through struts of deployed stents toward a SB. From October 2010 to January 2012, FKBD was attempted in 236 consecutive bifurcation lesions treated in our Institution. FKBD was successfully performed by conventional balloon catheters in 221 (93.5%) lesions (Conventional group). In the remaining 15 (6.5%) lesions, where a conventional balloon failed to cross the stent strut, the Glider balloon was attempted (Glider group). The angle beta (between the axis of the MV after the branch point and the SB axis at the point of divergence) was wider in the Glider group (83±17° versus 65±27°; p=0.032). A trend toward an higher rate of the true bifurcation lesions was observed in the Glider group (93% versus 70.5%; p=0.07). The Glider balloon successfully crossed through MV stent struts toward a SB in 12 patients (80%), whereas failed in the remaining 3 patients. The Glider balloon represents an unique bail-out device which offers an effective rescue strategy for recrossing stent struts during complex bifurcation stenting.


Draft Genome Sequence of the Extended-Spectrum β-Lactamase-Producing Escherichia coli Isolate INF13/18/A, Recovered from Kelantan, Malaysia.
We describe here the draft genome sequence and basic characteristics of Escherichia coli isolate INF13/18/A, which was isolated from Universiti Sains Malaysia (USM) Hospital. This isolate was identified as an extended-spectrum β-lactamase-producing Escherichia coli strain harboring the antimicrobial resistance genes TEM, CTX-M-1, and CTX-M-9.


Optimization of metabolomic data processing using NOREVA.
A typical output of a metabolomic experiment is a peak table corresponding to the intensity of measured signals. Peak table processing, an essential procedure in metabolomics, is characterized by its study dependency and combinatorial diversity. While various methods and tools have been developed to facilitate metabolomic data processing, it is challenging to determine which processing workflow will give good performance for a specific metabolomic study. NOREVA, an out-of-the-box protocol, was therefore developed to meet this challenge. First, the peak table is subjected to many processing workflows that consist of three to five defined calculations in combinatorially determined sequences. Second, the results of each workflow are judged against objective performance criteria. Third, various benchmarks are analyzed to highlight the uniqueness of this newly developed protocol in (1) evaluating the processing performance based on multiple criteria, (2) optimizing data processing by scanning thousands of workflows, and (3) allowing data processing for time-course and multiclass metabolomics. This protocol is implemented in an R package for convenient accessibility and to protect users' data privacy. Preliminary experience in R language would facilitate the usage of this protocol, and the execution time may vary from several minutes to a couple of hours depending on the size of the analyzed data.


Characterization of Vibrio cholerae O139 synonym Bengal isolated from patients with cholera-like disease in Bangladesh.
Vibrio cholerae O139 (synonym Bengal), a novel serovar of V. cholerae, is the causative agent of large outbreaks of cholera-like illness currently sweeping India and Bangladesh. Eight randomly selected V. cholerae O139 isolates were studied for their biological properties, which were compared with those of V. cholerae O1 and other V. cholerae non-O1. The V. cholerae O139 isolates were characterized by the production of large amount of cholera toxin, hemagglutination, weak hemolytic properties, resistance to polymyxin B, lysogeny with, and production of, kappa type phage (4/8 isolates only), and resistance to both classical and El Tor-specific phages. Thus, V. cholerae O139 isolates had an overall similarity with V. cholerae O1 El Tor.


Arcellacea (testate amoebae) as bio-indicators of road salt contamination in lakes.
Winter deicing operations occur extensively in mid- to high-latitude metropolitan regions around the world and result in a significant reduction in road accidents. Deicing salts can, however, pose a major threat to water quality and aquatic organisms. In this paper, we examine the utility of Arcellacea (testate amoebae) for monitoring lakes that have become contaminated by winter deicing salts, particularly sodium chloride. We analysed 50 sediment samples and salt-related water property variables (chloride concentrations; conductivity) from 15 lakes in the Greater Toronto Area and adjacent areas of southern Ontario, Canada. The sampled lakes included lakes in proximity to major highways and suburban roads and control lakes in forested settings away from road influences. Samples from the most contaminated lakes, with chloride concentrations in excess of 400 mg/l and conductivities of >800 μS/cm, were dominated by species typically found in brackish and/or inhospitable lake environments and by lower faunal diversities (lowest Shannon diversity index values) than samples with lower readings. Q-R-mode cluster analysis and detrended correspondence analysis (DCA) resulted in the recognition of four assemblage groupings. These reflect varying levels of salt contamination in the study lakes, along with other local influences, including nutrient loading. The response to nutrients can, however, be isolated if the planktic eutrophic indicator species Cucurbitella tricuspis is removed from the counts. The findings show that the group has considerable potential for biomonitoring in salt-contaminated lakes, and their presence in lake sediment cores may provide significant insights into long-term benthic community health, which is integral for remedial efforts.


The Resurgent Structure of Quantum Knot Invariants.
The asymptotic expansion of quantum knot invariants in complex Chern-Simons theory gives rise to factorially divergent formal power series. We conjecture that these series are resurgent functions whose Stokes automorphism is given by a pair of matrices of q-series with integer coefficients, which are determined explicitly by the fundamental solutions of a pair of linear q-difference equations. We further conjecture that for a hyperbolic knot, a distinguished entry of those matrices equals to the Dimofte-Gaiotto-Gukov 3D-index, and thus is given by a counting of BPS states. We illustrate our conjectures explicitly by matching theoretically and numerically computed integers for the cases of the 4 1 and the 5 2 knots.


The Wnt/β-Catenin Pathway is Activated as a Novel Nucleolar Stress Response.
Ribosomes are mandatory for growth and survival. The complex process of ribosome biogenesis is located in nucleoli and requires action of the RNA polymerases I-III, together with a multitude of processing factors involved in rRNA cleavage and maturation. Impaired ribosome biogenesis and loss of nucleolar integrity triggers nucleolar stress, which classically stabilizes the tumor suppressor p53 and induces cell cycle arrest and apoptosis. Nucleolar stress is implemented in modern anti-cancer therapies, however, also emerges as contributor to diverse pathological conditions. These include ribosomopathies, such as the Shwachman Bodian Diamond Syndrome (SBDS), which are not only characterized by nucleolar stress, but paradoxically also increased cancer incidence. Wnt signaling is tightly coupled to cell proliferation and is constitutively activated in various tumor types. In addition, the Wnt/β-Catenin pathway regulates ribosome formation. Here, we demonstrate that induction of nucleolar stress by different strategies stimulates the Wnt/β-Catenin pathway. We show that depletion of the key ribosomopathy factor SBDS, or the nucleolar factors Nucleophosmin (NPM), Pescadillo 1 (PES1) or Peter Pan (PPAN) by si RNA-mediated knockdown or CRISPR/Cas9 strategy activates Wnt/β-Catenin signaling in a β-Catenin-dependent manner and stabilizes β-Catenin in human cancer cells. Moreover, triggering nucleolar stress by the chemotherapeutic agents Actinomycin D or the RNA polymerase I inhibitor CX-5461 stimulates expression of Wnt/β-Catenin targets, which is followed by the p53 target CDKN1A (p21). As PPAN expression is induced by Wnt/β-Catenin signaling, our data establish a novel feedback mechanism and reveal that nucleolar stress over-activates the Wnt/β-Catenin pathway, which most likely serves as compensatory mechanism to sustain ribosome biogenesis.


Human elongation factor 1 alpha: a polymorphic and conserved multigene family with multiple chromosomal localizations.
One of the genes activated in human melanoma cells by the tumor-promoting phorbol ester is that of the elongation factor 1 alpha. A cDNA clone containing the complete 3'-end untranslated region and the nucleotide sequences coding for 227 carboxyterminal amino acids was isolated. Computer-assisted comparison with known sequences of elongation factors from other species revealed homologies up to 73% and 63% on amino acid and nucleotide sequences, respectively. Northern blot analysis of mRNA from unstimulated and phorbol ester-treated cells showed a 3- to 5-fold increase in cytoplasmic elongation factor 1 alpha mRNA after phorbol ester induction. When compared with the phorbol ester-inducible single-copy gene transcripts coding for the tissue-type plasminogen activator, the cellular mRNA content of elongation factor 1 alpha is 30 times higher. By Southern blot analysis experiments on human genomic DNA, a multi-gene family was found showing polymorphisms in restriction endonuclease fragment lengths (RFLP). Several polymorphisms were studied more extensively in the population on more than 100 DNA samples from normal individuals and in three-generation families. In situ hybridization of the cDNA probe to normal human metaphase chromosomes showed multiple chromosomal localizations of the elongation factor gene(s), with peak hybridization on the chromosomes 1, 2, 4, 5, 6, 7, and 15. The estimate of the gene copy number in humans is more than ten copies per (haploid) genome.


Similarities and variations among lobular carcinoma cells.
A cytomorphological description of lobular carcinoma of the breast is given based on imprints, paraffin-embedded 5-mu sections, and plastic-embedded 2-mu sections in nine patients. Both nuclear and cytoplasmic features are illustrated and tabulated. A basic lobular carcinoma cell is depicted. Cytoplasmic vacuolization is demonstrated in all tumors. Transitions from one lobular cell variation to another are demonstrated. It is suggested that more precise knowledge of the similarities and the variations in the morphology of the lobular carcinoma cell will help in both cytological and histological diagnosis.


European survey on the use of patient contact shielding during radiological examinations.
Contact shielding (CS) of patients during X-ray studies has been used for decades to protect radiosensitive organs. This practice has not changed much despite increasing evidence that CS is not useful in many cases. The Gonad And Patient Shielding (GAPS) group-founded by representatives of the main European bodies involved in radiology-promoted this survey to assess the current practice of CS among European radiology departments and the attitude towards a non-shielding policy. Over a four-month period (15 May-15th September 2021) European Society of Radiology and European Society of Paediatric Radiology radiologist members were invited to respond to a web-based questionnaire consisting of 59 questions. 225 centres from 35 countries responded to this survey. CS was routinely applied in at least one radiological modality in 49.2% of centres performing studies in adults, 57.5% of centres performing studies in children, and 47.8% of centres performing studies on pregnant women. CS was most frequently used in conventional radiography, where the most frequently shielded organs were the gonads, followed by thyroid, female breasts, and eye lens. 83.6% respondents would follow European recommendations on the use of CS when provided by the main European bodies involved in radiology. This review shows that CS is still largely used across Europe. However, a non-shielding policy could be adopted in most departments if European professional societies provided recommendations. In this regard, a strong commitment by European and national professional societies to educate and inform practitioners, patients and carers is paramount. According to this survey expectations of patients and carers, and skepticism among professionals about the limited benefits of CS are the most important obstacles to the application of a no-shielding policy. A strong commitment from European and national professional societies to inform practitioners, patients and carers is fundamental.


Correction to: Innate Immune Signaling and Alcohol Use Disorders.
In the second paragraph of section 1.3 on line 27, the text appears incorrect as glutamatergic and neurons. It should read as glutamatergic and GABAergic neurons. The original chapter was corrected.


Radiation associated hyperthyroidism in patients with gynecological malignancies.
To determine the effect of abdominal and/or pelvic irradiation for gynecological malignancies on the later development of hyperthyroidism, 1,884 medical records of the patients diagnoses as carcinomas of cervix and corpus uteri, and of ovary were reviewed. Among 1,269 patients with radiation therapy, 5 patients developed hyperthyroidism after irradiation to the abdomen and/or pelvis. This is a statistically significant increase when compared with an epidemiological study. Radiation dose to the thyroid was estimated to be 30 to 200 rads. Two other patients who were irradiated to the nose or supraclavicular region in addition to the abdomen also developed hyperthyroidism. However, none of 581 patients without radiation therapy became hyperthyroid. The results indicate that radiation therapy for treatment of gynecological malignancy gives a significant radiation exposure with an increase in the incidence of subsequent hyperthyroidism.


Myocardial structural protein expression in umbilical cord blood mesenchymal stem cells after myogenic induction.
To assess the effects of three methods of inducing myogenic cells differentiation, umbilical blood mesenchymal stem cells (UCMSCs) from nearly full-term pregnancy mongrel dogs were purified and cultured. Fourth-passage UCMSCs were used to detect surface antigens, including CD11a, CD11b, CD29, CD34 and CD71. The cells were induced by 5-azacytidine (5-aza), myocardial lysates and myocardial induced fluid. Positive expression of Nkx2.5, α-actin, desmin, β-MHC and troponin-I (TN I) were detected after 3 weeks. The immunohistochemical results were CD11a (-), CD11b (-), CD34 (-), CD29 (+) and CD71 (+). Nkx2.5 was detected in 5-aza group, myocardial lysates group and myocardial induced fluid group. Semi-quantitative analysis showed Nkx2.5 expression significantly higher in myocardial lysates group than in the 5-aza group or myocardial-induced fluid group (P < 0.05), but there was no significant difference between the 5-aza and myocardial-induced fluid groups for Nkx2.5 expression (P > 0.05). MSCs did not express myocardial structural proteins before differentiation, but α-actin, desmin, β-MHC and troponin-I were present after differentiation. The positive expression of four proteins differed with the differentiation conditions. The UCMSCs can be differentiated into myogenic cells by three methods, but the degrees of differentiation are inconsistent. Our results show that the effects of 5-aza and myocardial lysates are better than that of myocardial induced fluid.


Increase of ornithine decarboxylase activity elicited by reserpine in the peripheral and central monoaminergic systems of the rat.
Ornithine decarboxylase activity was increased about tenfold in adrenal glands and in brain regions preponderantly containing aminergic neurons, by a single dose of 16 mumol/kg of reserpine. Maximal enzyme activity in the adrenal glands was observed at about 8 hr after reserpine administration. The ornithine decarboxylase activity-time curves in the brain regions showed a concomitant polyphasic course, with the highest maximum at 12 hr postinjection. Ornithine decarboxylase induction is discussed as an early event in the cascade of molecular events preceding the induction of cell typic enzymes.


Discrimination between immunoaccessory and phagocytic monocytes/macrophages of the skin in paraffin-embedded tissue by the monoclonal antibody Ki-M1P.
The variety of functions performed by monocytes and macrophages is reflected in their phenotypic diversity. Investigation of this complex system is facilitated by Ki-M1P, a new monoclonal antibody which recognizes a differentiation antigen on monocytes/macrophages in paraffin-embedded tissues. To test its usefulness as a pan-macrophage marker in the skin, we immunohistochemically analysed paraffin-embedded biopsy material from seven healthy individuals and 190 patients with a variety of dermatoses. Immunoreactivity was compared with results obtained with the antibodies KP-1, MAC-387, UCHL-1 and S-100. In normal skin, epidermal Langerhans cells were Ki-M1P-. Strong expression of this marker was detected on spindle-shaped as well as dendritic perivascular and intervascular macrophages. Pathological reaction forms such as giant cells and epithelioid cells in granulomatous dermatoses were also Ki-M1P+. The high specificity of Ki-M1P is reflected in the lack of reactivity with tumour cells in non-monocytic neoplasms and Langerhans cell histiocytosis. Thus, Ki-M1P is a useful marker for skin macrophages, discriminating between the immunoaccessory and the phagocytic compartments.


Regulation of gene expression and the transcription factor cycle hypothesis.
Post-genomic data show unexpected extent of the transcribed genome and the size of individual primary transcripts. Hence, most cis-regulatory modules (CRMs) binding transcription factors (TFs) at promotor, enhancer and other sites are actually transcribed within full domain transcripts (FDTs). The ensemble of these CRMs placed way upstream of exon clusters, downstream and in intronic or intergenic positions represent a program of gene expression which has been formally analysed within the Gene and Genon concept [1,2]. This concept has emphasised the necessity to separate product information from regulative information to allow information-theoretic analysis of gene expression. Classically, TFs have been assumed to act at DNA level exclusively but evidence has accumulated indicating eventual post-transcriptional functions. The transcription factor cycle (TFC) hypothesis suggests the transfer of DNA-bound factors to nascent RNA. Exerting downstream functions in RNA processing and transport, these factors would be liberated by RNA processing and cycle back to the DNA maintaining active transcription. Sequestered on RNA in absence of processing they would constitute a negative feedback loop. The TFC concept may explain epigenetic regulation in mitosis and meiosis. In mitosis control factors may survive as single proteins but also attached to FDTs as organised complexes. This process might perpetuate in cell division conditioning of chromatin for transcription. As observed on lampbrush chromosomes formed in avian and amphibian oogenesis, in meiosis the genome is fully transcribed and oocytes conserve high Mr RNA of high sequence complexity. When new interphase chromosomes form in daughter cells and early embryogenesis, TFs and other factors attached to RNA might be reinserted onto the DNA.


Immune responses of thymus/lymphocyte embryonic chimeras: studies on tolerance and major histocompatibility complex restriction in Xenopus.
A new model has been developed to address the question of whether T cells that traverse an allogeneic thymus during early and late life become restricted to interact, in vivo, with other leukocytes and target cells that display the major histocompatibility complex (MHC) antigens of the thymus haplotype. Chimeras were made microsurgically with pairs of 24-h-old Xenopus embryos such that the anterior region of an embryonic chimera contained the thymus anlagen and was of one MHC genotype, whereas the posterior region contained the anlagen of all hemopoietic cells and was of another genotype. Assays to determine the MHC haplotype restriction specificity of T cells in chimeras that had been reared through metamorphosis involved: specific antibody responses (IgM and IgG) to dinitrophenylated keyhole limpet hemocyanin; rejection of minor H locus disparate skin grafts that expressed the MHC antigens of either the thymus donor or the lymphocyte donor; and mixed leukocyte culture. MHC-mismatched chimeras displayed split tolerance since they accepted skin grafts of the thymus haplotype but had lymphocytes that proliferated in response to MHC antigens of the thymus donor strain as well as to MHC antigens of third-party donors. IgM responses of MHC-matched and MHC-mismatched chimeras and of nonchimeric controls did not differ. However, the IgG responses of MHC-mismatched thymus/lymphocyte chimeras peaked later than those of MHC-matched chimeras and normal controls. Data from skin grafting protocols were consistent with the proposition that there may be in vivo selection of T cells reactive to minor H antigens presented in association with the MHC antigens of the thymus rather than the MHC antigens of the lymphocytes themselves. These data suggest that although it is not absolute, there is thymic selection of the T cell repertoire in Xenopus.


PM2.5 Constituents and Onset of Gestational Diabetes Mellitus: Identifying Susceptible Exposure Windows.
Fine particulate matter (PM2.5) has been linked to gestational diabetes mellitus (GDM). However, PM2.5 is a complex mixture with large spatiotemporal heterogeneities, and women with early-onset GDM (i.e., diagnosed before 24th gestation week) have distinct maternal characteristics and a higher risk of worse health outcomes compared with those with late-onset GDM (i.e., diagnosed in or after 24th gestation week). We aimed to examine differential impacts of PM2.5 and its constituents on early- vs. late-onset GDM, and to identify corresponding susceptible exposure windows. We leveraged statewide linked electronic health records and birth records data in Florida in 2012-2017. Exposures to PM2.5 and its constituents (i.e., sulfate [SO4 2-], ammonium [NH4 +], nitrate [NO3 -], organic matter [OM], black carbon [BC], mineral dust [DUST], and sea-salt [SS]) were spatiotemporally linked to pregnant women based on their residential histories. Cox proportional hazards models and multinomial logistic regression were used to examine the associations of PM2.5 and its constituents with GDM and its onsets. Distributed non-linear lag models were implemented to identify susceptible exposure windows. Exposures to PM2.5, SO4 2-, NH4 +, and BC were statistically significantly associated with higher hazards of GDM. Exposures to PM2.5 during weeks 1-12 of gestation were positively associated with GDM. Associations of early-onset GDM with PM2.5 in the 1st and 2nd trimesters, SO4 2- in the 1st and 2nd trimesters, and NO3 - in the preconception and 1st trimester were considerably stronger than observations for late-onset GDM. Our findings suggest there are differential associations of PM2.5 and its constituents with early- vs. late-onset GDM, with different susceptible exposure windows. This study helps better understand the impacts of air pollution on GDM accounting for its physiological heterogeneity.


One-step sonochemical fabrication of biomass-derived porous hard carbons; towards tuned-surface anodes of sodium-ion batteries.
A facile one-step sonochemical activation method is utilized to fabricate biomass-derived 3D porous hard carbon (PHC-1) with tuned-surface and is compared with the conventional two-step activation method. As raw biomass offers good KOH impregnation, ultrasonication power diffuses both K+ and OH- ions deep into its interior, creating various nanopores and attaching copious functional groups. In contrast, conventional activation lacks these features under the same carbonization/activation parameters. The high porosity (1599 m2/g), rich functional groups (O = 8.10%, N = 0.95%), and well-connected nanoporous network resulting from sonochemical activation, remarkably increased specific capacity, surface wettability, and electrode stability, consequently improved electrochemical performance. Benefiting from its suitable microstructure, PHC-1 possesses superior specific capacity (330 mAh/g at 20 mA/g), good capacity retention (89.5%), and excellent structural stability over 500 sodiation/desodiation cycles at high current density (1000 mA/g). Apart from modus operandi comparison, the two activation methods also provide mechanistic insights as the low-voltage plateau region and graphitic layers decrease simultaneously. This work suggests a scalable and economical approach for synthesizing large-scale activated porous carbons that are used in various applications, be it energy storage, water purification, or gas storage, to name a few.


The roles of reactive oxygen species (ROS) and autophagy in the survival and death of leukemia cells.
As a clonal disease of hematopoietic stem cells (HSCs), the etiology and pathogenesis of leukemia is not fully understood. Recent studies suggest that cellular homeostasis plays an essential role in maintaining the function of HSCs because dysregulation of cellular homeostasis is one of the major factors underlying the malignant transformation of HSCs. Reactive oxygen species (ROS) and autophagy, key factors regulating cellular homeostasis, are commonly observed in the human body. Autophagy can be induced by ROS through a variety of signaling pathways, and conversely inhibits ROS-induced damage to cells and tissues. ROS and autophagy coordinate to maintain cellular homeostasis. Previous studies have demonstrated that both of ROS and autophagy play important roles in the development of leukemia and are closely involved in drug resistance in leukemia. Interference with cellular homeostasis by promoting programmed leukemia cell death via ROS and autophagy has been verified to be an efficient technique in the treatment of leukemia. However, the critical roles of ROS and autophagy in the development of leukemia are largely unknown. In this review, we summarize the roles of ROS and autophagy in the pathogenesis of leukemia, which may allow the identification of novel targets and drugs for the treatment of leukemia based on the regulation of HSCs homeostasis through ROS and autophagy.


Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime?
Microglia-astrocyte interactions represent a delicate balance affecting neural cell functions in health and disease. Tightly controlled to maintain homeostasis during physiological conditions, rapid and prolonged departures during disease, infection, and following trauma drive multiple outcomes: both beneficial and detrimental. Recent sequencing studies at the bulk and single-cell level in humans and rodents provide new insight into microglia-astrocyte communication in homeostasis and disease. However, the complex changing ways these two cell types functionally interact has been a barrier to understanding disease initiation, progression, and disease mechanisms. Single cell sequencing is providing new insights; however, many questions remain. Here, we discuss how to bridge transcriptional states to specific functions so we can develop therapies to mediate negative effects of altered microglia-astrocyte interactions.


Enigmatic roles of Mcm10 in DNA replication.
Minichromosome maintenance protein 10 (Mcm10) is required for DNA replication in all eukaryotes. Although the exact contribution of Mcm10 to genome replication remains heavily debated, early reports suggested that it promotes DNA unwinding and origin firing. These ideas have been solidified by recent studies that propose a role for Mcm10 in helicase activation. Whereas the molecular underpinnings of this activation step have yet to be revealed, structural data on Mcm10 provide further insight into a possible mechanism of action. The essential role in DNA replication initiation is not mutually exclusive with additional functions that Mcm10 may have as part of the elongation machinery. Here, we review the recent findings regarding the role of Mcm10 in DNA replication and discuss existing controversies.


The beneficial effect of providing kidney transplantation information on transplantation status differs between for-profit and nonprofit dialysis centers.
Informing end-stage kidney disease patients about kidney transplantation options increases the likelihood of kidney transplant waiting list (WL) enrollment and live donor kidney transplant (LDKT) receipt. Patients in for-profit dialysis centers have lower rates of WL enrollment and LDKT receipt. This study examined if the ownership status of dialysis centers modified the association between informing patients about transplantation options and patients' transplantation status. Multilevel analysis using mixed-effect multinomial logistic regression was performed using the United States Renal Data System (USRDS) data (January 2005 to December 2017). The study showed that informing patients improved the odds of WL enrollment and LDKT receipt. However, the effect of informing patients on transplantation status was less pronounced at for-profit as compared with nonprofit centers (Nonprofit: WL enrollment OR: 2.23 [95% CI: 2.07-2.40], and LDKT receipt OR: 3.35 [95% CI: 2.65-4.25]. For-profit: WL enrollment OR: 1.73 [95% CI: 1.66-1.79], and LDKT receipt OR: 2.35 [95% CI: 2.08-2.66]), although the odds of informing patients was higher for for-profit centers, and type of patients informed were similar across both types of centers. Information provided by for-profit centers was potentially less effective than those provided by nonprofit centers. Standardized guidelines for transplantation information provision are needed in order to ensure similar informational quality across centers.


Isolation of 3beta,7alpha-dihydroxychol-5-enoic acid, an intermediate of chenodeoxycholic acid biogenesis, and 3alpha,7alpha-dihydroxychol-4-enoic acid from bladder bile of hens.
Two Lifschütz-positive C24-bile acids were isolated from bladder bile of hens. One of these was identified by isotope dilution experiments after conversion to a 3H-labeled compound, and also by GLC after methoxylation, as 3beta,7alpha-dihydroxychol-5-enoic acid, a key intermediate of chenodeoxycholic acid biogenesis. The other, to which the structure 3beta,7alpha-dihydroxychol-4-enoic acid had been assigned previously, was proved to be its 3alpha-epimer by several experiments. These findings favor the alternative pathway of chenodeoxycholic acid biogenesis proposed by Yamasaki and his associates.


Projection of the entorhinal layer II neurons in the rat as revealed by intracellular pressure-injection of neurobiotin.
A component of the perforant path, projection of the entorhinal layer II neurons, was investigated by recovering intracellularly labeled layer II neurons from the medial or intermediate entorhinal cortex in rats. The labeled layer II spiny stellate neurons had axon collaterals in layers I, II, and III of the entorhinal cortex as well as some axon collaterals in the subiculum. The stem axons gave rise to terminal axon branches that covered the entire extent (suprapyramidal blade, crest, and infrapyramidal blade) of the dentate gyrus and the CA2-3 fields in the transverse plane, forming a sheet-like formation. The axon arbor in the hippocampal formation spread up to 2 mm wide in a septotemporal direction. The sheet-like formation of the axon arbors was a narrow layer in the suprapyramidal blade and in the stratum lacunosum-moleculare of the CA2-3 fields. The layer became wider in the crest and infrapyramidal blade of the dentate gyrus. This study shows that the entorhinohippocampal circuit is not a simple circle from single cells level.


Test-retest repeatability of ultrasonographic shear wave elastography in a rat liver fibrosis model: toward a quantitative biomarker for preclinical trials.
This study evaluated the test-retest repeatability and measurement variability of ultrasonographic shear wave elastography (SWE) for liver stiffness in a rat liver fibrosis model. In 31 Sprague-Dawley rats divided into three groups (high-dose, low-dose, and control), liver fibrosis was induced by intraperitoneal administration of thioacetamide for 8 weeks. A dedicated radiographer performed SWE to measure liver stiffness in kilopascals in two sessions at a 3-day interval. We calculated correlations between liver stiffness and histopathologic results, measurement variability in each session using coefficients of variation (CoVs) and interquartile/median (IQR/M), and test-retest repeatability between both sessions using the repeatability coefficient. Different levels of liver fibrosis in each group were successfully induced in the animal model. The mean liver stiffness values were 8.88±1.48 kPa in the control group, 11.62±1.70 kPa in the low-dose group, and 11.91±1.73 kPa in the high-dose group. The correlation between collagen areas and liver stiffness values was moderate (r=0.6). In all groups, the second session yielded lower CoVs (i.e., more reliable results) for liver stiffness than the first session, suggesting a training effect for the operator. The mean IQR/M values were also lower in the second session than in the first session, which had four outliers (0.21 vs. 0.12, P<0.001). The test-retest repeatability coefficient was 3.75 kPa and decreased to 2.82 kPa after removing the four outliers. The use of ultrasonographic SWE was confirmed to be feasible and repeatable for evaluating liver fibrosis in preclinical trials. Operator training might reduce variability in liver stiffness measurements.


Ca2(+)-calmodulin-dependent protein kinase II phosphorylates various types of non-epithelial intermediate filament proteins.
We have investigated the actions of Ca2(+)-calmodulin (CaM)-dependent protein kinase II on various types of non-epithelial intermediate filament proteins, vimentin, desmin, glial fibrillary acidic protein (GFAP) and neurofilament triplet proteins. Most of these filament proteins could serve as substrates. The effects of phosphorylation on the filamentous structure of vimentin were investigated in sedimentation experiments and by using electron microscopy. The amount of unassembled vimentin increased linearly with increased phosphorylation. However, the extent of the effect of phosphorylation on the potential to polymerize was also affected by the MgCl2 concentration, under conditions for reassembly. The actions of Ca2(+)-CaM-dependent protein kinase II on non-epithelial intermediate filaments under physiological conditions are given attention.


Hemoglobin Hijiyama: a new fast-moving hemoglobin in a Japanese family.
A variant of hemoglobin A, named Hb Hijiyama, found in two generations of a Japanese family living in Hiroshima, Japan, has a higher anodal electrophoretic mobility than hemoglobin A; a gain of two negative charges per molecule is indicated. Fingerprinting and amino acid analysis showed the biochemical anomaly to be in the beta chain at residue 120, where lysine is replaced by glutamic acid. In the heterozygote carriers of the abnormal hemoglobin there is no apparent association with clinical or hematologic abnormalities.


Structural characterization of the rhenium(v) oxo complex of mercaptoacetyltriglyclne in its dianionic form.
Dianionic [MO(MAG(3))](2-)(MAG(3) = penta-anionic form of mercaptoacetyltriglycine, M = (186)Re, (99m)Tc) complexes have important applications in nuclear medicine. In vivo the complexes have a deprotonated carboxyl group that is important to their biodistribution. The solid-state structures of (99)Tc and Re complexes with mercaptoacetyltriglycine reported previously are monoanions with protonated carboxyl groups. In the present work, we report the preparation and X-ray crystal structure of Na(2)[ReO(MAG(3))].5H(2)O (1), which contains the physiologically relevant dianion. The dianion is a distorted square pyramid with the nitrogen and sulphur donor atoms forming the base and the oxo ligand at the apex. The terminal carboxyl group is deprotonated, uncoordinated and has a syn orientation with respect to the oxo ligand. The syn conformation of the dianion in 1 differs in conformation from the anti-monoanion in [Bu(4)N][ReO(MAG(3)H)] but is similar to the syn-monoanion in [Ph(4)P][(99)TcO(MAG(3) H)].


Molecular Taxonomy and Immune Checkpoint Therapy in Bladder Cancer.
Bladder cancer is a heterogeneous disease, which exhibits a wide spectrum of clinical and pathologic features. Recent genomic studies have revealed that distinct molecular alterations may underlie the diverse clinical behaviors of bladder cancer, leading to a novel molecular classification. The intrinsic molecular subtypes exhibit distinct gene expression signatures and different clinicopathologic features. Genomic alterations also underlie the development of bladder cancer histologic subtypes. Genomic characterization provides new insights to understanding the biology of bladder cancer and improves the diagnosis and treatment of this complex disease. Biomarkers can aid the selection of patients for immune checkpoint therapy.


Acquired left ventricular to coronary sinus fistula: an unusual complication of acute myocardial infarction.
Anatomical complications of myocardial infarction include ventricular septal defect and mitral regurgitation. Another unusual complication of myocardial infarction is described, and its diagnosis and surgical management are discussed.


A novel human model of the neurodegenerative disease GM1 gangliosidosis using induced pluripotent stem cells demonstrates inflammasome activation.
GM1 gangliosidosis (GM1) is an inherited neurodegenerative disorder caused by mutations in the lysosomal β-galactosidase (β-gal) gene. Insufficient β-gal activity leads to abnormal accumulation of GM1 gangliosides in tissues, particularly in the central nervous system, resulting in progressive neurodegeneration. Here, we report an in vitro human GM1 model, based on induced pluripotent stem cell (iPSC) technology. Neural progenitor cells differentiated from GM1 patient-derived iPSCs (GM1-NPCs) recapitulated the biochemical and molecular phenotypes of GM1, including defective β-gal activity and increased lysosomes. Importantly, the characterization of GM1-NPCs established that GM1 is significantly associated with the activation of inflammasomes, which play a critical role in the pathogenesis of various neurodegenerative diseases. Specific inflammasome inhibitors potently alleviated the disease-related phenotypes of GM1-NPCs in vitro and in vivo. Our data demonstrate that GM1-NPCs are a valuable in vitro human GM1 model and suggest that inflammasome activation is a novel target pathway for GM1 drug development.


An alternative route to the arylvinyltriazole nucleosides.
A new pathway to synthesis of arylvinyl ribavirin analogues is developed which makes it possible to obtain not only trans- but also cis-isomers at vinyl bond. By this route eight ribavirin 5-arylvinyl analogues are synthesized and their antiviral activity is evaluated.


Quantitative Proteomics in Drosophila with Holidic Stable-Isotope Labeling of Amino Acids in Fruit Flies (SILAF).
Protein-focused research has been challenging in Drosophila melanogaster due to few specific antibodies for Western blotting and the lack of effective labeling methods for quantitative proteomics. Herein, we describe the preparation of a holidic medium that allows stable-isotope labeling of amino acids in fruit flies (SILAF). Furthermore, in this chapter, we provide a protocol for mitochondrial enrichments from Drosophila larvae and flies together with a procedure to generate high-quality peptides for further analysis by mass spectrometry. Samples obtained following this protocol can be used for various functional studies such as comprehensive proteome profiling or quantitative analysis of posttranslational modifications upon enrichment. SILAF is based on standard fly routines in a basic wet lab environment and provides a flexible and cost-effective tool for quantitative protein expression analysis.


The Role of Hyperarousal and Aberrant Salience in the Acceptance of Anti-COVID-19 Vaccination.
Background and Objectives: This present study was aimed at exploring hyperarousal and aberrant salience in a sample of the Italian general population to understand their possible role in the acceptance of anti-COVID-19 vaccination. Materials and Methods: Sociodemographic data questions, the "Acceptance of Vaccination" measure, the Hyperarousal Scale (H-Scale), and the Aberrant Salience Inventory (ASI) were sent as an unpaid online survey to the general population (age range 18-80 years) within the Italian territory. Results: The enrolled subjects were divided into two subgroups: "Pro-vax" (n = 806; 87.4%) and "No-vax" (n = 116; 12.6%). Statistical analysis showed significant differences between groups in the "Education Level" (p = 0.001) category, higher in the "Pro-vax" group, and in the ASI "Senses Sharpening" (p = 0.007), "Heightened Emotionality" (p = 0.008), and "Heightened Cognition" (p = 0.002) subscales with the "Total Score" (p = 0.015), all higher in "No-vax" subjects. Furthermore, a linear regression model evidenced that only "Education Level" (β = 0.143; p < 0.0001) and "Senses Sharpening" (β = -0.150; p = 0.006) were, respectively, direct and inverse predictors of "Acceptance of Vaccination". Conclusions: Our results show that several subthreshold conditions, such as somatosensory amplification, anxiety traits, and panic experiences, should be taken into account by authoritative sources involved in health education, communication, and policy to alleviate public concerns about vaccine safety, for the present and also future pandemics, and to provide more inclusive, informed, and accurate public health preventive and treatment programs.


Pharmacodynamic and pharmacokinetic interactions of psychotropic drugs with antiepileptic drugs.
Co-morbid psychiatric disorders are relatively frequent in patients with epilepsy. The prevalence rates of mood and anxiety disorders, psychotic disorders and attention deficit/hyperactivity disorder have been found to be significantly higher in patients with epilepsy than in the general population. While co-morbid psychiatric disorders have frequently been considered as complications of the seizure disorder, there is an increasing body of literature that points to a complex relationship between psychiatric and seizure disorders. Because of this, it is crucial that clinicians consider the presence of co-morbid psychiatric disorders when planning the treatment of patients with epilepsy. Having a clear understanding of the pharmacodynamic and pharmacokinetic interactions between antiepileptic drugs and psychotropic drugs is of the essence to avert unnecessary adverse events and loss of efficacy of psychotropic drugs. This chapter provides a practical review on the use of psychotropic drugs for the treatment of these psychiatric co-morbidities in patients with epilepsy.


Towards depersonalized abacavir therapy: chemical modification eliminates HLA-B*57 : 01-restricted CD8+ T-cell activation.
Exposure to abacavir is associated with T-cell-mediated hypersensitivity reactions in individuals carrying human leukocyte antigen (HLA)-B57 : 01. To activate T cells, abacavir interacts directly with endogenous HLA-B57 : 01 and HLA-B57 : 01 expressed on the surface of antigen presenting cells. We have investigated whether chemical modification of abacavir can produce a molecule with antiviral activity that does not bind to HLA-B57 : 01 and activate T cells. An interdisciplinary laboratory study using samples from human donors expressing HLA-B57 : 01. Researchers were blinded to the analogue structures and modelling data. Sixteen 6-amino substituted abacavir analogues were synthesized. Computational docking studies were completed to predict capacity for analogue binding within HLA-B57 : 01. Abacavir-responsive CD8 clones were generated to study the association between HLA-B57 : 01 analogue binding and T-cell activation. Antiviral activity and the direct inhibitory effect of analogues on proliferation were assessed. Major histocompatibility complex class I-restricted CD8 clones proliferated and secreted IFNγ following abacavir binding to surface and endogenous HLA-B57 : 01. Several analogues retained antiviral activity and showed no overt inhibitory effect on proliferation, but displayed highly divergent antigen-driven T-cell responses. For example, abacavir and N-propyl abacavir were equally potent at activating clones, whereas the closely related analogues N-isopropyl and N-methyl isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to HLA-B57 : 01 revealed a quantitative relationship between drug-protein binding and the T-cell response. These studies demonstrate that the unwanted T-cell activity of abacavir can be eliminated whilst maintaining the favourable antiviral profile. The in-silico model provides a tool to aid the design of safer antiviral agents that may not require a personalized medicines approach to therapy.


Delayed spontaneous resolution of high grade vesicoureteral reflux after reimplantation.
Significant (grade III/V or greater, International Reflux Study) postoperative vesicoureteral reflux was noted in 4 children who underwent technically satisfactory ureteral reimplantation. All patients had moderate to severe preoperative ureteral dilatation necessitating ureteral tapering in 3 of the 8 ureters reimplanted. Reoperation was considered in all 4 children but a conservative approach was used, with subsequent spontaneous resolution of the reflux 19 to 55 months after reimplantation. We conclude that even high grade reflux after satisfactory reimplantation can resolve spontaneously.


International guidelines for the in vivo assessment of skin properties in non-clinical settings: Part 2. transepidermal water loss and skin hydration.
There is an emerging perspective that it is not sufficient to just assess skin exposure to physical and chemical stressors in workplaces, but that it is also important to assess the condition, i.e. skin barrier function of the exposed skin at the time of exposure. The workplace environment, representing a non-clinical environment, can be highly variable and difficult to control, thereby presenting unique measurement challenges not typically encountered in clinical settings. An expert working group convened a workshop as part of the 5th International Conference on Occupational and Environmental Exposure of Skin to Chemicals (OEESC) to develop basic guidelines and best practices (based on existing clinical guidelines, published data, and own experiences) for the in vivo measurement of transepidermal water loss (TEWL) and skin hydration in non-clinical settings with specific reference to the workplace as a worst-case scenario. Key elements of these guidelines are: (i) to minimize or recognize, to the extent feasible, the influences of relevant endogenous-, exogenous-, environmental- and measurement/instrumentation-related factors; (ii) to measure TEWL with a closed-chamber type instrument; (iii) report results as a difference or percent change (rather than absolute values); and (iv) accurately report any notable deviations from this guidelines. It is anticipated that these guidelines will promote consistent data reporting, which will facilitate inter-comparison of study results.


Acute effects of cigarette smoking on global cerebral blood flow in overnight abstinent tobacco smokers.
We examined whether cerebral vascular reactivity to 5% CO2/95% O2 would be a useful, independent measure of effects of tobacco smoking on global cerebral blood flow (gCBF). The acute effects during smoking one's favorite brand of cigarettes were determined after overnight tobacco abstinence. Positron emission tomography was used to quantitatively measure gCBF using H(2)15O in 10 right-handed young-adult male volunteer tobacco smokers. After a 12-hr abstinence, gCBF measurements were repeated six times at 15-min intervals: First baseline, 5% CO2/95% O2 inhalation, first cigarette smoking, second baseline, 5% CO2/95% O2 inhalation, and second cigarette smoking. Surprisingly, no significant change was seen in mean gCBF during smoking compared with baseline. However, the increase in arterial plasma concentration of nicotine correlated inversely with gCBF. Out of 19 smoking sessions, gCBF increased in 7, decreased in 7, and was unchanged in 5 sessions. The gCBF increased during smoking when baseline gCBF was relatively low, whereas gCBF decreased when baseline gCBF was relatively high. Both vascular reactivity and estimated gCBF plus arterial nicotine concentrations were useful measures to predict the changes in measured gCBF. These individual differences result in important bimodal effects of smoking on the brains of different young adult tobacco smokers.


Fine-needle aspiration of cystic nephroma (multilocular cyst of the kidney).
Cystic nephromas are rare tumors of the kidney most commonly affecting boys or adult females. The fine-needle aspiration cytomorphology has not yet been described. A renal cystic mass in a 56 year old female was aspirated under ultrasound guidance. Papanicolaou stained smears of the cyst fluid revealed markedly atypical cells forming papillary clusters. Subsequent nephrectomy showed a typical cystic nephroma with lining epithelium resembling that seen in the aspirate. The cytomorphology of cystic nephroma has been misdiagnosed as renal cell carcinoma in the literature. Low cellularity, absence of necrosis, and paucity of single cells are features that should raise the possibility of cystic nephroma in a cystic renal mass.


Variations in maternal adenylate cyclase genes are associated with congenital Zika syndrome in a cohort from Northeast, Brazil.
Vertical transmission of Zika virus (ZIKV) is associated with congenital malformations but the mechanism of pathogenesis remains unclear. Although host genetics appear to play a role, no genetic association study has yet been performed to evaluate this question. In order to investigate if maternal genetic variation is associated with Congenital Zika Syndrome (CZS), we conducted a case-control study in a cohort of Brazilian women infected with ZIKV during pregnancy. A total of 100 women who reported symptoms of zika during pregnancy were enrolled and tested for ZIKV. Among 52 women positive for ZIKV infection, 28 were classified as cases and 24 as controls based on the presence or absence of CZS in their infants. Variations in the coding region of 205 candidate genes involved in cAMP signaling or immune response were assessed by high throughput sequencing and tested for association with development of CZS. From the 817 single nucleotide variations (SNVs) included in association analyses, 22 SNVs in 17 genes were associated with CZS under an additive model (alpha = 0.05). Variations c.319T>C (rs11676272) and c.1297G>A, located at ADCY3 and ADCY7 genes showed the most prominent effect. The association of ADCY3 and ADCY7 genes was confirmed using a Sequence Kernel Association Test to assess the joint effect of common and rare variations, and results were statistically significant after adjustment for multiple comparisons (P < 0.002). These results suggest that maternal ADCY genes contribute to ZIKV pathogenicity and influence the outcome of CZS, being promising candidates for further replication studies and functional analysis.


Thermal behavior of HeLa and KB cells in suspension and attached to glass.
HeLa S-3 and KB cells were grown in a LKB Batch Microcalorimeter under a variety of nutrient medium conditions amd mixing intervals. These conditions produced rather large apparent endothermic and exothermic responses on mixing that could be correlated with the presence of suspended cells (unattached) as well as cells attached to the glass calorimeter vessel. Cells capable of being resuspended upon mixing of the calorimeter vessel produces first an endothermic followed by an exothermic signal while attached cells produced only an apparent endothermic response. The exothermic response is believed to be associated with increased metabolic heat on suspending the cells followed by partial suppression of the steady state metabolic heat on cell settling. Rates of cell settling correlated well with the rate of decay of the exothermic signal. The rapid appearance of endothermicity on mixing suggests it is associated with rapid events such as binding of nutrients to cell surfaces. The response in the endothermic direction on mixing is discussed in terms of the disruption of mechanisms which tend to exclude nutrients from the surface of the cell.


Diltiazem. A review of its pharmacological properties and therapeutic efficacy.
Diltiazem is an orally and intravenously active calcium channel blocking agent shown to be an effective and well-tolerated treatment for stable angina and angina due to coronary artery spasm. Its efficacy in these diseases has generally been similar to that of nifedipine or verapamil - alternative calcium channel blockers with which diltiazem has many electrophysiological, haemodynamic, and antiarrhythmic similarities. The antianginal mechanism of diltiazem cannot be precisely described; however, it appears to increase myocardial oxygen supply and decrease myocardial oxygen demand, mainly by coronary artery dilatation and/or via both direct and indirect haemodynamic alterations. Diltiazem has also shown substantial efficacy in the treatment of unstable angina, hypertension, and supraventricular tachyarrhythmias, but further study is necessary before its place in the treatment of these diseases may be clearly established. Although headache due to peripheral vasodilatation and depression of atrioventricular nodal conduction may be troublesome, side effects occur in only 2 to 10% of patients receiving diltiazem and are generally minor in nature. Thus, diltiazem offers a worthwhile alternative to other agents currently available for the treatment of angina pectoris. Although the infrequency of serious side effects may offer an advantage, its relative place in therapy compared with that of other calcium channel blockers remains to be clarified.


Responder rates to fampridine differ between clinical subgroups of MS patients and patient reported outcome influences treatment decision making.
Fampridine is an effective treatment to improve ambulation for some multiple sclerosis (MS) patients. Remarkable discrepancies exist between responder rates in clinical trials and the proportion of patients continuing treatment in clinical practice. This may be related to clinical phenotypes of MS patients, and the influence of patient reported outcome (PRO) on treatment decision making. To analyse responder rates to fampridine on ambulation and upper extremity function (UEF) and the influence on treatment decision making in different clinical subgroups in a real-world setting. MS patients with ambulatory impairment treated with fampridine were included. Patients were subdivided based on disease duration, clinical phenotype, Expanded Disability Status Scale (EDSS), baseline walking speed, and presence of UEF impairment. Ambulatory response was assessed with the Timed 25-Foot Walk (T25FW, responder defined as ≥20% improvement) and with the MS Walking Scale (MSWS, responder defined as ≥8 points improvement) as a PRO. For patients also reporting impaired UEF, the Arm Function in MS Questionnaire (AMSQ, responder defined as ≥15 improvement) was the PRO of choice. Decision on treatment continuation was based on improvement of T25FW, MSWS and the clinicians' overall impression for improvement. In total 344 patients were included of which 75.3% continued treatment. More patients with a relapsing clinical phenotype continued treatment vs patients with a progressive phenotype (83.6 vs 68.6%, p < 0.01). A positive linear trend was found between severity of walking disability, as determined by baseline walking speed, and T25FW response (p < 0.01), while there was an inverse linear association between walking disability and MSWS response (p = 0.03). However, the proportion of patients continuing treatment was similar between subgroups of baseline walking speed. Impaired UEF was reported by 183 (66.5%) patients, of which 64 (39.3%) were AMSQ responders. Patients responding on AMSQ compared to non-responders, were also more frequently MSWS responders (82.8 vs 65.3%, p = 0.02), while response on T25FW was similar, and continued treatment more often (85.9 vs 70.7%, p = 0.04). This suggests an influence of PRO on treatment decision making. Responder rates and treatment continuation of fampridine differed between clinical subgroups of MS. PROs influenced treatment decision making of fampridine in clinical practice, particularly in patients with mild ambulatory impairment or those reporting UEF impairment. To some extent, these findings explain discrepancies found between clinical trials and clinical practice, and support the importance of subgroup analyses and incorporation of PROs in clinical trials. For clinical practice, using PROs to assess patients experience in conjunction with performance measures helps in treatment decision making.


Prevalence of Specific Helicobacter PyloricagA, vacA, iceA, ureC Genotypes and its Clinical Relevance in the Patients with Acid-Peptic Diseases.
Virulent markers of H. pylori, the vacuolating cytotoxin (vacA), cytotoxin-associated gene A (cagA), induced by contact with epithelium factor antigen (iceA gene) and the urease C gene (ureC) may plays a major role in determining the clinical outcome of Helicobacter infections. To detect the prevalence of the cagA, vacA, ureC and iceA genotypes of H. pylori from antral biopsy specimens of patients and to associate its role in specific disease. The study was conducted at Department of Microbiology of Shree P.M. Patel College of Paramedical Sciences, Anand, Gujarat, India. Seventy one antral biopsies of symptomatic patients referred for endoscopy from October 2012 to September 2013 were subjected to Multiplex PCR. DNA isolation from 71 biopsy samples was done by using "QIAamp DNA mini kit" from QIAGEN (GmbH, Hilden, Germany). Data was analysed using Chi square (χ2) test and p-value<0.05 was considered significant. Out of the 71 biopsies screened, 22(31%) samples were positive for H. pylori by PCR, with high proportion of cagA positive (17/22 specimen; 77.27%), followed by ureC positive (4/22 specimen; 18.18%) and vacA positive (1/22 specimen; 4.54%) strains. Significant association was found between cagA and female gender (p-value=0.042). Out of 17 cagA positive strains, 9(52.94%) were found in patients with gastritis, 5(29.41%) in reflux oesophagitis and 3(17.64%) in patients with diodenal ulcer. We found 0% prevalence of iceA gene; conversely we had three peptic ulcer patients with only cagA positivity. The cagA positive strain mainly affects the patients with gastritis specifically of female gender and iceA genotype is not a useful marker associated with peptic ulcer disease. Patients should be screened for cagA genotype when reported to be a case of gastritis for early treatment to prevent further complications such as cancer.


Gastric electrical stimulation does not significantly affect canine gastric acid secretion and 24-hour gastric pH.
Gastric electrical stimulation (GES) was shown to improve symptoms in patients with gastroparesis. However, the underlying mechanisms remain unclear. This study assessed the influence of various patterns of GES on fasting and postprandial gastric acid secretion and 24-hr gastric pH. Eight healthy dogs were studied and we found that in the fasting state, low-frequency, long-pulse (6/12-cpm, 375-msec, 4-mA) GES at the proximal stomach significantly inhibited the secretion of gastric juice (P < 0.05). No such effect was observed during GES (6/12 cpm) at the distal stomach. In the postprandial period, low-frequency, long-pulse GES at both proximal and distal sites and at both frequencies did not significantly affect gastric acid secretion. High-frequency, short-pulse GES, investigated for obesity (21 Hz, 8 mA, and 250 microsec, with 2 secs on, 3 sec off), at the proximal and distal stomach did not significantly affect the 24-hr gastric pH profile. In conclusion, GES with various stimulation parameters, and at various sites, has little effect on gastric acid secretion. The clinical effects induced by GES at these parameters may not be related to their effect on gastric acid homeostasis.


Patterns of alveolar macrophage activation upon attenuated and virulent African swine fever viruses in vitro.
The pattern of porcine alveolar macrophage (AM) activation upon classical stimuli of two strains of African swine fever (ASF) viruses, an attenuated ASFV-BA71V and virulent ASFV-Georgia2007 were investigated. In an in vitro experiment ASFV-Georgia2007-infected AM showed M1 polarization pattern different from the one induced by classical stimuli. Altered morphology, appearance of binuclear cells, decreased synthesis of IFN-alpha as well as IFN-epsilon was observed compared with attenuated ASFV-BA71V, and decreased synthesis of IFN-omega compared with intact cells. However, CD68 level did not significantly differ between alveolar macrophage populations infected by ASFV-Georgia2007 and control group, while both LPS/IFN-gamma stimulation and non-pathogenic ASFV-BA71V virus increased the level of CD68 soluble receptor. AM infection with ASFV-Georgia2007 resulted in remarkable DNA proliferation whereas LPS/IFN-gamma and ASFV-BA71V induced less expressed DNA proliferation in activated cells. The higher value of nitric oxide was obvious in the cells infected with ASFV-BA71V, compared to ASFV-Georgia2007 and LPS/IFN-gamma activated cells. In conclusion, pattern of activation of alveolar macrophages induced by ASFV-Georgia2007 virus differs from the one expressed in LPS/IFN-gamma- and ASFV-BA71V-activated cells. ASFV-BA71V and LPS/IFN-gamma share similar antiviral response of porcine AM. Therefore we assume that wild type virulent ASFV can partially down regulate antiviral response of AM and conclude that evolutionary decrease of virulence in ASFV is related to alterations of control of the host cell antiviral response.


Valproate-induced teratogenesis in Japanese rice fish (Oryzias latipes) embryogenesis.
Fertilized eggs of Japanese rice fish (medaka) at three developmental stages (Iwamatsu stages 4-30) were exposed to waterborne valproic acid (VPA) (0-80 mM) in hatching solution for 48 h. The amount of valproate to cause 50% mortality (IC(50)) is found to be developmental stage-specific. The embryos were more sensitive to valproate at early stages of development (Iwamatsu stages 4-10) than in the embryos in late stages (Iwamatsu stages 17-30). Valproate exposed embryos have microcephaly and disrupted cardiovasculature with delayed vessel circulation, thrombus formation, and slow heart rate. The hatching efficiency is also reduced by valproate exposure due to developmental delay. The mRNA analysis of nine genes belong to oxidative stress (catalase, gsr, gst), neurogenesis (iro3, wnt1, shh, otx2, nlgn3b) and cell cycle regulation (ccna2) have been done. It was observed that the genes belong to oxidative stress remained unaltered after valproate exposure. However, some of the genes belong to neurogenesis (wnt1,shh, otx2 and nlgn3b) and cell cycle (ccna2) showed developmental stage-specific alteration after valproate exposure. This study indicates that valproate is able to induce some of the phenotypic features which are analogous to human fetal valproate syndrome (FVS). Modulation of genes expressed in neural tissues indicates that this fish can be used to analyze the mechanisms of many neurobehavioral disorders like Autism spectrum disorder (ASD) in human.