Incidence, prevalence and characteristics of MS in São Miguel, an island in the Atlantic.
Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the central nervous system (CNS). With approximately 2.3 million people estimated to live with MS globally, incidence and prevalence of the disease vary significantly across regions. Generically, the global distribution of MS varies with geographic latitude. However, MS epidemiological data in Southern Europe and Mediterranean countries revealed areas of unexpectedly high prevalence and incidence of MS, thereby demonstrating that clear exceptions to the variation of MS with latitude exist. Epidemiological evidence on MS in Portugal is limited to studies concerning specific regions of the country and therefore not representative of the entire country. More studies form different regions of the country are needed in order to effectively establish MS prevalence and incidence in Portugal. The aim of this study is to determine MS incidence and prevalence, as well as gather information on other clinical data in São Miguel, the biggest island of the Azores, a Portuguese archipelago situated in the North Atlantic. This is a cross-sectional study of MS patients from the only hospital of São Miguel, an island with a population of 137,150 habitants. Only patients from São Miguel were included in the study. 1/07/2019 was established as the prevalence day and demographic characteristics (sex, age at diagnosis and year of diagnosis) and clinical outcome (type of the disease, treatment, clinical severity score [EDSS]) were reported. 5-year Incidence of MS was studied from 1/07/2014 to 01/07/2019. 47 patients were enrolled in the study, 27 (57.4%) were female and 20 (42.6%) were male. 43 patients were classified as having RRMS and 4 patients classified as having SPMS. Prevalence of MS in São Miguel island was 34.3/100.000. The prevalence for females was 38.5/100.000 and for males was 29.9/100.000. Age-adjusted and sex-adjusted (to the population of the European Union in 2019) MS prevalence were 31.1/100.000 and 34.3/100.000 respectively. Incidence was 2.04/100,000 person-years for the overall population, 2.56/100,000 person-years for females and 1.49/100,000 person-years for males. Age-adjusted and sex-adjusted MS incidence were 1.74/100.000 person-years and 2.04/100.000 person-years respectively. Regarding clinical characteristics, the mean EDSS was 2.93 ± 1.85, the mean age at the time of the diagnosis was 31.77 ± 8.47 years and the mean time of evolution of the disease (period between diagnosis and prevalence date) was 9.19 ± 6.55 years. Treatment options were diverse and included first and second-line treatments as well as Immune reconstitution therapies. Interferon-beta was the most prescribed medication. 2 patients were not making any DMT. The incidence and prevalence of MS reported by our study is lower than what was registered by other studies. Several reasons may explain these results such as the ancestry of the population of São Miguel, migratory flows and limitations in detecting all MS patients. Incidence and prevalence were higher in females. A marked heterogeneity in clinical characteristics was seen, with great variability in degree of disability, age at diagnosis and time of MS evolution. Treatment options were quite varied in the population, with Interferon-beta being the most prescribed DMT.


Treatment of carpet and textile industry effluents using Diplosphaera mucosa VSPA: A multiple input optimisation study using artificial neural network-genetic algorithms.
The wastewater treatment efficiency of Diplosphaera mucosa VSPA was enhanced by optimising five input parameters and increasing the biomass yield. pH, temperature, light intensity, wastewater percentage (pollutant concentration), and N/P ratio were optimised, and their effects were studied. Two competitive techniques, response surface methodology (RSM) and artificial neural network (ANN), were applied for constructing predictive models using experimental data generated according to central composite design. Both MATLAB and Python were used for constructing ANN models. ANN models predicted the experimental data with high accuracy and less error than RSM models. Generated models were hybridised with a genetic algorithm (GA) to determine the optimised values of input parameters leading to high biomass productivity. ANN-GA hybridisation approach performed in Python presented optimisation results with less error (0.45%), which were 7.8 pH, 28.8 °C temperature, 105.20 μmol m-2 s-1 light intensity, 93.10 wastewater % (COD) and 23.5 N/P ratio.


On the degradation of heparin by human blood platelets.
Human blood platelets are able to degrade heparin from different tissues and species. The main degradation product is an oligosaccharide. Low molecular weight components such as inorganic sulfate or monosaccharides, i.e. products released by exoenzymes are not detected. The in vitro degradation of heparin by the crude enzyme is observed at pHs below 6.5 with an optimum temperature around 37 degrees C. The presence of sulfate in the substrate structure is shown to be essential for the enzyme activity. Since the oligosaccharides formed have only 10 per cent of the anticoagulant activity of the heparins tested, it is conceivable that the platelet enzyme may play an important role in the inactivation of some of the biological properties of heparin.


Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264.
Bacteria produce a diverse array of secondary metabolites that have been invaluable in the clinic and in research. These metabolites are synthesized by dedicated biosynthetic gene clusters (BGCs), which assemble architecturally complex molecules from simple building blocks. The majority of BGCs in a given bacterium are not expressed under normal laboratory growth conditions, and our understanding of how they are silenced is in its infancy. Here, we have addressed this question in the Gram-negative model bacterium Burkholderia thailandensis E264 using genetic, transcriptomic, metabolomic, and chemical approaches. We report that a previously unknown, quorum-sensing-controlled LysR-type transcriptional regulator, which we name ScmR (for secondary metabolite regulator), serves as a global gatekeeper of secondary metabolism and a repressor of numerous BGCs. Transcriptionally, we find that 13 of the 20 BGCs in B. thailandensis are significantly (threefold or more) up- or down-regulated in a scmR deletion mutant (ΔscmR) Metabolically, the ΔscmR strain displays a hyperactive phenotype relative to wild type and overproduces a number of compound families by 18- to 210-fold, including the silent virulence factor malleilactone. Accordingly, the ΔscmR mutant is hypervirulent both in vitro and in a Caenorhabditis elegans model in vivo. Aside from secondary metabolism, ScmR also represses biofilm formation and transcriptionally activates ATP synthesis and stress response. Collectively, our data suggest that ScmR is a pleiotropic regulator of secondary metabolism, virulence, biofilm formation, and other stationary phase processes. A model for how the interplay of ScmR with pathway-specific transcriptional regulators coordinately silences virulence factor production is proposed.


A six-degree-of-freedom transducer for in vitro measurement of patellofemoral contact forces.
A satisfactory design of the patellar component used in total knee arthroplasty and a general understanding of the effects of orthopedic procedures require, in part, an accurate description of patellofemoral contact forces. Experimental determination of the contact stress distribution requires integration to estimate the contact forces. Due to complex patellar geometry, the determination of the components of the resultant load is difficult. Current techniques for the direct measurement of contact loads either report a single load component or require sequential experiments to fully describe the contact force. The present study describes the development of a six-degree-of-freedom patellofemoral force transducer. This transducer allows the simultaneous determination of the three components of the contact force with an increase in accuracy over available devices. The contact forces components are accurate to 1% of full scale (900 N anterior-posterior, +/- 200 N medial-lateral and inferior-superior). The location on the patella where the resultant force acts is determined to within 1 mm. Relative movement of this point as a function of either normal change in knee flexion angle or as a result of a typical orthopedic procedure is determined to within 0.1 mm. A protocol is presented that allows the contact forces to be determined for either the anatomically normal patella or a patella following total knee arthroplasty.


[Advances in pathogenesis of anemia in rheumatoid arthritis].
The growing importance of anaemia in rheumatoid arthritis (RA) let us to analyze the problems connected with etiopathology and diagnosis of this disease. The main attention was put on iron metabolism disturbances in the pathomechanism of the anaemia in RA.


STAT1- and NFAT-independent amplification of purinoceptor function integrates cellular senescence with interleukin-6 production in preadipocytes.
Senescent preadipocytes promote adipose tissue dysfunction by secreting pro-inflammatory factors, although little is known about the mechanisms regulating their production. We investigated if up-regulated purinoceptor function sensitizes senescent preadipocytes to cognate agonists and how such sensitization regulates inflammation. Etoposide was used to trigger senescence in 3T3-L1 preadipocytes. CRISPR/Cas9 technology or pharmacology allowed studies of transcription factor function. Fura-2 imaging was used for calcium measurements. Interleukin-6 levels were quantified using quantitative PCR and ELISA. Specific agonists and antagonists supported studies of purinoceptor coupling to interleukin-6 production. Experiments in MS1 VEGF angiosarcoma cells and adipose tissue samples from obese mice complemented preadipocyte experiments. DNA damage-induced senescence up-regulated purinoceptor expression levels in preadipocytes and MS1 VEGF angiosarcoma cells. ATP-evoked Ca2+ release was potentiated in senescent preadipocytes. ATP enhanced interleukin-6 production, an effect mimicked by ADP but not UTP, in a calcium-independent manner. Senescence-associated up-regulation and activation of the adenosine A3 receptor also enhanced interleukin-6 production. However, nucleotide hydrolysis was not essential because exposure to ATPγS also enhanced interleukin-6 secretion. Pharmacological experiments suggested coupling of P2X ion channels and P2Y12 -P2Y13 receptors to downstream interleukin-6 production. Interleukin-6 signalling exacerbated inflammation during senescence and compromised adipogenesis. We report a previously uncharacterized link between cellular senescence and purinergic signalling in preadipocytes and endothelial cancer cells, raising the possibility that up-regulated purinoceptors play key modulatory roles in senescence-associated conditions like obesity and cancer. There is potential for exploitation of specific purinoceptor antagonists as therapeutics in inflammatory disorders.


Casual blood glucose levels and prevalence of undiscovered diabetes mellitus in Lagos Metropolis Nigerians.
A diabetic screening exercise involving 1627 subjects (1050 males and 577 females) was carried out in the Lagos Metropolis of Nigeria. Casual capillary blood glucose and/or urine glucose were tested for by means of dipsticks. The prevalence rates of undetected diabetes in the males and females were respectively 1.5% and 1.9%. Mean (+/- SD) casual blood glucose levels were higher in the females (82.8 (+/- 19.1) mg/100 ml) than in the males (75.9 (+/- 16.2) mg/100 ml). The prevalence of renal glycosuria was 1.3% in the males and 0.2% in the females. The prevalence of diabetes mellitus in the Lagos Metropolis appears high but similar to that in many other countries. The ambient blood glucose in the non-hospitalized subjects also seems to be not significantly different from values reported in other places.


Electrokinetic ion transport through unsaturated soil: 2. Application to a heterogeneous field site.
Results of a field demonstration of electrokinetic transport of acetate through an unsaturated heterogeneous soil are compared to numerical modeling predictions. The numerical model was based on the groundwater flow and transport codes MODFLOW and MT3D modified to account for electrically induced ion transport. The 6-month field demonstration was conducted in an unsaturated layered soil profile where the soil moisture content ranged from 4% to 28% (m3 m(-3)). Specially designed ceramic-cased electrodes maintained a steady-state moisture content and electric potential field between the electrodes during the field demonstration. Acetate, a byproduct of acetic acid neutralization of the cathode electrolysis reaction, was transported from the cathode to the anode by electromigration. Field demonstration results indicated preferential transport of acetate through soil layers exhibiting higher moisture content/electrical conductivity. These field transport results agree with theoretical predictions that electromigration velocity is proportional to a power function of the effective moisture content. A numerical model using a homogeneous moisture content/electrical conductivity domain did not adequately predict the acetate field results. Numerical model predictions using a three-layer electrical conductivity/moisture content profile agreed qualitatively with the observed acetate distribution. These results suggest that field heterogeneities must be incorporated into electrokinetic models to predict ion transport at the field-scale.


Model for the regulation of platelet volume and responsiveness by the trans-membrane Na+/K(+)-pump.
The correspondence between K+ uptake in platelets to their responsiveness was studied using 86Rb+ as an analogue of K+. An average 86Rb+ uptake rate of 0.73 (+/- 0.140) x 10(-15) mole Rb+/min-plt (n = 20) was observed. By the use of K(+)-influx inhibitors, we were able to distinguish three distinct 86Rb+ uptake pathways: an ouabain-sensitive (61% +/- 2% inhibitable) pump and two equivalent channels, only one of which is sensitive to furosemide. Other platelet parameters were also examined in conjunction with K(+)-uptake. Platelets incubated with ouabain exhibited an overall rise in their cell volume (MPV) with incubation time (delta MPV = 7.4 x 10(-17) L/min-1 plt-1). Concomitantly, over 24 hours, a steady decrease in platelet number was recorded by blood cell coulter, which correlated inversely with the counts of particles, which by their size resemble white blood cells (r = 0.89). On a cellular level, incubation with ouabain induced greater expression of surface fibrinogen-receptor (GPIIb), increased binding of FITC-labelled fibrinogen, and increased responsiveness to ADP. Our observations suggest the following sequence of events: Ouabain turns off the Na+/K(+)-ATPase pump, which leads to water accumulation in platelets and concomitant increased MPV. Greater expression of fibrinogen receptors on the distended platelet surface corresponds to spontaneous microaggregate formation as well as greater responsiveness to agonists. Our model links volume regulation, the expression of fibrinogen receptors, and the sensitivity of platelets to agonists to the activity of the Na+/K(+)-ATPase pump.


Pulmonary capillary hemangiomatosis in Chinese patients without EIF2AK4 mutations.
Pulmonary capillary hemangiomatosis (PCH) is a very rare and refractory pulmonary vascular disease that causes pulmonary hypertension. Differentiation of PCH from idiopathic pulmonary arterial hypertension (iPAH) is essential because treatment and prognosis can vary greatly between these two diseases. A 20-year-old female and a 33-year-old male both presented with progressive exertional dyspnea and cough. High-resolution computed tomography (HRCT) showed bilateral, diffuse, ill-defined centrilobular nodules of ground-glass opacity, without subpleural thickened septal lines or mediastinal lymphadenopathy. Both cases showed clinical and imaging features characteristic of pulmonary veno-occlusive disease (PVOD) or PCH. The entire EIF2AK4 coding sequence was detected with Sanger sequencing, and no pathogenic EIF2AK4 mutations were identified in either case. Video-assisted thoracoscopic surgery (VATS) was safely performed in both cases, and histopathological examinations of biopsies showed that both patients had PCH. Two patients presented with clinical and imaging characteristics suspicious for PVOD/PCH. Despite having no pathogenic EIF2AK4 mutations, both were diagnosed with PCH by VATS lung biopsies. The diagnostic distinction of PCH is important to prompt timely evaluations of patients who may need lung transplantations.


Estimating the prevalence of hepatitis B by wastewater-based epidemiology in 19 cities in China.
China has the world's largest burden of Hepatitis B virus (HBV) infection, with 86 million HBV carriers, including 32 million chronic Hepatitis B patients. To monitor the HBV prevalence in near real-time, a wastewater-based epidemiology (WBE) method by using lamivudine as a biomarker was conducted in 19 cities in the Southern part of China. LC-MS/MS was utilized to quantify lamivudine in sewage, and satisfactory method validation results were achieved. The average concentration of lamivudine in sewage was 156.4 ± 107.1 ng/L, and the daily consumption was 30.1 ± 19.8 mg/day/1000inh in average ranging from 0.4 to 105.5 mg/day/1000inh. The prevalence of chronic Hepatitis B was estimated to be 2.5% ± 1.7% based on the prevalence of lamivudine usage, which was 0.035% ± 0.023%. Besides, the estimated HBV prevalence in population aged over 15 years in 19 cities was 6.8% ± 4.5% and was consistent with the previous statistical data of 7% in 2018. This research demonstrated that the estimation of HBV prevalence by WBE with lamivudine as a biomarker is feasible in big cities in Southern China.


Precise measurement of single-mode fiber lengths using a gain-switched distributed feedback laser with delayed optical feedback.
A simple method to measure single-mode optical fiber lengths is proposed and demonstrated using a gain-switched 1.55-μm distributed feedback laser without a fast photodetector or an optical interferometer. From the variation in the amplified spontaneous emission noise intensity with respect to the modulation frequency of the gain switching, the optical length of a 1-km single-mode fiber immersed in water is found to be 1471.043915 m ± 33 μm, corresponding to a relative standard deviation of 2.2 × 10(-8). This optical length is an average value over a measurement time of one minute under ordinary laboratory conditions.


Polyamines stimulate lysosomal cystine transport.
Lysosomal cystine transport is a carrier-dependent process that, in isolated lysosomes, is stimulated by proton gradients, membrane potential, and millimolar concentrations of divalent cations. The importance of these regulatory factors in vivo is not well established. Polyamines were found to stimulate cystine transport in Percoll gradient purified rat liver lysosomes with spermidine greater than putrescine = cadaverine greater than spermine in order of effectiveness. Maximal stimulation was achieved with 500 microM spermidine. The effects of optimal concentrations of polyamines and divalent cations on cystine transport were not additive. Spermidine stimulated cystine efflux from lysosomes of cultured human diploid fibroblasts, but had no effect on lysosomes of cystinotic fibroblasts which have defective cystine transport. Spermidine did not accumulate within lysosomes in exchange for cystine, had no effect on lysosomal pH, had only slight effects on the lysosomal membrane potential, and had little effect on either methionine or tyrosine efflux. Polyamines are cellular cytoplasmic components that, in physiologic concentrations, stimulate lysosomal cystine transport.


The reaction mechanism of N-benzoylimidazole with ribonucleotides.
The reaction of uridine 3'-phosphate with benzoylimidazole in the absence and presence of a strong base was followed up by 31P and 1H nmr as well as paper electrophoresis. Possible reaction courses were proposed, the reaction rate constants were calculated and the reaction mechanism was discussed. It is possible to selectively acylate ribonucleotides with benzoylimidazole by appropriate choice of the base used.


Opiate modulation of glucose turnover in dogs.
We examined the effect of opiate infusion and of opiate blockage on glucose turnover in the basal state, using isotope dilution techniques in trained conscious dogs (n = 5). After a primed-continuous infusion of 3-3H glucose to steady state specific activity (90 minutes), infusion of one of the following was given: D-met2 pro5 enkephalinamide (DMPE), a potent morphine-like opiate, 0.5 mus g/kg/min; naloxone, an opiate antagonist, 1.25 mg followed by 10 mus g/min; or saline control. Infusion of DMPE led to a fall in glucose from 92 +/- 3 to 87 +/- 3 mg/dL by 60 minutes (P less than 0.05), associated with a rise in glucose utilization (Rd) from 3.0 +/- 0.4 to 3.9 +/- 0.6 mg/kg/min by 30 minutes (P less than 0.05); a transient rise in glucose production (Ra; from 3.2 +/- 0.4 to 4.3 +/- 0.4 mg/kg/min; P less than 0.05). Changes in counterregulatory hormones did not account for these findings; insulin was unchanged during all infusions; glucagon showed small late rises at 75 minutes during both DMPE and naloxone infusion; cortisol rose by 30 and 15 minutes, respectively, of DMPE and naloxone infusion; epinephrine rose transiently after 5 minutes of naloxone but was unchanged during DMPE, and norepinephrine was unchanged throughout. Saline infusion had no effects on any of these indices. We conclude that a potent opiate with morphine-like effects (DMPE) can lower glucose in dogs by enhancing peripheral glucose utilization independently of hormonal changes.


Close orthopedic surgery skin incision with combination of barbed sutures and running subcuticular suturing technique for less dermal tension concentration: a finite element analysis.
Mechanical forces have an important role in the initiation and progression of orthopedic surgical incisions complications. To avoid incision complications with the reduction of dermal tension, surgeons may choose a buried continuous suture technique other than the traditional interrupted vertical mattress suture. Absorbable barbed sutures are widely used in orthopedics due to their convenience and reducing wound tension. The aim of this research is to compare and explain the advantages of running subcuticular suturing technique with absorbable barbed sutures for orthopedic surgical incisions closure. Finite element models of layered skin and two different suture techniques, running subcuticular suture and intradermal buried vertical mattress suture, ware constructed. The mechanical property difference between standard sutures and barbed sutures was modelled using different contact friction coefficient. Pulling the skin wound was simulated, and the sutures' pressure on the skin tissue was determined. Compared with traditional smooth sutures, the barbed sutures effectively increased the contact force for subepidermal layers, which led the less force variation between different layers. The results also suggested that subcuticular suture caused less stress concentration compared with intradermal buried vertical mattress suture. In conclusion, our study indicated that running subcuticular suturing technique with absorbable barbed sutures for orthopedic surgical incisions closure results in more uniform stress distribution in the dermis. We recommend this combination as the preferred method of skin closure in orthopedic surgery unless contraindicated.


Illness behaviour and action: the patient-role.
This article is part of the general report presenting results of a survey made on a 1165-person representative sample of the Warsaw adult population. The purpose of the survey was to verify an hypothesis concerning the occurrence of social stratification differentiation of attitudes and behaviours related to illness. In Poland, free public medical care service covers the whole society. Hence we can talk about meeting fundamental health needs if the public access to services of official medical institutions is understood under this term. Thus, in this part of the general analysis of behaviours related to illness we can concentrate on differentiations 'of the second rank'. We mean here differences in the medical services utilizations. How and where Warsaw inhabitants use health care services is shown on the example of one chosen case as well as on the example of various utilizations of services of both out-patients' polyclinics and hospitals. There has been observed the phenomenon of increasing frequency of visiting cooperative and private medical centres alongside with their rising social status. These medical centres are considered in public opinion as 'better' than the state-owned ones.


13q interstitial deletion in a moroccan child with hereditary retinoblastoma and intellectual disability: A case report.
Retinoblastoma is the most common malignant tumor of the eye in children (incidence:1/15,000 to 1/20,000 births), with a sex ratio of 1,5/1. Retinoblastoma, in its inherited form, is a disease caused by a syndrome of genetic predisposition to cancer. The RB1 gene, a tumor suppressor gene, is localized at 13q14. This case report shows the indication of the cytogenetic analysis in the management of patients with retinoblastoma, and the interest of a genetic counseling. We report the medical observation of a five and a half years old patient who was followed in the medical genetic's department for intellectual disability: associated with facial dysmorphia. The cytogenetic study objectified the presence of an interstitial deletion of the long arm of chromosome 13: 46, XX, del (13) (q14q22). A genetic counseling, with study of the karyotype of the parents is planned, specially to search for a balanced insertion: 13q14 insertion and deletion. In addition, the patient has been followed since the age of 9 months at the pediatric ophthalmology department for a bilateral retinoblastoma, in remission. A subject carry in constitutional mutation of the RB1 gene has a greater than 90% risk of developing retinoblastoma, and moreover has a genetic predisposition to secondary tumors. This medical observation shows the benefit of the constitutional cytogenetic study for patients with retinoblastoma, in particular in the event of bilateral retinoblastoma. The monitoring of psychomotor development must supplement the ophthalmological monitoring of these patients, with a systematic genetic counseling.


Overexpression of Six1 gene suppresses proliferation and enhances expression of fast-type muscle genes in C2C12 myoblasts.
Sine oculis homeobox 1 (Six1) homeodomain transcription factor is implicated in the genesis of muscle fiber type diversity, but its regulatory mechanisms on the formation of muscle fiber type are still poorly understood. To elucidate the biological roles of Six1 gene in muscle fiber formation, we established C2C12 cell line overexpressing Six1 and determined the effects of forced Six1 expression on muscle-specific genes expression, cell proliferation, and cell cycles. Our results indicated that Six1 overexpression could significantly promote the expression of fast-type muscle genes Atp2a1, Srl, and Mylpf. Furthermore, Six1 overexpressing C2C12 cells displayed a relative lower proliferative potential, and cell cycle analysis showed that Six1 exerted its role in cell cycle primarily through the regulation of G1/S and G2/M phases. In conclusion, Six1 plays an essential role in modulation of the fast-twitch muscle fiber phenotype through up-regulating fast-type muscle genes expression, and it could suppress the proliferation of muscle cells.


Analysis of the O-methylated metabolites of isoprenaline, adrenaline and noradrenaline in physiological salt solutions by high-performance liquid chromatography with electrochemical detection.
This study provides the first report of a sensitive, simple and rapid high-performance liquid chromatographic (HPLC) assay for the simultaneous analysis of isoprenaline and its metabolite, 3-O-methylisoprenaline, in samples of physiological salt solutions. The assay does not require time-consuming sample clean-up or extraction procedures and uses a Nova-Pak C18 column, an isocratic mobile phase and an amperometric detector. In addition, small modifications to the composition of the mobile phase have also provided sensitive assays for noradrenaline and adrenaline and their O-methylated or O-methylated deaminated metabolites (normetanephrine, metanephrine, 3-methoxy-4-hydroxyphenylethylene glycol and 3-methoxy-4-hydroxymandelic acid). These HPLC assays are sufficiently sensitive and rapid to replace the use of [3H]amines and column chromatographic separation of the metabolites for most in vitro studies on the uptake and subsequent metabolism of catecholamines by monoamine oxidase and/or catechol-O-methyltransferase in tissues.


New linkage findings in affective disorders.
Identification of single-gene forms of manic-depressive illness, through linkage demonstrations in pedigrees, offers important opportunities for identification of pathophysiological mechanisms, and for genetic counseling in families with a valid marker of vulnerability.


More than a box to check: Research sponsor and clinical investigator perspectives on making GCP training relevant.
Good clinical practice (GCP) training is the industry expectation for ensuring quality conduct of registrational clinical trials. However, concerns exist about whether the current structure and delivery of GCP training sufficiently prepares clinical investigators and their delegates to conduct clinical trials. We conducted qualitative semi-structured interviews with 13 clinical investigators and 10 research sponsors to 1) examine characteristics of the quality conduct of sponsored clinical trials, including critical tasks and concerns perceived as essential for trial quality, 2) identify key knowledge and skills required to perform critical tasks, and 3) identify gaps and redundancies in GCP training and areas of improvement to ensure quality conduct of clinical trials. Data were examined using applied thematic analysis. The top three tasks identified as critical for the quality conduct of clinical trials were obtaining informed consent, ensuring protocol compliance, and protecting participants' health and safety. Respondents acknowledged that GCP principles address each of these critical tasks but also described many challenges and burdens of GCP training, including high training frequency and repetitive content. Respondents suggested moving beyond GCP training as a mere check-box activity by making it more effective, engaging, and interactive. They also emphasized that applying GCP principles in a real-world, skills-based environment would increase the perceived relevance of GCP training. Our findings indicate that although investigators and sponsors recognize that GCP training addresses tasks critical to the quality conduct of clinical trials, the need for significant improvement in the design, content, and presentation of GCP training remains.


Glutathione S-transferase T1 null genotype is associated with oral cancer susceptibility in Asian populations.
Though there are many studies assessing the association between glutathione S-transferase T1 (GSTT1) null genotype and oral cancer risk, the association between GSTT1 null genotype and oral cancer in Asian populations is still inconclusive. We performed a meta-analysis of 19 studies including 2,845 cases and 4,295 controls to derive a more precise estimation of the relationship. The pooled odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI) was used to assess the relationship. Meta-analysis of those 19 studies suggested that there was an association between GSTT1 null genotype and elevated risk of oral cancer risk (OR = 1.25, 95 % CI = 1.00-1.56, P = 0.047). Sensitivity analysis by omitting one study at a time showed that the significance of the corresponding pooled ORs was materially altered frequently, indicating that the pooled ORs were not statistically stable. In addition, there was no obvious risk of publication bias in the meta-analysis. Therefore, the present meta-analysis suggests that the GSTT1 null genotype is a risk allele for oral cancer development in Asian populations, but more studies with large sample and well-matched controls are needed to further confirm the finding from the meta-analysis.


[CLINICAL, ENDOSCOPIC AND MORPHOLOGICAL FEATURES OF GASTROESOPHAGEAL REFLUX DISEASE IN PATIENTS WITH CERTAIN SURGICAL DISEASES OF THE UPPER GASTROINTESTINAL TRACT].
To reveal the peculiarities of manifestations and treatment of gastroesophageal reflux disease (GERD) in patients with peptic ulcer disease of the stomach and duodenum, hiatal hernia (HH) and after stomach resection. 387 patients with GERD, peptic ulcer disease of the stomach and duodenum (200 patients), after resection of the stomach Billroth II (150 patients), 37 patients with HH. Videoendoscopic equipment company OLYMPUS (Japan) was used. Biopsies of the mucous membranes of the pylorus, body, angle of the stomach and esophagus were studied to identify preneoplastic changes. HP was determined histologically, cytologically, urease tests. The patients with GERD and peptic ulcer disease of the stomach and duodenum were complained on the heartburn, the patients after resection of the stomach--on feeling bitterness in the mouth, with HH--on the pain behind the breastbone. More severe degree of GERD (C and D) was endoscopic feature in patients with HH and A degree or endoscopic negative form--after resection of the stomach. Preneoplastic changes of the esophageal mucosa with columnar epithelium were found in cases of less severe degrees of inflammation. The degree of esophagitis, presence of preneoplastic changes were determined depending on the presence of Helicobacter pylori. Antireflux surgery was performed under strict indications. Clinical features, endoscopic, morphological manifestations of GERD in patients with pectic ulcer disease of the stomach and duodenum, with resection of the stomach and patients with HH were determined. This is dictated the individual differentiated approach to the choice of the treatment.


[Authorization of tissue and blood stem cell preparations for hematopoietic reconstitution: Documentation of clinical and nonclinical data in a central expert report].
In order to address the European Directive 2004/23 on human tissues and cells, the authorization obligation for tissue and blood stem cell preparations was introduced (§ 21a AMG) in the year 2007 in the German medicinal products act. Stem cell transplantation for hematopoietic reconstitution has been in use for decades and is well established for the treatment of many malignancies. The manufacture of stem cell preparations varies, but in terms of hematopoietic reconstitution, different products are intended for the same indication. Taking these aspects into account, it was considered inappropriate that every single applicant should provide their own documentation, including an expert report on clinical and nonclinical data. Consequently, the idea came up to create a central expert report, to which all applicants could refer and would include relevant clinical and nonclinical data according to current knowledge. A central expert report was therefore generated, called the "Gemeinsame Stellungnahme der Fachgesellschaften Deutsche Gesellschaft für Transfusionsmedizin und Immunhämatologie (DGTI), Deutsche Gesellschaft für Hämatologie und Onkologie (DGH) und Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH)". Applicants are allowed to refer to this central expert report provided their stem cell product is comparable with the cell preparations included in the report. In order to represent current knowledge, the content of the central expert report was already reworked once, but should be updated regularly.


Addressing joint action challenges in HRI: Insights from psychology and philosophy.
The vast expansion of research in human-robot interactions (HRI) these last decades has been accompanied by the design of increasingly skilled robots for engaging in joint actions with humans. However, these advances have encountered significant challenges to ensure fluent interactions and sustain human motivation through the different steps of joint action. After exploring current literature on joint action in HRI, leading to a more precise definition of these challenges, the present article proposes some perspectives borrowed from psychology and philosophy showing the key role of communication in human interactions. From mutual recognition between individuals to the expression of commitment and social expectations, we argue that communicative cues can facilitate coordination, prediction, and motivation in the context of joint action. The description of several notions thus suggests that some communicative capacities can be implemented in the context of joint action for HRI, leading to an integrated perspective of robotic communication.


The impact of pre-eclampsia definitions on the identification of adverse outcome risk in hypertensive pregnancy - analyses from the CHIPS trial (Control of Hypertension in Pregnancy Study).
To examine the association between pre-eclampsia definition and pregnancy outcome. Secondary analysis of Control of Hypertension in Pregnancy Study (CHIPS) trial data. International multicentre randomised controlled trial (RCT). In all, 987 women with non-severe non-proteinuric pregnancy hypertension. We evaluated the association between pre-eclampsia definitions and adverse pregnancy outcomes, stratified by hypertension type and blood pressure control. Main CHIPS trial outcomes: primary (perinatal loss or high-level neonatal care for >48 hours), secondary (serious maternal complications), birthweight <10th centile, severe maternal hypertension, delivery at <34 or <37 weeks, and maternal hospitalisation before birth. Of 979/987 women with informative data, 280 (28.6%) progressed to pre-eclampsia defined restrictively by new proteinuria, and 471 (48.1%) to pre-eclampsia defined broadly as proteinuria or one/more maternal symptoms, signs or abnormal laboratory tests. The broad (versus restrictive) definition had significantly higher sensitivities (range 62-79% versus 36-50%), lower specificities (range 53-65% versus 72-82%), and similar or higher diagnostic odds ratios and 'true-positive' to 'false-positive' ratios. Stratified analyses showed similar results. Addition of available fetoplacental manifestations (stillbirth or birthweight <10th centile) to the broad pre-eclampsia definition improved sensitivity (74-87%). A broad (versus restrictive) pre-eclampsia definition better identifies women who develop adverse pregnancy outcomes. These findings should be replicated in a prospective study within routine healthcare to ensure that the anticipated increase in surveillance and intervention in a larger number of women with pre-eclampsia is associated with improved outcomes, reasonable costs and congruence with women's values. A broad (versus restrictive) pre-eclampsia definition better identifies the risk of adverse pregnancy outcomes.


Simulation of electrophoretic separations: effect of numerical and molecular diffusion on pH calculations in poorly buffered systems.
A poorly buffered cationic isotachophoresis separation, first simulated by Reijenga and Kasica, has been revisited to demonstrate that an inconsistent description of solute and charge transport can lead to significant errors in the pH calculation. The separation is first simulated using a second-order finite difference scheme to show that omission of molecular diffusion from the charge balance results in a pH profile with spurious dips in the steady-state zone boundaries. The separation is also simulated using two first-order methods that employ numerical diffusion to stabilize solutions against spatiotemporal oscillations. Similar pH dips are generated by these first-order schemes, even when molecular diffusion is included in the charge balance, if numerical diffusion is not considered amongst the charge transport mechanisms. When numerical diffusion, inherent in the discretization of the component balances, is introduced to the charge balance, the spurious pH dips are eliminated. The results indicate that (i) pH dips originally reported by Reijenga and Kasicka are merely artifacts of their numerical model, and (ii) nonoscillatory numerical techniques, such as upwinding and flux limiters, should incorporate artificial transport mechanisms in the charge as well as the solute balances.


Can we utilize photorefractive keratectomy to improve visual acuity in adult amblyopic eyes?
To report the results of photorefractive keratectomy (PRK) in adult amblyopic patients. Noncomparative case series. Thirty-eight amblyopic eyes of 36 adult patients who had undergone PRK ranging from -14.63 diopters (D) to +3.75 D (mean, -6.38+/-4.10) were analyzed. Preoperative and postoperative (1, 3, and 6 months) refractions and measurements of the best spectacle-corrected visual acuity (BSCVA) were reviewed. Statistical evaluation was performed using a paired Student's t test. Best-corrected visual acuity before and after PRK. Before PRK, BSCVA ranged between 0.2 and 0.7 lines (mean, 0.60+/-0.13). One month after PRK, BSCVA ranged between 0.2 and 1.2 lines (mean, 0.77+/-0.24), with a significant difference (P = 3x10(-5)). Three months after PRK, BSCVA ranged between 0.15 and 1.15 lines (mean, 0.84+/-0.23), with a significant difference (P = 5x10(-7)). Six months after PRK, BSCVA ranged between 0.25 and 1.3 lines (mean, 0.88+/-0.25), with a significant difference (P = 8x10(-8)). Our study does not imply that refractive surgery should or may be performed in young children but, rather, that adults wishing to undergo refractive surgery may undertake such procedures despite an amblyopic eye thought to be refractory to visual rehabilitation by conventional methods, such as spectacles and contact lenses.


Androcoll-E large selects a subset of live stallion spermatozoa capable of producing ROS.
The aim of this study was to elucidate if SLC after 24 h storage selects the subpopulation of spermatozoa that better withstands osmotic shock. To test this hypothesis, viability, mitochondrial membrane potential (MMP) and superoxide anion (O(2)(·-)) production of uncentrifuged (UC) and single layer centrifugation (SLC) - selected spermatozoa were analyzed following SLC after storage of the semen. An aliquot of the extended ejaculate (100×10(6) spermatozoa/mL) was centrifuged through a single layer of a silane-coated silica based colloid formulation optimized for equine spermatozoa (Androcoll-E large, SLU, Sweden) and the rest was used as control. UC and SLC-sperm samples were subjected to osmotic challenges (75 and 900 mOsm) with a subsequent return to isosmolarity (300 mOsm) using Biggers-Whitten-Whittingham (BWW) medium. Viability and MMP decreased after the different osmotic stress in UC and SLC spermatozoa, and return to isosmolarity did not reverse these effects. O(2)(·-) production was enhanced after SLC in all osmolarities tested. Interestingly, the percentage of living spermatozoa showing O(2)(·-) production was increased after 900 mOsm stress in UC spermatozoa, this increase being more evident in SLC spermatozoa. Returning spermatozoa to 300 mOsm enhanced this percentage in UC viable cells but not in SLC spermatozoa. The scenario observed for UC spermatozoa shows that O(2)(·-) is produced in response to isolated hyperosmolarities and subsequent osmotic excursions. As the viability, MMP and cell volume remained the same between SLC and UC spermatozoa, we conclude that Androcoll-E large is likely selecting a higher percentage of physiologically O(2)(·-) producing spermatozoa.


[Solitary bone plasmocytoma: Experience from the radiotherapy department at Mohammed-V military teaching hospital in Rabat (Morocco)].
The primary objective was to determine in our department the progression-free survival rate of patients with solitary bone plasmocytoma and secondarily to evaluate its diagnostic, therapeutic and evolutionary aspects. This is a retrospective review of 12 patients monitored and treated in the radiotherapy department of the Mohammed-V military medical teaching hospital in Rabat for a solitary bone plasmocytoma between January 2012 and December 2018. The average age of our patients were 53.8 years old (range: 31-72 years old). Pain was the most common telltale sign. The site of the lesions was spinal in four cases, iliac in four cases, mandibular, ribal, humeral and at the level of the astragalus in one case respectively. All patients received radiotherapy. This irradiation was delivered alone in 60% of cases or associated with surgery in 40% of cases. The average dose of radiotherapy was 47.3Gy (range: 45 to 50.4Gy) and this was delivered by a modulated volumetric arc therapy technique in ten patients and conformal tridimensional radiotherapy in two patients. Local control, defined by stability or radiological regression, was obtained in ten patients and four patients progressed to multiple myeloma, two of whom died. The average duration of follow-up was 51 months. Radiation therapy is the standard treatment for solitary bone plasmocytoma. It ensures good local control in 90% of cases. The prognosis is affected by progression to multiple myeloma, which justifies rigorous monitoring after treatment and suggests a reflection on the exact place of chemotherapy.


Intracerebral hemorrhage after transcatheter thrombolysis of non-occluding superior mesenteric artery thrombosis.
We performed transcatheter thrombolysis on a 64-year-old man with non-occluding superior mesenteric artery (SMA) thrombosis because his severe symptoms could not be controlled with medication. An enhanced computed tomography (CT) scan revealed intramural thrombosis in the SMA. We were concerned that the narrowing of the SMA lumen might progress to complete occlusion, resulting in a high likelihood of mortality. After dissolution of the SMA thrombosis, the original symptoms almost completely disappeared. However, intracranial hemorrhage occurred 8 hr after thrombolysis, requiring surgical intervention. Transcatheter thrombolysis is thought to be a useful treatment for SMA thrombosis, especially in elderly patients with a high operative risk; however, the possibility of intracerebral hemorrhage must be taken into consideration.


Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukaemia: a Nordic series comparing two treatment periods. For the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Leukaemia Cytogenetic Study Group.
The prognostic impact of acquired chromosome abnormalities was evaluated in a population-based consecutive series of 768 children (< 15 years of age) with acute lymphoblastic leukaemia (ALL). The study cohort included all cases of cytogenetically abnormal childhood ALL diagnosed between 1986 and 1997 in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). The probability of event-free survival (pEFS) for the total cohort was 0. 72 +/- 0.02. When comparing the two treatment periods of July 1986 to December 1991 and January 1992 to December 1997, a better survival was seen for the latter time period (pEFS of 0.69 +/- 0.02 vs. 0.76 +/- 0.02, P = 0.05). Hypodiploidy with less than 45 chromosomes, t(9;22)(q34;q11) and 11q23 translocations were associated with a dismal outcome during the whole study period (pEFS of 0.57 +/- 0.12, 0.41 +/- 0.14 and 0.37 +/- 0.10 respectively). The poor prognostic influence of 11q23 rearrangements seemed to be restricted to infants and older children (> 10 years), who differed significantly from children aged 1-10 years in this regard (P < 0. 01). Patients with t(9;22)-positive ALL seemed to benefit from allogeneic bone marrow transplantation in first remission (P = 0.05). The pEFS for children with t(1;19)(q23;p13)-positive ALL was intermediate (0.63 +/- 0.17), with a tendency to a better outcome for patients with the unbalanced variant der(19)t(1;19). Hyperdiploid ALL patients, subdivided into moderate hyperdiploidy (47-51 chromosomes), massive hyperdiploidy (52-60 chromosomes) and cases in the tri-/tetraploid range (> 60 chromosomes) had the best outcome in the last treatment period (pEFS of 0.81 +/- 0.06, 0.80 +/- 0.04 and 0.88 +/- 0.07 respectively), unless t(1;19), t(8;14), t(9;22) or 11q23 translocations were present. In a multivariate analysis including white blood cell (WBC) count, immunophenotype, age, mediastinal mass, central nervous system involvement and leukaemia karyotype, only WBC and modal chromosome number were shown to be significant independent risk factors (P < 0.01).


Changing natural conditions and their impact on the Mt. Śnieżnica landscape, Outer Western Carpathians - Reconstruction of the Holocene environment based on geochemical indices and radiocarbon dating.
Environmental changes during the Holocene impacted the development of all civilizations, and it is important to understand the power of this influence through, for instance, the reconstruction of these changes. However, when the climate and environmental conditions of the deep past are analyzed, researchers need to rely on various types of proxy data that are only approximations of the required information. In addition, this type of information is often absent or has several gaps (hiatuses). In the present study, we analyzed a 4.4-m deep core excavated from the fen formed within the landslide body on the northern side of Mt. Śnieżnica in the Wyspowy Beskidy Mountains, the Outer Western Carpathians, southern Poland. In total, we analyzed 405 samples in terms of 29 geochemical components (e.g., nitrogen (N), carbon (C), sulfur (S), and the total organic carbon (TOC)) and physical properties, namely particle-size distribution, loss on ignition (LOI), and microcharcoal content. Additionally, to establish geochronology, we dated 27 samples of different biological materials using the Accelerator Mass Spectrometry radiocarbon method. A detailed examination of plant macrodetritus and wood anatomy supported our interpretation based on the geochemical data. The Mt. Śnieżnica landslide probably formed ca. 14,000 cal BP in the first phase of the Allerød Interstadial. For almost 9000 years, there were no appropriate terrain conditions for the long-term accumulation of organo-mineral materials. At ca. 4400 cal BP, peat accumulation commenced. The beginning of peat accumulation correlates with the global 4.2 Bond event of cold climate conditions. After another ca. 2000 years, the core sediments were dominated by limnetic mud, suggesting aquatic conditions in the landslide depression. This sudden shift in the characteristics of sedimentation is loosely linked to the boundary between the Subboreal and Subatlantic phases (ca. 2500 cal BP). The apparent dichotomy of the depositional record agrees with the reconstructed climatic conditions during the second part of the Holocene. Up to 3000 cal BP, the regional climate was warm and humid, which allowed fast biomass production and hillslope stabilization by trees. Forest fires occurred only at the beginning and end of this period (4400-3000 cal BP). After 3000 cal BP, the regional climate became cool and dry. In this period, we found evidence of intensified erosion, but it was unrelated to forest fire activity.


Adults' Stress Response to Unexpected Oral and Arithmetic Tasks in Supine Position.
To study the autonomic nervous system (ANS) and hypothalamus pituitary adrenal axis (HPA) response before and after mental stress test in healthy adolescents and adults, is the aim of this study. Twenty healthy adults (aged 23-46 years) entered the Trier Social Stress Test (TSST), after informed consent signing. The procedure was modified: (a) the participants' position was supine as ANS system changes were to be assessed, (b) the interviewers were entering and departing from the session room. Salivary cortisol (marker of HPA axis response) samples were collected at the end of the baseline and 20 min after TSST. ANS of the heart was measured with CNS Task Force Monitor in supine position and was recorded during relaxation (15 min) and after TSST. The sympathovagal balance (LF/HF ratio) for each phase was computed. Evaluations were conducted with R. The HPA axis disturbance between baseline and 20 min after TSST was significant (g = 0.545 [0.092, 0.999]) and in adolescents (whereas, the mean intervals of the sinus rhythm RR parameter were found largely changed (g = 0.834 [0.340, 1.327]). The sympathovagal balance component of heart rate variability LF/HF ratio was founded unchanged (g = 0.215 [-0.211, 0.641]). RR changes were not correlated to salivary cortisol concentrations at any phase. Mean RRIs and salivary cortisol levels were significantly increased, although HPA axis showed medium size effect. However, the systems effectively counterbalance the perturbation, since the LF/HF ratio does not change. Our findings suggest further research in stress effect on HPA and ANS cross-talk and dynamics.


Nanoscale zero-valent iron supported on mesoporous silica: characterization and reactivity for Cr(VI) removal from aqueous solution.
MCM-41-supported nanoscale zero-valent iron (nZVI) was sytnhesized by impregnating the mesoporous silica martix with ferric chloride, followed by chemical reduction with NaHB4. The samples were studied with a combination of characterization techniques such as powder X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) and Mössbauer spectroscopy, N2 adsorption measurements, transmission electron microscopy (TEM), magnetization measurements, and thermal analysis methods. The experimental data revealed development of nanoscale zero-valent iron particles with an elliptical shape and a maximum size of ∼80 nm, which were randomly distributed and immobilized on the mesoporous silica surface. Surface area measurements showed that the porous MCM-41 host matrix maintains its hexagonal mesoporous order structure and exhibits a considerable high surface area (609 m(2)/g). Mössbauer and magnetization measurements confirmed the presence of core-shell iron nanoparticles composed of a ferromagnetic metallic core and an oxide/hydroxide shell. The kinetic studies demonstrated a rapid removal of Cr(VI) ions from the aqueous solutions in the presence of these stabilized nZVI particles on MCM-41, and a considerably increased reduction capacity per unit mass of material in comparison to that of unsupported nZVI. The results also indicate a highly pH-dependent reduction efficiency of the material, whereas their kinetics was described by a pseudo-first order kinetic model.


Concomitant secretion of Schwangerschaftsprotein 1 and human chorionic gonadotrophin following conception.
Daily measurements of serum oestradiol, progesterone, Schwangerschaftsprotein 1 (SP1) and hCG were made in 13 menstrual cycles during which conception occurred. The assays were continued until 21 d after ovulation. SP1 was detected in maternal blood 8-14 d after ovulation and hCG 9-13 d after ovulation. We conclude that these two proteins are secreted simultaneously but independently by the syncytiotrophoblast.


Kinin antagonist activity of compounds from Mandevilla velutina in the rat isolated uterus.
The effect of four semi-purified compounds obtained from Mandevilla velutina crude extract by silica gel chromatography fractionization were analysed for their inhibitory effects on uterine contractions induced by bradykinin (BK), lysylbradykinin (L-BK), acetylcholine (ACh) and oxytocin, in vitro. None of the compounds tested affected uterine tone. Pre-incubation for 20 min with fraction 12 (20 to 80 micrograms ml-1), isolated from M. velutina produced a parallel and concentration-dependent displacement to the right of the concentration-response curves for BK and L-BK (1 to 1000 nM). Schild plots of these data were linear (correlation close to unity) and yielded a nominal pA2 value (as g ml-1) of 5.1 and 4.9, respectively, and the values of the slopes were not significantly different from unity. Fraction 11 (10 to 40 micrograms ml-1) also produced a parallel and concentration-dependent displacement to the right of the BK concentration-response curve. The Schild plot gave a mean pA2 value (g ml-1) of 5.4 and a slope not significantly different from unity. Fraction 12 did not influence the uterine contractile responses induced by ACh (0.1 to 100 microM) and oxytocin (0.01 to 30 miu ml-1) at concentrations less than 80 micrograms ml-1. Fraction 16 (20 to 80 micrograms ml-1) antagonized the action of BK only at concentrations greater than 40 micrograms ml-1, whereas fraction 5 (20 to 80 micrograms ml-1) was completely inactive against BK-induced responses. 5 As observed previously with the crude extract, the onset of the BK antagonistic action of these compounds was rapid and completely reversible following intermittent washing of the preparation for 30-60 min. 6 These results indicate the existence of at least two compounds in the crude extract of Mandevilla velutina that act as competitive and selective kinin antagonists on the isolated uterus of the rat.


[Effectiveness of lidocaine use in the initial period of acute myocardial infarct].
The efficiency of variant regimens of lidocaine management of acute myocardial infarction is compared. The need for continuous infusion of the drug throughout the first day of the attack at the rate of 1 mg per minute, and the reduction in the maximum heart rate as well as the incidence, rate and duration of the ventricular tachycardia runs are demonstrated.


Practice of walking and its association with perceived environment among elderly Brazilians living in a region of low socioeconomic level.
The aim of this study was analyze associations between the practice of walking and environmental perception among elderly Brazilians in a region of low socioeconomic level. A cross-sectional study was conducted among 385 elderly people aged 60 years and over. To evaluate walking, the International Physical Activity Questionnaire (IPAQ), long version (leisure and transport modules) was used. The environment was evaluated by means of the Neighborhood Environmental Walkability Scale (NEWS) (adapted Brazilian version). For the statistical analysis, multiple logistic regression models were created separately for men and women. The practice of at least 150 minutes a week of walking was the dependent variable, and the variables of environmental perception were the independent variables. All the models were controlled for schooling level and age. The proportion of elderly people active in walking was 56.9% for the men and 26.4% for the women. The perception of the presence of soccer fields (OR = 4.12) and their proximity, within ten minutes' walk from home (OR = 3.43), were associated with the practice of walking among the men. The perception of the presence of public squares (OR = 4.70) and the proximity of primary healthcare units, within ten minutes' walk from home (OR = 3.71), were associated with the practice of walking among the women. An association with adequate perception of vehicle traffic remained at the threshold of significance for the women. Accessibility of leisure structures such as football fields and public squares and of health services such as primary healthcare units were important environmental variables associated with the practice of walking among elderly people living in a region of low socioeconomic level in Brazil. These variables need to be taken into consideration when aiming to promote the practice of walking among elderly people living in similar regions.


All-cause and cardiovascular mortality risk estimation using different definitions of metabolic syndrome in Lithuanian urban population.
The objective of the study was to assess mortality risk in the subjects with diagnosed metabolic syndrome (MS) using National Cholesterol Educational Program (NCEP-ATPIII), American Heart Association and National Heart Lung and Blood Institute (AHA/NHLBI) International Diabetes Federation (IDF) and Joint Interim Societies (JIS) definitions. Two random samples aged 35-64 years were examined in 1992-2002 in the framework within the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study (N=2455). The follow-up was carried out in terms of the end points reached from the baseline health examinations until December 31, 2009. Cox regressions demonstrated that MS defined by IDF and JIS definitions remained the only significant determinants for all-cause mortality (RR=1.48 and RR=1.41; p<0.05) and cardiovascular disease (CVD) mortality in men (RR=1.81 and RR=1.66; p<0.05). In men (without previous CVD) the NCEP-ATPIII definition had increased mortality risk from CVD (RR=1.98; p=0.012), than in men with identified MS by the IDF and the new JIS definition. In women the MS was not associated with risk of mortality from CVD. The MS definitions according to the IDF and JIS criteria appear to be a slightly better predictor of all-cause mortality and mortality from CVD; MS according to the NCEP-ATPIII criteria appears to be a better predictor of mortality from CVD in men.


Synthesis and in vivo pharmacology of new derivatives of isothiazolo[5,4-b]pyridine of Mannich base type.
Recently we reported on 2H-4,6-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridine (V), which exhibited high anorectic action in animal models as a result of stimulation of serotoninergic system. This paper describes the synthesis of the series 3-5 of analogues of V prepared from 2-hydroxymethyl-4,6-dimethylisothiazolopyridine (2) and corresponding 4-substituted-piperazines(piperidines) or tetrahydroisoquinoline. The 12 compounds obtained were screened in standard CNS tests in in vivo (mice and rats). In contrast to V, none of its analogues showed serotoninergic activity, whereas several of these compounds were found to be active as weak to moderate analgesic agents. According to X-ray and molecular modeling studies the different pharmacological profile of V and its o-OCH3 analog 3a, taken as an example, should be referred back to the conformational restriction incorporated by the o-substitution rather than effects of different lipophlicity or basicity of these compounds.


Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1-7.
Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1-7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) stress and apoptosis in AECs and cause lung fibrosis. This study tested the hypothesis that ER stress-induced apoptosis of AECs might also be regulated by the autocrine ANGII/ANG1-7 system of AECs. ER stress was induced in A549 cells or primary cultures of human AECs with the proteasome inhibitor MG132 or the SP-C BRICHOS domain mutant G100S. ER stress activated the ANGII-generating enzyme cathepsin D and simultaneously decreased the ANGII-degrading enzyme ACE-2, which normally generates the antiapoptotic peptide ANG1-7. TAPI-2, an inhibitor of ADAM17/TACE, significantly reduced both the activation of cathepsin D and the loss of ACE-2. Apoptosis of AECs induced by ER stress was measured by assays of mitochondrial function, JNK activation, caspase activation, and nuclear fragmentation. Apoptosis induced by either MG132 or the SP-C BRICHOS mutant G100S was significantly inhibited by the ANG receptor blocker saralasin and was completely abrogated by ANG1-7. Inhibition by ANG1-7 was blocked by the specific mas antagonist A779. These data show that ER stress-induced apoptosis is mediated by the autocrine ANGII/ANG1-7 system in human AECs and demonstrate effective blockade of SP-C mutation-induced apoptosis by ANG1-7. They also suggest that therapeutic strategies aimed at administering ANG1-7 or stimulating ACE-2 may hold potential for the management of ER stress-induced fibrotic lung disorders.


Differences in Liver Graft Survival by Recipient Sex.
We aimed to characterize patterns of differences in liver graft failure rates by recipient sex, accounting for the modifying effects of donor sex and recipient age. We evaluated 144 212 first deceased donor liver transplant recipients [1988-2019; Scientific Registry of Transplant Recipients (SRTR)]. We used multivariable time-varying Cox models, considering a recipient sex by donor sex by recipient age (0-12, 13-24, 25-44, ≥45 y) interaction. Among recipients of male donors, females <45 y had higher graft failure rates than males of the same age, but none of these differences were statistically significant [0-12 y: adjusted hazard ratio (aHR) 1.17 (0.98, 1.40); 13-24 y: aHR 1.18 (0.96, 1.46); 25-44 y: aHR 1.11 (0.96, 1.28)]; there was no material or statistically significant difference between female and male recipients ≥45 y [aHR 1.01 (0.97, 1.06)]. When the donor was female, recipients <45 y showed no statistically significant differences in graft outcomes by recipient sex [0-12 y: aHR 0.91 (0.74, 1.11); 13-24 y: aHR 0.98 (0.77, 1.25); 25-44 y: aHR 0.86 (0.73, 1.01)], whereas female recipients ≥45 y had significantly lower graft failure rates [aHR 0.85 (0.81, 0.89)] than males of the same age. Among recipients of female donors, female recipients ≥45 y had significantly better outcomes than males of the same age; there were no clear differences by recipient sex in younger recipients. When the donor was male, there was no material or statistically significant difference in graft failure rates between males and females ≥45 y; among younger recipients point estimates suggested higher failure rates in females than males recipients, but confidence intervals were wide making firm conclusions impossible. Larger studies combining multiple datasets are needed.


A versatile reactor for continuous monitoring of biofilm properties in laboratory and industrial conditions.
The understanding of the dynamics of surface microbial colonization with concomitant monitoring of biofilm formation requires the development of biofilm reactors that enable direct and real-time evaluation under different hydrodynamic conditions. This work proposes and discusses a simple flow cell reactor that provides a means to monitoring biofilm growth by periodical removing biofilm-attached slides for off-line, both non-destructive and destructive biofilm analyses. This is managed without the stoppage of the flow, thus reducing the contamination and the disturbance of the biofilm development. With this flow cell, biofilm growth and respiratory activity can be easily followed, either in well-defined laboratory conditions or in an industrial environment. The reproducible and typical biofilm development curves obtained, validated this flow cell and confirmed its potential for different biofilm-related studies, which can include biocidal treatment.


Metabolic engineering of Aspergillus oryzae for efficient production of l-malate directly from corn starch.
l-Malate, an important chemical building block, has been widely applied in the food, pharmaceutical, and bio-based materials industries. In previous work, we engineered Aspergillus oryzae by rewiring the reductive tricarboxylic acid pathway to produce l-malate from glucose. To decrease the production cost, here, we further engineered A. oryzae to efficiently produce l-malate directly from corn starch with simultaneous liquefaction-saccharification and fermentation. First, a promoter PN5 was constructed by quintuple tandem of the 97-bp fragment containing the cis-element of the glucoamylase gene promoter (PglaA), and with the promoter PN5, the transcriptional level of glaA gene increased by 25-45%. Then, by co-overexpression of glaA, a-amylase (amyB) and a-glucosidase (agdA) genes with the promoter PN5, the l-malate titer increased from 55.5g/L to 72.0g/L with 100g/L corn starch in shake flask. In addition, to reduce the concentration of byproducts succinate and fumarate, a fumarase from Saccharomyces cerevisiae, which facilitated the transformation of fumarate to l-malate, was overexpressed. As a result, the concentration of succinate and fumarate decreased from 12.6 and 1.29g/L to 7.8 and 0.59g/L, and the l-malate titer increased from 72.0g/L to 78.5g/L. Finally, we found that the addition of glucose at the initial fermentation stage facilitated the cell growth and l-malate synthesis, and the l-malate titer further increased to 82.3g/L by co-fermentation of 30g/L glucose and 70g/L corn starch, with a productivity of 1.18g/L/h and a yield of 0.82g/g total carbon sources.


The status of international collaborations in compilation of Iranian scientific articles on environmental health engineering.
Scientific cooperation is one of the effective methods to access current knowledge and technologies and also to use successful experiences of researchers in developed countries by academicians living in developing countries. This study aimed to determine the level of international contribution in compilation of scientific articles in Iranian journals published in the field of environmental health engineering. This descriptive and retrospective study was conducted within a 10-year period (2008-2017), in which all articles published in five specialized Iranian journals of environmental health engineering were reviewed using a researcher-made checklist. The information collected in the checklist included: the year of publication, number of issues and articles, information about the status of authors' participation in terms of number of authors, sex, institutional affiliation, country, continents, and research centers. Descriptive and inferential statistics such as index of dispersion, measures of central tendency, and Chi-square and t tests were used to statistically analyze the data. Besides, VOSviewer software was used to visualize the data. The review of 1276 articles published in 102 issues of the five journals of environmental health engineering in Iran showed that 184 articles were written with the participation of researchers from other countries. Most articles with the participation of international authors during the last decade were published in 2014. Chi-square test indicated a significant difference in the publication of these articles within 2014-2015 than other years (P = 0.001). Among the five journals, the best participation of international researchers was observed in J Environ Health Sci Engineer (168 articles, 91.3%). Considering the number of joint articles with Iran, the top continents were Asia, Europe, and Africa each with 117, 52, and 32 articles, respectively. India, Turkey, and Malaysia had the highest level of cooperation with Iranian researchers with 53, 16, and 14 articles, respectively. 637 authors contributed in 184 articles, of whom 469 (73.6%) were male and 121 (18.9%) were female. T test was used to compare the mean number of male and female authors in the articles with or without the participation of international researchers, which showed no significant difference. International contribution of researchers in compilation of specialized environmental health articles was good. Given the low level of cooperation between researchers from developed European and American countries and their Iranian counterparts, it seems necessary to adopt different methods to attract more collaboration from researchers working in developed countries considering their significant role in health-related areas.


Splicing and Dicing MYC-Mediated Synthetic Lethality.
In a recent issue of Nature, Hsu and colleagues report that oncogenic MYC activation is synthetic lethal with inhibition of the core spliceosome, because MYC-driven growth and increased transcription leave tumors dependent on pre-mRNA processing for survival. As direct targeting of MYC has remained elusive, synthetic lethal strategies are attractive.


Isolation and characterization of two protamines St1 and St2 from stallion spermatozoa, and amino-acid sequence of the major protamine St1.
Two protamines, St1 and St2, were isolated from stallion sperm nuclei, where they represent about 75 and 25%, respectively, of the total basic protein complement. The primary structure of protamine St1 (49 residues; Mr approximately equal to 6600) has been determined. The structure of this protamine is compared to the amino-acid sequence of other mammalian protamines already known.


Efficacy of tocilizumab highlighted by FDG-PET/CT in a patient with relapsing polychondritis-associated aortitis.
Relapsing polychondritis (RP) is a rare systemic inflammatory disease primarily affecting the ears, nose and tracheobronchial tree cartilage, but also the cardiovascular system. Cardiovascular complications are the second cause of mortality in RP. We report the case of a woman with a corticosteroid-resistant RP-associated aortitis, who was successfully treated with tocilizumab (TCZ). The FDG-PET/CT was a useful tool for diagnosing aortitis and assessing the effect of biotherapy. We conducted a systematic literature review confirming this is the first case of rapid and sustained remission in a patient with corticosteroid-resistant RP-associated aortitis after TCZ treatment administered as a first-line immunotherapy. However, further studies are needed to confirm the beneficial effect of TCZ used in this life-threatening condition.


Gypenosides Synergistically Enhances the Anti-Tumor Effect of 5-Fluorouracil on Colorectal Cancer In Vitro and In Vivo: A Role for Oxidative Stress-Mediated DNA Damage and p53 Activation.
5-Fluorouracil (5-Fu) has been widely used as a first-line drug for colorectal cancer (CRC) treatment but limited by drug resistance and severe toxicity. The chemo-sensitizers that augment its efficiency and overcome its limitation are urgently needed. Gypenosides (Gyp), the main components from Gynostemma pentaphyllum (Thunb.) Makino, has shown potential anti-tumor property with little side-effect. Here, we carefully explored the chemo-sensitization of Gyp to potentiate the anti-tumor effect of 5-Fu in vitro and in vivo. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltertrazolium bromide tetrazolium assay and colony formation test reveal that Gyp could significantly enhance the 5-Fu-caused SW-480,SW-620 and Caco2 cells viability loss. Calcusyn analysis shows that Gyp acts synergistically with 5-Fu. Annexin V-PE/7-AAD staining indicates 5-Fu + Gyp could induce SW-480 cell apoptosis. The activations of caspase 3, caspase 9 and poly (ADP-ribose) polymerase (PARP) were involved in the process. Gyp was also found to up-regulate 5-Fu-caused phospho-p53 expression and thus augment 5-Fu-induced G0/G1 phase arrest. Gyp elevated intracellular ROS level, significantly enhanced 5-Fu-triggered DNA damage response as evidenced by flow cytometry, comet assay and the expression of Ser139-Histone H2A.X. Inhibition of ROS and p53 respectively reversed the cell death induced by 5-Fu + Gyp, suggesting the key roles of ROS and p53 in the process. Moreover, 5-Fu and Gyp in combination exhibits much superior tumor volume and weight inhibition on CT-26 xenograft mouse model in comparison to 5-Fu or Gyp alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation. Preliminary toxicological results show that 5-Fu + Gyp treatment is relatively safe. As a potential chemo-sensitizer, Gyp displays a splendid synergistic effect with 5-Fu to inhibit cancer cell proliferation and tumor growth. By using 5-Fu and Gyp in combination would be a promising therapeutic strategy for CRC treatment.


Association between chronic idiopathic urticaria and hypertension: A population-based retrospective cohort study.
Chronic idiopathic urticaria (CIU) is defined as urticaria that is not caused by external triggers. The pathogenesis of CIU remains unknown. A previous study investigated whether hypertension is associated with extended duration of CIU. To investigate the possible association between CIU and hypertension. We performed a population-based retrospective cohort study of 2,460 patients with CIU and 9,840 age-, sex-, and index year-matched comparison patients, using the National Health Insurance of Taiwan database. The median follow-up periods were 7.13 years for the CIU cohort and 7.20 years for the non-CIU cohort. The distributions by sex and age were similar for both cohorts. The CIU cohort had a 1.37-fold (95% CI, 1.22-1.53) greater risk of developing subsequent hypertension than the non-CIU cohort after adjusting for sex, age, comorbidities, and nonsedating antihistamine use. This nationwide retrospective cohort study found that CIU is associated with a higher future risk of hypertension after adjusting for sex, age, comorbidities, and nonsedating antihistamine use. The detailed pathophysiologic mechanisms require further clarification in prospective studies.


B-cell acquisition of antigen: Sensing the surface.
B-cell antigen receptor (BCR) recognition and acquisition of antigen by B cells is the essential first step in the generation of effective antibody responses. As B-cell-mediated antigen presentation is also believed to play a significant role in the activation of CD4(+) Th-cell responses, considerable effort has focused on clarifying the nature of antigen/BCR interactions. Following earlier descriptions of interactions of soluble antigens with the BCR, it is now clear that B cells also recognize, physically extract and present antigens that are tethered to, or integral components of, the surfaces or extracellular matrix of other cells. In this issue of the European Journal of Immunology, Zeng et al. [Eur. J. Immunol. 2015. 45: XXXX-XXXX] examine how the physical property or "stiffness" of the surface displaying antigens to B cells influences the B-cell response. This commentary reports that antigen tethered on "less stiff" surfaces induces increased B-cell activation and antibody responses. I then infer how "sensing the surface" by B cells may represent a new component of the immune system's ability to detect "damage," and how this understanding may influence approaches to clinical therapies where immune activity is either unwanted or desired.


[The impact of COVID-19 according to people in care at FACT and autism teams: wave 1 and 2 and Omikron wave].
COVID-19 affected our collective well-being. Measures during a pandemic may disproportionately impact individuals with mental illness. To measure the impact of COVID-19 on clients of FACT and autism teams over three waves. Through a digital questionnaire participants (wave 1: n=100; wave 2: n=150; Omikron wave: n=15) reported on: <br />1. mental health, 2. outpatient care experiences, 3. government measures and information services. Happiness was rated on average with a 6 in the first two waves, positive consequences of wave 1 (clearer world, more reflection) persisted. The most frequently mentioned negative consequences were: decreased social interactions, increased mental problems and daily functioning. No new experiences were mentioned during the Omikron wave. The quality and amount of mental health care was rated ≥7 by 75-80%. Phone and video consultations were the most frequently mentioned positive care experience; missing face-to-face contact was considered most negative. Measures were harder to sustain in the second wave. Vaccination readiness and vaccination coverage were high. All COVID-19-waves show a consistent picture. Telepsychiatry was evaluated positively. Considering the results, the mental health sector could be ready for a next lockdown taking into account possibly higher expectations of clients.


Need for resuming sports and physical activity for children and adolescents following COVID-19 infection.
A decline in sports activities among children and adolescents was noted during the stay-at-home restrictions imposed by COVID-19. With the easing of restrictions, physical activities are being resumed. A data search was conducted to identify the role of parents in resuming sporting activities, the risks and benefits of doing so, the physical examination to be conducted prior to physical activity, the existence of guidelines/protocols for return to sports and physical activity, the role of comorbidities in influencing the restart of the same. Parents should consult the child's physician prior to allowing he/she to resume physical exercise. In preparation for this, a careful physical examination should be performed. Children with COVID-19, even if asymptomatic, should not resume any physical activity until at least 10 days after testing positive. Those with moderate or severe COVID-19 should be referred for cardiological evaluation. The level of activity should be resumed gradually, as per the GRTP protocol. Athletes with a positive COVID-19 test in the presence of concomitant medical conditions (diabetes, cardiovascular or respiratory or renal disease) should undergo medical evaluation prior to adhering to a GRTP. Those with complicated COVID19 infection or long Covid may need additional investigations. While there is no doubt that it will bring multiple benefits in terms of general health, returning to play sport should be gradual and preceded by an accurate physical examination in those young subjects previously affected by the coronavirus disease, especially when their heart and/or lungs and/or kidneys were affected.


The menopausal transition and cardiovascular risk.
The incidence of cardiovascular disease, which is the leading single cause of death among women, increases substantially after menopause. This may be related to adverse changes in cardiovascular risk factors that occur during the menopausal transition. Proatherogenic changes in lipid and apolipoprotein profiles seem to be specifically related to ovarian aging; unfavorable changes in other cardiovascular risk factors may be influenced more by chronologic aging. Whether these changes are due to aging or to menopause itself, increased attention to risk factor modification in the pre- and perimenopausal years will help reduce future cardiovascular disease risk among women.


Predictors of High Serum Casein Antibody Levels among Malnourished Infants and Young Children with Congenital Heart Disease.
Factors predictive of growth retardation and malnutrition in patients with congenital heart disease remain unclear. This study aimed to measure antibody response to bovine casein through assessing serum casein antibody levels in malnourished patients three year or younger with CHD, and to determine its relationship to gastrointestinal symptoms, anthropometric measures, and laboratory data. This cross sectional case control study was conducted in sixty patients with CHD aged 4 to 72 months. They were subdivided into thirty patients with cyanotic and thirty patients with acyanotic CHD compared with thirty apparently healthy children. On comparison with controls, patients showed highly significant lower anthropometric measures, calcium, iron, hemoglobin levels, and higher serum levels of casein antibody, total iron binding capacity, and alkaline phoshatase activity (P<0.000). Serum levels of casein antibody showed significantly positive correlations with serum total iron binding capacity and alkaline phosphatase activities and negatively correlated with the age at onset of symptoms, anthropometric measures, serum calcium, and iron levels. Serum casein antibody levels play a significant role in the pathogenesis of malnutrition. Encouragement of breast feeding and avoidance of early cow's milk consumption could prevent the development of antibody response to bovine casein.


Aquaculture bacterial pathogen database: Pathogen monitoring and screening in coastal waters using environmental DNA.
Increasingly diverse pathogen occurrence in coastal and mariculture areas demands improved monitoring platforms to prevent economic and public health implications. Accessible databases with up-to-date knowledge and taxonomy are critical for detecting and screening environmental pathogens. Condensed from over 3000 relevant reports in peer reviewed articles, we constructed an aquaculture bacterial pathogen database that provides specialized curation of over 210 bacterial pathogenic species impacting aquaculture. Application of the aquaculture bacterial pathogen database to environmental DNA metabarcoding monitoring data in Hong Kong coastal and mariculture waters effectively characterized regional pathogen profiles over a one-year period and improved identification of new potential pathogen targets. The results highlighted the increase in potential pathogen abundance related to aquaculture activity and the associated inorganic nitrogen load, which was chiefly due to the enrichment of Vibrio during the atypical dry winter season. The value of the aquaculture bacterial pathogen database for empowering environmental DNA-based approaches in coastal marine pathogen surveillance benefits water resource management and aquaculture development on a global scale.


UV and solar-based photocatalytic degradation of organic pollutants from ceramics industrial wastewater by Fe-doped ZnS nanoparticles.
UV and solar-based photocatalytic degradation of 2,4-dichlorophenol (2,4-DCP) as an organic contaminant in ceramics industry wastewater by ZnS and Fe-doped ZnS NPs was the focus of this research. Nanoparticles were prepared using a chemical precipitation process. The cubic, closed-packed structure of undoped ZnS and Fe-doped ZnS NPs was formed in spherical clusters, according to XRD and SEM investigations. According to optical studies, the optical band gaps of pure ZnS and Fe-doped ZnS nanoparticles are 3.35 and 2.51 eV, respectively, and Fe doping increased the number of carriers with high mobility, improved carrier separation and injection efficiency, and increased photocatalytic activity under UV or visible light. Doping of Fe increased the separation of photogenerated electrons and holes and facilitated charge transfer, according to electrochemical impedance spectroscopy investigations. Photocatalytic degradation studies revealed that in the present pure ZnS and Fe-doped ZnS nanoparticles, 100% treatment of 120 mL of 15 mg/L phenolic compound was obtained after 55- and 45-min UV-irradiation, respectively, and complete treatment was attained after 45 and 35-min solar light irradiation, respectively. Because of the synergistic effects of effective surface area, more effective photo-generated electron and hole separation efficiency, and enhanced electron transfer, Fe-doped ZnS demonstrated high photocatalytic degradation performance. The study of Fe-doped ZnS's practical photocatalytic treatment capability for removing 120 mL of 10 mg/L 2,4-DCP solution made from genuine ceramic industrial wastewater revealed Fe-doped ZnS's excellent photocatalytic destruction of 2,4-DCP from real industrial wastewater.


Non-contrast myocardial perfusion in rest and exercise stress using systolic flow-sensitive alternating inversion recovery.
To evaluate systolic flow-sensitive alternating inversion recovery (FAIR) during rest and exercise stress using 2RR (two cardiac cycles) or 1RR intervals between inversion pulse and imaging. 1RR and 2RR FAIR was implemented on a 3T scanner. Ten healthy subjects were scanned during rest and stress. Stress was performed using an in-bore ergometer. Heart rate, mean myocardial blood flow (MBF) and temporal signal-to-noise ratio (TSNR) were compared using paired t tests. Mean heart rate during stress was higher than rest for 1RR FAIR (85.8 ± 13.7 bpm vs 63.3 ± 11.1 bpm; p < 0.01) and 2RR FAIR (83.8 ± 14.2 bpm vs 63.1 ± 10.6 bpm; p < 0.01). Mean stress MBF was higher than rest for 1RR FAIR (2.97 ± 0.76 ml/g/min vs 1.43 ± 0.6 ml/g/min; p < 0.01) and 2RR FAIR (2.8 ± 0.96 ml/g/min vs 1.22 ± 0.59 ml/g/min; p < 0.01). Resting mean MBF was higher for 1RR FAIR than 2RR FAIR (p < 0.05), but not during stress. TSNR was lower for stress compared to rest for 1RR FAIR (4.52 ± 2.54 vs 10.12 ± 3.69; p < 0.01) and 2RR FAIR (7.36 ± 3.78 vs 12.41 ± 5.12; p < 0.01). 2RR FAIR TSNR was higher than 1RR FAIR for rest (p < 0.05) and stress (p < 0.001). We have demonstrated feasibility of systolic FAIR in rest and exercise stress. 2RR delay systolic FAIR enables non-contrast perfusion assessment during stress with relatively high TSNR.


Minimally invasive percutaneous plate osteosynthesis for ankle fractures: a prospective observational cohort study.
The gold standard for the surgical management of ankle fractures is through open reduction and internal fixation. The rate of wound problems has been reported to be as high as 18%, especially in patients with poor vascular supply or in diabetics. Minimally invasive percutaneous plate osteosynthesis (MIPPO) has been described as a potential solution for these patients. This is a prospective observational cohort study. From October 2009 to February 2010, and following ethical approval of our research, adult patients admitted at our level I trauma center with a closed lateral malleolar displaced unstable fracture (Lauge-Hansen supination-external rotation) with or without a medial-sided injury and patients with an undisplaced fracture associated with medial clear space opening on external rotation stress radiographs were recruited and managed using MIPPO technique. All patients were followed up for a minimum of 12 months post-surgery (12-20 with a mean of 16.5 months). Trauma mechanism, comorbidities, classifications, trauma-surgery interval, image intensifier duration, surgery duration, complications, and function American Orthopaedic Foot and Ankle Society (AOFAS) were analyzed. Thirty-two patients were recruited of which 20 fulfilled the inclusion criteria (16 females, 4 males) and were available for follow-up. Ten fractures (50%) were classified as 44-B1, 7 fractures (35%) as 44-B2, and 3 fractures (15%) as 44-B3 according to the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association classification (100% were supination-external rotation injuries). At 8 weeks post-surgery, all fractures had healed. The duration of surgery ranged between 15 and 73 min (average 32.8) from skin incision to closure. There were 2 complications (1 malunion and 1 skin necrosis requiring implant removal). At 12-month follow-up, AOFAS average was 88.3 (72-100 standard deviation of 6.8 points). MIPPO technique proved to be a viable option for lateral malleolar fracture treatment with a low complication rate and high functional outcome at 1 year. It is particularly useful in patients with a high risk of wound complication.


Novel hexamerization motif is discovered in a conserved cytoplasmic protein from Salmonella typhimurium.
The cytoplasmic protein Stm3548 of unknown function obtained from a strain of Salmonella typhimurium was determined by X-ray crystallography at a resolution of 2.25 A. The asymmetric unit contains a hexamer of structurally identical monomers. The monomer is a globular domain with a long beta-hairpin protrusion that distinguishes this structure. This beta-hairpin occupies a central position in the hexamer, and its residues participate in the majority of interactions between subunits of the hexamer. We suggest that the structure of Stm3548 presents a new hexamerization motif. Because the residues participating in interdomain interactions are highly conserved among close members of protein family DUF1355 and buried solvent accessible area for the hexamer is significant, the hexamer is most likely conserved as well. A light scattering experiment confirmed the presence of hexamer in solution.


The influence of urea on the penetration kinetics of topically applied corticosteroids.
The effect of urea on the penetration of hydrocortisone and triamcinolone acetonide into human skin from topically applied vehicles was studied. The resulting penetration promotion has two possible applications in topical therapy: (a) An increased therapeutic effect for a given concentration of the active constituent. (b) A given therapeutic effect could be obtained with a reduced concentration of the active ingredient.


NF-kappaB signaling, liver disease and hepatoprotective agents.
The NF-kappaB signaling pathway has particular relevance to several liver diseases including hepatitis (liver infection by Helicobacter, viral hepatitis induced by HBV and HCV), liver fibrosis and cirrhosis and hepatocellular carcinoma. Furthermore, the NF-kappaB signaling pathway is a potential target for development of hepatoprotective agents. Several types of drugs including: selective estrogen receptor modulators (SERMs), antioxidants, proteasome inhibitors, IKK inhibitors and nucleic acid-based decoys have been shown to interfere with NF-kappaB activity at different levels and may be useful for the treatment of liver diseases. However, NF-kappaB also plays an important hepatoprotective function that needs to be taken into consideration during development of new therapeutic regimens.


Patients Undergoing Primary Hip Arthroscopy Report Favorable Outcomes at Minimum 10 Year Follow-Up: A Systematic Review.
(1) To evaluate minimum 10-year PROs (patient-reported outcomes) and survivorship after primary hip arthroscopy and (2) to identify predictors of failure for secondary arthroscopy and conversion to total hip arthroplasty (THA). A systematic review of the literature was conducted with the following key words: "hip arthroscopy," "long-term," "outcomes," "ten-year," "survivorship," "10-year," "15-year," "fifteen-year," 20-year," "twenty-year," and "femoroacetabular impingement" in PubMed and Embase in March 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Level I to Level IV evidence was included and reported on minimum 10-year outcomes or greater after primary hip arthroscopy. Long-term studies were defined as minimum 10-year follow-up in accordance with established standards in the literature. Case reports, review articles, technique articles, and opinion articles were excluded. Articles not in English were excluded. Title, author, publication date, study design, demographic, number of hips, follow-up time, study period, indications for hip arthroscopy, PROs, predictors of failure for THA, and rates of secondary surgeries were recorded. Survivorship was defined as a nonconversion to THA. P < .05 was defined as statistical significance. Twelve studies met the inclusion criteria. In total, 4 studies were Level III, and 8 studies were Level IV. A total of 1,344 hips were included, and follow-up ranged from 10 to 20 years. Femoroacetabular impingement syndrome was the most common indication for hip arthroscopy. Ten of the 12 studies reported on PROs, and 8 studies reported significant improvement after hip arthroscopy at long-term follow-up. The remaining 2 studies reported favorable outcomes that satisfied clinical benefit thresholds at minimum 10-year follow-up. Five studies reported clinical benefit where each patient cohort achieved 80% minimal clinically important difference and 75% patient acceptable symptomatic state for at least one PRO. Rates of secondary arthroscopy ranged from 4.5% to 24%, and rates of conversion to THA varied from 0% to 44.1%. Older age and chondral damage were the most commonly cited predictors for conversion to THA. At long-term follow-up, patients who underwent primary hip arthroscopy demonstrated favorable outcomes and variable rates of secondary surgeries. Patients undergoing hip arthroscopy within the last 20 years with Tönnis grade <1 and labral repair experienced greater than 90% survivorship. Chondral damage and older age were the most cited predictors for conversion to THA. Level IV, systematic review of Level III and Level IV studies.


Silybin-Phosphatidylcholine Complex Protects Human Gastric and Liver Cells from Oxidative Stress.
Silybin is the main component of silymarin with antioxidant, anti-inflammatory and cytoprotective actions. Our aim was to compare the effect of silybin used as single substance, silybin-phosphatidylcholine complex (SilPho), and derivatives of silybin (MannpSil, GalpSil, GlcpSil, LactpSil) on MKN28 and HepG2 cell viability and cell death, in vitro, after induction of oxidative stress. Oxidative stress was induced by incubating HepG2 and MKN28 cells with xanthine oxidase in the presence of its substrate xanthine. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide assay. Determination of Malondialdehyde (MDA) in MKN28 cells was performed by high-performance liquid chromatography. Quantitative analysis of apoptotic cells was carried-out using annexin. SilPho and new silybin glycoconjugates did not affect cell viability, while silybin induced about 50% cell death in both MKN28 and in HepG2 cells. Pre-treatment of cells with silybin and new silybin glycoconjugates (before oxidative stress induction) did not affect cell viability, while SilPho had a protective effect. Exposure of MKN28 cells to oxidative stress caused a two-fold increase in cellular MDA concentration compared to untreated cells. Moreover, pre-treatment with SilPho, but not with silybin, significantly prevented oxidative stress-induced increase in cellular Malondialdehyde. Moreover, silybin induced apoptosis potentiated by oxidative stress, while SilPho did not induce any effect. Oxidative stress caused cell death primarily by necrosis, antagonized by SilPho. The protective effect of SilPho is partially due to inhibition of radical oxidative species.