Bariatric surgery reduces cancer risk in morbidly obese patients.
To assess the effect of bariatric surgery on the cancer risk of patients with morbid obesity because evidence is mounting of an association between obesity and cancer. We performed an observational 2-cohort study. The treatment cohort (n = 1035) included patients who had undergone bariatric surgery from 1986 to 2002. The control group (n = 5746) included age- and gender-matched morbidly obese patients who had not undergone weight-reduction surgery and who were identified from a single-payor administrative database. The subjects with physician or hospital visits for a cancer-related diagnosis or treatment within the 6 months previous to the beginning of the study were excluded. The cohorts were followed up for a maximum of 5 years from study inception. Bariatric surgery resulted in a significant reduction in the mean percentage of excess weight loss (67.1%, P <.001). The surgery patients had significantly fewer physician/hospital visits for all cancer diagnoses (n = 21, 2.0%) compared with the controls (n = 487, 8.45%; relative risk .22, 95% confidence interval .143-.347; P = .001). The physician/hospital visits for common cancers such as breast cancer were significantly reduced in the surgery group (P = .001). For all other cancers, the physician/hospital visits showed a trend toward being lower in the surgery group. Because of the low frequencies, statistical significance could not be demonstrated for individual cancer diagnoses. The data suggest that bariatric surgery improves the cancer outcomes in some morbidly obese patients.


Extra-axial chordoma: a clinicopathologic analysis of six cases.
Extra-axial chordoma is an exceedingly rare tumor, with only 28 cases reported in the literature to date. Axial and extra-axial chordoma exhibits complete morphologic and immunophenotypic (expression of brachyury) overlap. However, in consideration of the non-canonical presentation, extra-axial chordoma is under-recognized and often misdiagnosed, most often as extraskeletal myxoid chondrosarcoma or myoepithelioma. To increase our understanding of the clinicopathologic features of extra-axial chordoma, six cases have been retrieved from the files of the Istituto Ortopedico Rizzoli and of the General Hospital of Treviso. The clinicoradiologic, morphologic, and molecular features have been analyzed, and the follow-up was updated. Our series included four female and two male patients; their ages ranged from 20 to 67 years (mean 45.8 years). All patients presented with a single mass localized in four cases in the soft tissue (posterior arm, left leg, dorsal aspect of the foot, and popliteal fossa), and in two cases in the bone (radius and second metacarpal bone). Grossly, the neoplasm was lobulated, with a fleshy cut surface and a diameter ranging between 0.8 and 8 cm (mean 3.4 cm). Morphologically, all six cases showed an epithelioid cell proliferation organized in nests and cords demarcated by fibrous septa and set in an abundant extracellular myxoid matrix. Neoplastic cells featured hyperchromatic nuclei and abundant vacuolated cytoplasm. Immunohistochemically, all six cases were strongly positive for EMA, cytokeratin AE1/AE3, S100, and brachyury. INI1 nuclear expression was retained. Smooth muscle actin, calponin, p63, and GFAP were all negative. Fluorescent in situ hybridization (FISH) analysis did not reveal rearrangements involving NR4A3, FUS, and EWSR1 genes. At follow-up (mean 55 months), all patients were alive without disease after local surgical treatment. One patient underwent thigh amputation following multiple local recurrences and inguinal node metastases treated with marginal resection. In conclusion, primary extra-axial chordoma is an extremely rare neoplasm with distinct morphological and immunohistochemical features. Immunomorphology and molecular analysis allow distinction from both extraskeletal myxoid chondrosarcoma and myoepithelioma. Complete surgical resection appears to be curative.


pH-induced conformational transitions of the propeptide of human cathepsin L. A role for a molten globule state in zymogen activation.
Synthesis of proteases as inactive zymogens is a very important mechanism for the regulation of their activity. For lysosomal proteases proteolytic cleavage of the propeptide is triggered by the acidic pH. By using fluorescence, circular dichroism, and NMR spectroscopy, we show that upon decreasing the pH from 6.5 to 3 the propeptide of cathepsin L loses most of the tertiary structure, but almost none of the secondary structure is lost. Another partially structured intermediate, prone to aggregation, was identified between pH 6.5 and 4. The conformation, populated below pH 4, where the activation of cathepsin L occurs, is not completely unfolded and has the properties of molten globule, including characteristic binding of the 1-anilinonaphthalene-8-sulfonic acid. This pH unfolding of the propeptide parallels a decrease of its affinity for cathepsin L and suggests the mechanism for the acidic zymogen activation. Addition of anionic polysaccharides that activate cathepsin L already at pH 5.5 unfolds the tertiary structure of the propeptide at this pH. Propeptide of human cathepsin L which is able to fold independently represents an evolutionary intermediate in the emergence of novel inhibitors originating from the enzyme proregions.


Structural requirements of guanide, biguanide, and bisbiguanide agents for antiplaque activity.
The bactericidal efficacy of 16 guanide, biguanide, and bisbiguanide agents was studied in vitro against intact preformed plaques of four oral (plaque-forming) microorganisms: Streptococcus mutans, S. sanguis, Actinomyces viscosus, and A. naeslundii. The activities of these agents were examined in relation to their molecular configurations. These studies indicated that the bis- and biguanide configurations are important for efficacy, as is the length of the alkyl side chain. No structural moiety determined efficacy by itself. Furthermore, the activities of these agents were studied to determine the minimal conditions (concentration, duration, and frequency) of treatment required for likely clinical efficacy. At least six agents were judged to have equal or greater efficacy than the reference agent, chlorhexidine digluconate. A plaque bactericidal index was derived for the most potent agents, and comparison to the bactericidal properties of chlorhexidine was expressed as a chlorhexidine coefficient.


How Neutrophils Shape Adaptive Immune Responses.
Neutrophils are classically considered as cells pivotal for the first line of defense against invading pathogens. In recent years, evidence has accumulated that they are also important in the orchestration of adaptive immunity. Neutrophils rapidly migrate in high numbers to sites of inflammation (e.g., infection, tissue damage, and cancer) and are subsequently able to migrate to draining lymph nodes (LNs). Both at the site of inflammation as well as in the LNs, neutrophils can engage with lymphocytes and antigen-presenting cells. This crosstalk occurs either directly via cell-cell contact or via mediators, such as proteases, cytokines, and radical oxygen species. In this review, we will discuss the current knowledge regarding locations and mechanisms of interaction between neutrophils and lymphocytes in the context of homeostasis and various pathological conditions. In addition, we will highlight the complexity of the microenvironment that is involved in the generation of suppressive or stimulatory neutrophil phenotypes.


Cyclic conversion of the novel Src kinase inhibitor [7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (TG100435) and Its N-oxide metabolite by flavin-containing monoxygenases and cytochrome P450 reductase.
[7-(2,6-Dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (TG100435) is a novel multi-targeted Src family kinase inhibitor with demonstrated anticancer activity in preclinical species. Potent kinase inhibition is associated with TG100435 and its major N-oxide metabolite [7-(2,6-dichlorophenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine (TG100855). The objectives of the current study were to identify the hepatic enzyme(s) responsible for 1) the total metabolic flux of TG100435, 2) the formation of TG100855, and 3) the subsequent metabolism of TG100855. Flavin-containing monooxygenases (FMO) and cytochrome P450 monooxygenases (P450s) contribute to TG100435 total metabolic flux. TG100435 metabolic flux was completely inhibited by methimazole and ketoconazole, suggesting only FMO- and CYP3A4-mediated metabolism. TG100855 formation was markedly inhibited (~90%) by methimazole or heat inactivation (>99%). FMO3 was the primary enzyme responsible for TG100855 formation. In addition, an enzyme mediated retroreduction of TG100855 back to TG100435 was observed. The N-oxidation reaction was approximately 15 times faster than the retroreduction reaction. Interestingly, the retroreduction of TG100855 to TG100435 in recombinant P450 or liver microsomes lacked inhibition by the P450 inhibitors. TG100435 formation in the human liver microsomes or recombinant P450 increased as a function of cytochrome P450 reductase activity, suggesting potential involvement of cytochrome P450 reductase. The results of this in vitro study demonstrate the potential of TG100435 and TG100855 to be interconverted metabolically. FMO seem to be the major N-oxidizing enzymes, whereas cytochrome P450 reductase seems to be responsible for the retroreduction reaction.


Risk of cancer in patients treated with recombinant human growth hormone in childhood.
Recombinant human growth hormone (GH) has been in use for over 30 years, and its indications have gradually expanded from the classical replacement therapy in GH deficiency (GHD) to pharmacological therapy in patients with normal GH secretion. The insulin-like growth factor-I (IGF-I ) is closely GH dependent and is the effector of GH biological actions in peripheral tissues. Since IGF-I has potent mitogenic and antiapoptotic effects, the use of GH, especially outside GHD, has raised safety concern regarding cancer risk. The results of experimental, epidemiological and observational studies are not univocal and a number of biases and confounders affect the interpretation of data. The aim of this review is to critically review the data linking GH therapy during childhood with cancer risk, highlighting strengths and weaknesses of the available evidence.


Successful intravenous thrombolysis in acute ischemic stroke after reversal of dabigatran etexilate with idarucizumab at the end of therapeutic time window.
Dabigatran is a direct oral anticoagulant that is widely used for stroke prevention in patients with atrial fibrillation. We report a case of an 80-year-old stroke patient on dabigatran for permanent atrial fibrillation, who presented with an initial National Institutes of Health Stroke Scale (NIHSS) of 8. Dabigatran was reversed with idarucizumab, and intravenous tissue-type plasminogen activator (IV-tPA) was administrated beginning 4 h and 28 min after the symptom onset. The patient was discharged with an NIHSS of 1. Our case is an additional proof of safety and efficiency of idarucizumab in the clinical setting of ischemic stroke before the administration of IV-tPA.


Design of an intraoperative peritoneal lavage device.
This paper consists of the design and construction of an intraoperative peritoneal lavage device. It is intended for cleaning the intra-abdominal cavity during a surgical procedure, once the etiology of a peritonitis has been identified and treated. Its purpose is to improve the current standard treatment consisting of simple pouring saline solution. A good washing procedure aids stopping the inflammatory and infectious process generated after the contamination due to the perforation of a hollow viscera. COMSOL Multiphysics software was used to simulate the biomechanical behavior of the liver against localized pressure. A graphical interface allows the user to predict liver deformation under different fluid pressures and positions simulating the lavage procedure. A preliminary prototype was implemented and a clinical trial was approved in an animal model. Three intraperitoneal structures belonging to a sheep were analyzed to observe the effect of the lavage. In closing, the final prototype implemented delivers a maximum force of 0.08 [N] and a pressure of 25.6 [kPa], and complied with the specialist's expectations.


Regenerative Medicine: Taming the Chimaera.
In this issue of Stem Cell Reports, Hamanaka et al. (2018) describe the generation of chimeric mice with all vascular endothelial cells derived from pluripotent stem cells. This approach is desirable to prevent immune rejection when human stem cells are combined with animal embryos to grow human organs in animals.


Nephron sparing surgery for renal cell carcinoma and von Hippel-Lindau's disease: a single center experience.
We reviewed the efficacy and safety of nephron sparing surgery for renal cell carcinoma in patients with von Hippel-Lindau disease. Data were collated for all 56 patients with a mean age of 37.2 +/- 11.3 years (range 14 to 62) with von Hippel-Lindau disease who underwent radical nephrectomy or nephron sparing surgery at our department for 1 or more 25 to 60 mm renal cell carcinomas between 1988 and 2001. Overall 30 nephrectomies (33%) and 62 enucleations (67%) were performed for 62 bilateral and 30 unilateral tumors. For nephron sparing surgery estimated intraoperative blood loss was 175 +/- 231.7 cc (range 50 to 1,300), 97% of surgeries had vascular pedicle clamping for 32 +/- 10.4 minutes (range 10 to 50) and there were 4 immediate complications (1 perinephric abscess, 2 urinary fistulas and 1 acute renal failure requiring temporary dialysis). Renal atrophy was noted in 7.3% of cases. Tumor diameter was 31.2 +/- 10.7 mm (range 15 to 60) and recurrence diameter was 22 +/- 7.8 mm (range 4 to 45). Hospital stay was 7.6 +/- 2.4 days (range 5 to 21). Preoperative and postoperative creatinine was 1.0 +/- 0.2 (range 0.6 to 1.7) and 1.2 +/- 0.9 mg/dl (range 0.7 to 6.5), respectively. Median followup was 55.9 months. There were 17 local recurrences (27.4%) and no metastases at recurrence. The overall survival rate was 100% at 5 years and 67% at 10 years. Nephron sparing surgery is effective and, when feasible, it need not be called into question. However, it may probably be superseded by less invasive techniques for tumors less than 20 mm diagnosed early after these techniques have been validated in long-term trials.


Parent-of-origin and trans-generational germline influences on behavioral development: the interacting roles of mothers, fathers, and grandparents.
Mothers and fathers do not contribute equally to the development of their offspring. In addition to the differential investment of mothers versus fathers in the rearing of offspring, there are also a number of germline factors that are transmitted unequally from one parent or the other that contribute significantly to offspring development. This article shall review four major sources of such parent-of-origin effects. Firstly, there is increasing evidence that genes inherited on the sex chromosomes including the nonpseudoautosomal part of the Y chromosome that is only inherited from fathers to sons, contribute to brain development and behavior independently of the organizing effects of sex hormones. Secondly, recent work has demonstrated that mitochondrial DNA that is primarily inherited only from mothers may play a much greater than anticipated role in neurobehavioral development. Thirdly, there exists a class of genes known as imprinted genes that are epigenetically silenced when passed on in a parent-of-origin specific manner and have been shown to regulate brain development and a variety of behaviors. Finally, there is converging evidence from several disciplines that environmental variations experienced by mothers and fathers may lead to plasticity in the development and behavior of offspring and that this phenotypic inheritance can be solely transmitted through the germline. Mechanistically, this may be achieved through altered programming within germ cells of the epigenetic status of particular genes such as retrotransposons and imprinted genes or potentially through altered expression of RNAs within gametes.


Omeprazole 40 mg o.m. combined with amoxycillin alone or with amoxycillin and metronidazole in the eradication of Helicobacter pylori.
Our objectives were to determine the effect of dual therapy with omeprazole and amoxicillin and of triple therapy with omeprazole, amoxicillin, and metronidazole in the eradication of Helicobacter pylori (HP) and to study the long-term results of eradication in these patients. A prospective, randomized, controlled trial was performed. Patients who were recruited had unequivocal evidence of HP infection based on culture, histology, rapid urease test, and Gram's stain of a tissue smear. Eradication was defined as the absence of bacteria in all tests performed on both corpus and antral biopsies. The infection was eradicated in 15 of 19 (78.9%) patients randomized to receive dual therapy and in 19 of 22 (86.4%) patients who received triple therapy. We followed the course of 30 patients in whom HP had been eradicated for a prolonged term (up to 12 months). All remained clear of HP. Twenty-five of 28 patients (89.3%) with duodenal ulcers in whom HP was successfully eradicated remained healed at 12 months. Fewer side effects were reported among patients who received the dual therapy. Combination therapy with omeprazole and amoxicillin with or without metronidazole is effective in the eradication of HP. In particular, the dual therapy regimen with amoxicillin is not only effective but is also well tolerated by patients.


Changes in free energy barrier for water permeation by stretch-induced phase transitions in phospholipid/cholesterol bilayers.
Water permeation through phospholipid/cholesterol bilayers is the key to understanding tension-induced rupture of biological cell membranes. We performed molecular dynamics simulations of stretched phospholipid/cholesterol bilayers to investigate changes in the free energy profile of water molecules across the bilayer and the lipid structure responsible for water permeation. We modeled stretching of the bilayer by applying areal strain. In stretched phospholipid/cholesterol bilayers, the hydrophobic tail of the phospholipids became disordered and the free energy barrier to water permeation decreased. Upon exceeding the critical areal strain, a phase transition to an interdigitated gel phase occurred before rupture, and the hydrophobic tail ordering as well as the free energy barrier were restored. In pure phospholipid bilayers, we did not observe such recoveries. These transient recoveries in the phospholipid/cholesterol bilayer suppressed water permeation and membrane rupture, followed by an increase in the critical areal strain at which the bilayer ruptured. This result agrees with experimental results and provides a reasonable molecular mechanism for the toughness of phospholipid/cholesterol bilayers under tension.Communicated by Ramaswamy H. Sarma.


Cell surface gamma-glutamyl transpeptidase in live cultures.
A physiological assay for measuring surface accessible gamma-glutamyl transpeptidase activity in adherent, living cultures is described. Cell surface transpeptidase activity remained linear throughout a 60-min time course over a wide range of cell densities. In addition, the assay conditions have neither acute nor long-term effects on cell growth potential, cellular morphology, or cell surface transpeptidase activity levels. As a result, cell surface transpeptidase activity can be continually evaluated in the same cultures during proliferation. The assay appears to be specific for cell surface transpeptidase and can be used to study the partitioning of the enzyme between substrate-accessible and substrate-inaccessible pools. This method utilizes an automated microtiter plate reader for the spectrophotometric quantification of small aliquots removed from cultures incubated with the chromogenic substrate L-gamma-glutamyl-p-nitroanilide. The use of a microtiter plate autoreader and the minimal handling of the cells permit a large number of cultures to be assayed with a substantial reduction in the time required to measure surface transpeptidase activity. The assay described is a nondestructive means for studying cell surface-accessible gamma-glutamyl transpeptidase catalytic activity within the microenvironment of the living culture.


In vivo study of lipid accumulation in the microalgae marine diatom Thalassiosira pseudonana using Raman spectroscopy.
An in vivo non-invasive quantitative analysis technique was introduced for evaluating the fat composition of living marine diatoms by using Raman spectroscopy in conjunction with a chemometric method. This technique enabled the observation of real-time variations in individual lipids in diatom cells without specific treatment or fat extraction. A confocal Raman spectroscope was used to measure the marine centric diatom Thalassiosira (T.) pseudonana that was cultured under six stress conditions, and the spectral data of accumulated fatty acids were obtained. A model-based chemometrics technique, ordinary least square was then used to extract specific signals from Raman spectra obtained for a mixture of fatty acids. The levels of four major lipid moieties from diatoms were extracted simultaneously, including myristic acid, palmitic acid, palmitoleic acid, and eicosapentaenoic acid from the Raman spectra. These results indicate that Raman spectroscopy in conjunction with a chemometrics method is reliable for the quantitative determination of the lipid composition accumulated in the cells of marine diatoms.


Bartonella species as a cause of infective endocarditis in the UK.
Bartonella spp. are increasingly implicated in infectious endocarditis cases in the UK. Herein, we attempted to quantify their role in this syndrome and explored the epidemiology of Bartonella-associated endocarditis in the UK. Between November 2005 and October 2010, samples from 685 endocarditis patients were submitted to the Health Protection Agency for Bartonella serology. Serological evidence of infection was obtained for 57 (8·3%) patients. PCR-based evidence of infection was obtained from 13 out of 14 patients for whom heart valve tissue was available, with Bartonella quintana implicated in 12 cases and B. henselae in one. Six patients with B. quintana endocarditis were recent immigrants into the UK, of whom four lived in poor socioeconomic conditions. These results indicate that Bartonella is a not uncommon cause of endocarditis in the UK and should be considered particularly in patients raised in eastern Europe and/or with a history of homelessness or alcoholism.


Elective parotidectomy in the management of advanced auricular malignancies.
The purpose of this study is to determine whether elective parotidectomy is necessary in patients with clinically and radiographically N0 parotid disease with isolated primary auricular nonmelanoma cutaneous malignancies. Auricular malignancies are typically managed by wedge resection or wide local excision. Although small lesions are easily managed by conservative excision, large bulky tumors, those with multifocal involvement, and recalcitrant lesions, often require more extensive resection including total auriculectomy, parotidectomy, and/or neck dissection. A 10-year retrospective case review from four tertiary university medical centers from 1992 to 2002. Information was retrospectively retrieved using a database of patients from the department of pathology. Seventy-one charts were reviewed. Patients with a clinical history of advanced nonmelanoma auricular carcinoma undergoing elective parotidectomy and/or neck dissection with clinically and radiographically N0 nodal disease were evaluated for the presence of occult parotid metastasis. All patients underwent parotidectomy in conjunction with a total auriculectomy for surgical extirpation of their primary auricular carcinoma. Parotid specimens were evaluated for histopathologic evidence of metastatic neoplastic disease. Pathological examination showed no histological evidence of occult parotid metastasis in all 19 patients who underwent elective parotidectomy in the presence of clinically and radiographically N0 nodal disease of the parotid or cervical regions. Parotidectomy may not be necessary in the surgical management of advanced auricularcarcinoma in the absence of clinically positive parotid disease or external auditory canal involvement.


The Rho-kinase inhibitor fasudil restores normal motor nerve conduction velocity in diabetic rats by assuring the proper localization of adhesion-related molecules in myelinating Schwann cells.
The Rho/Rho-kinase signaling pathway has been shown to be involved in the complications of diabetes. In this study, we found that fasudil, a specific Rho-kinase inhibitor, had a beneficial effect on the motor nerve conduction velocity (MNCV), which is delayed in rats with streptozotocin (STZ)-induced diabetes. Cadherin-dependent adherens junctions (AJs) in myelinating Schwann cells, necessary for proper myelin formation and rapid propagation of action potentials, are regulated by Rho/Rho-kinase signaling. These AJ structures are maintained by E-cadherin and catenin complexes such as β-catenin and p120 catenin. To elucidate the mechanism underlying the effect of fasudil on MNCV, we examined alterations in AJ structure in the peripheral nerves of the experimental rats. Our results showed that the activities of Rho and Rho-kinase increased simultaneously in the sciatic nerves of the diabetic rats. Fasudil restored the MNCV by suppressing the up-regulation of the Rho-kinase. In the diabetic state, enhanced Rho and Rho-kinase activity reduced p120 catenin expression and altered the distribution of p120 catenin and E-cadherin, which are normally localized in the paranodal compartment of the nodes of Ranvier and Schmidt-Lanterman incisures where autotypic AJs stabilize myelin structure. Fasudil restored normal p120 catenin expression and the distribution of p120 catenin and E-cadherin in the myelin sheath. In conclusion, reduced expression and altered distribution of the adhesion molecules in the myelin sheath might contribute to the slowing of the MNCV in the diabetic rats. Fasudil, through its effect on the distribution of the adhesion-related molecules, might prevent slowing of the MNCV.


Temporary arterial stenting: comparison to permanent stenting and conventional balloon injury in a rabbit carotid artery model.
The objective was to assess the arterial wall response to temporary stenting with a removable nitinol stent in comparison with permanent stenting and balloon injury at 28 days in the rabbit carotid artery. Restenosis remains an important limiting factor after the implantation of permanent metallic stents and balloon angioplasty. We have developed a temporary nitinol stent that uses a bolus injection of warmed saline to collapse the stent for percutaneous removal. Vascular changes related to the thermal saline bolus injection required to remove a nitinol implanted stent were assessed in 12 rabbit carotid arteries at 7 and 28 days postinjection. Nitinol stents, inflated to 3.0 mm diameter, were implanted for 3 days (n = 6) and histology and quantitative histomorphometry examined at 28 days. Results were compared with permanently implanted stents (n = 5) and balloon injury (n = 9). Dual bolus injection of 10 ml at 70 degrees C created an acute necrotizing injury and chronic neointimal proliferation, whereas injections of 5 ml at 63 degrees C were minimally injurious. Temporary stenting resulted in the least neointimal proliferation measured by the intima to media ratio (0.22 +/- 0.10 vs. 1.59 +/- 0.31 for permanent stenting and; 0.49 +/- 0.14 for balloon injury; P < 0.001). Temporary stenting maintained a significantly larger lumen than balloon (1.53 +/- 0.72 mm2 vs. 0.64 +/- 0.14 mm2; P < 0.001), which could not be explained by absolute changes in intimal cross sectional area (0.14 +/- 0.07 mm2 vs. 0.21 +/- 0.06 mm2 respectively; P = 0.33). Temporary stenting resulted in a relatively larger vessel area within the external elastic lamina than with balloon (2.28 +/- 1.06 mm2 vs. 1.30 +/- 0.18 mm2; P = 0.007). The thermal stent recovery process can create necrotizing vascular injury and neointimal proliferation at higher temperatures and injectate volumes. Stent removal after 3 days using 63 degrees C saline bolus injection results in less neointimal proliferation than with permanent stents or balloon injury. In comparison to balloon injury, temporary stenting also may have a long-lasting beneficial effect on vessel recoil and remodeling, resulting in larger lumen size after stent removal.


Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies.
Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as acute myocardial infarction and postischemic heart failure, heart failure of other etiologies, and cardiac arrhythmias, belong to the leading causes of death. Activation of capsaicin-sensitive sensory nerves by the transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor and other receptors, as well as neuropeptide mediators released from them upon stimulation, play important physiological regulatory roles. Capsaicin-sensitive sensory nerves also contribute to the development and progression of some cardiac diseases, as well as to mechanisms of endogenous stress adaptation leading to cardioprotection. In this review, we summarize the role of capsaicin-sensitive afferents and the TRPV1 ion channel in physiological and pathophysiological functions of the heart based mainly on experimental results and show their diagnostic or therapeutic potentials. Although the actions of several other channels or receptors expressed on cardiac sensory afferents and the effects of TRPV1 channel activation on different non-neural cell types in the heart are not precisely known, most data suggest that stimulation of the TRPV1-expressing sensory nerves or stimulation/overexpression of TRPV1 channels have beneficial effects in cardiac diseases.


Dystrophin and dysferlin double mutant mice: a novel model for rhabdomyosarcoma.
Although researchers have yet to establish a link between muscular dystrophy (MD) and sarcomas in human patients, literature suggests that the MD genes dystrophin and dysferlin act as tumor suppressor genes in mouse models of MD. For instance, dystrophin-deficient mdx and dysferlin-deficient A/J mice, models of human Duchenne MD and limb-girdle MD type 2B, respectively, develop mixed sarcomas with variable penetrance and latency. To further establish the correlation between MD and sarcoma development, and to test whether a combined deletion of dystrophin and dysferlin exacerbates MD and augments the incidence of sarcomas, we generated dystrophin and dysferlin double mutant mice (STOCK-Dysf(prmd)Dmd(mdx-5Cv)). Not surprisingly, the double mutant mice develop severe MD symptoms and, moreover, develop rhabdomyosarcoma (RMS) at an average age of 12 months, with an incidence of >90%. Histological and immunohistochemical analyses, using a panel of antibodies against skeletal muscle cell proteins, electron microscopy, cytogenetics, and molecular analysis reveal that the double mutant mice develop RMS. The present finding bolsters the correlation between MD and sarcomas, and provides a model not only to examine the cellular origins but also to identify mechanisms and signal transduction pathways triggering development of RMS.


Comorbidity index for predicting mortality at 6 months after reperfusion therapy.
The eligibility of reperfusion therapy has been expanded to increase the number of patients. However, it remains unclear the reperfusion therapy will be beneficial in stroke patients with various comorbidities. We developed a reperfusion comorbidity index for predicting 6-month mortality in patients with acute stroke receiving reperfusion therapy. The 19 comorbidities included in the Charlson comorbidity index were adopted and modified. We developed a statistical model and it was validated using data from a prospective cohort. Among 1026 patients in the retrospective nationwide reperfusion therapy registry, 845 (82.3%) had at least one comorbidity. As the number of comorbidities increased, the likelihood of mortality within 6 months also increased (p < 0.001). Six out of the 19 comorbidities were included for developing the reperfusion comorbidity index on the basis of the odds ratios in the multivariate logistic regression analysis. This index showed good prediction of 6-month mortality in the retrospective cohort (area under the curve [AUC], 0.747; 95% CI, 0.704-0.790) and in 333 patients in the prospective cohort (AUC, 0.784; 95% CI, 0.709-0.859). Consideration of comorbidities might be helpful for the prediction of the 6-month mortality in patients with acute ischemic stroke who receive reperfusion therapy.


Plastic surgical trauma: A single-centre experience.
To analyse the demographics, mechanism, nature, anatomical distribution, management and complications in trauma patients presenting to the plastic surgery unit. Descriptive cross-sectional study. This study was conducted in the Plastic and Reconstructive Surgery Unit, Hayatabad Medical Complex, Peshawar, from 1(st) January 2009 to 30(th) April 2012. All trauma patients referred from emergency department and other departments irrespective of age and gender were enrolled in the study, excluding acute burns and trauma sequelae patients. The details were obtained from the data sheets of the patients. All the data were analysed and projected in the form of tables and figures. A total of 1034 patients including 855 (82.7%) males and 179 (17.3%) females presented with plastic surgical trauma, with age ranging from 1 to 86 years, with a mean age of 20.84 ± 15.469 SD. The upper limb was affected in 492 (47.6%) patients, followed by head and neck in 273 (26.4%) cases. Road traffic accidents (RTAs) were the main cause of trauma, affecting 340 (32.9%) patients. Wound excision and closure was performed in 473 (45.7%) patients, followed by skin grafting and flap coverage in 232 (22.4%) and 132 (13.2%) patients, respectively. Postoperative complications were observed in 45 (4.35%) patients. Males in their young age mainly presented with plastic surgical trauma with RTA as the main mechanism and laceration as the most common type of these injuries. The upper limb was the most commonly affected region. The frequency of different types of surgical procedures and postoperative complications observed are comparable with international literature except for the microvascular surgery which is not performed in our centre. Regular audit of the plastic surgical trauma should be conducted in all plastic surgical units to both improve trauma care and reaffirm the role of Plastic Surgery in the new age trauma.


Superimposition of 3D cone-beam CT models of orthognathic surgery patients.
To evaluate the registration of 3D models from cone-beam CT (CBCT) images taken before and after orthognathic surgery for the assessment of mandibular anatomy and position. CBCT scans were taken before and after orthognathic surgery for ten patients with various malocclusions undergoing maxillary surgery only. 3D models were constructed from the CBCT images utilizing semi-automatic segmentation and manual editing. The cranial base was used to register 3D models of pre- and post-surgery scans (1 week). After registration, a novel tool allowed the visual and quantitative assessment of post-operative changes via 2D overlays of superimposed models and 3D coloured displacement maps. 3D changes in mandibular rami position after surgical procedures were clearly illustrated by the 3D colour-coded maps. The average displacement of all surfaces was 0.77 mm (SD=0.17 mm), at the posterior border 0.78 mm (SD=0.25 mm), and at the condyle 0.70 mm (SD=0.07 mm). These displacements were close to the image spatial resolution of 0.60 mm. The average interobserver differences were negligible. The range of the interobserver errors for the average of all mandibular rami surface distances was 0.02 mm (SD=0.01 mm). Our results suggest this method provides a valid and reproducible assessment of craniofacial structures for patients undergoing orthognathic surgery. This technique may be used to identify different patterns of ramus and condylar remodelling following orthognathic surgery.


Machine learning reveals a non-canonical mode of peptide binding to MHC class II molecules.
MHC class II molecules play a fundamental role in the cellular immune system: they load short peptide fragments derived from extracellular proteins and present them on the cell surface. It is currently thought that the peptide binds lying more or less flat in the MHC groove, with a fixed distance of nine amino acids between the first and last residue in contact with the MHCII. While confirming that the great majority of peptides bind to the MHC using this canonical mode, we report evidence for an alternative, less common mode of interaction. A fraction of observed ligands were shown to have an unconventional spacing of the anchor residues that directly interact with the MHC, which could only be accommodated to the canonical MHC motif either by imposing a more stretched out peptide backbone (an 8mer core) or by the peptide bulging out of the MHC groove (a 10mer core). We estimated that on average 2% of peptides bind with a core deletion, and 0·45% with a core insertion, but the frequency of such non-canonical cores was as high as 10% for certain MHCII molecules. A mutational analysis and experimental validation of a number of these anomalous ligands demonstrated that they could only fit to their MHC binding motif with a non-canonical binding core of length different from nine. This previously undescribed mode of peptide binding to MHCII molecules gives a more complete picture of peptide presentation by MHCII and allows us to model more accurately this event.


Empirical valence bond model of an S(N)2 reaction in polar and nonpolar solvents.
A new model for the substitution nucleophilic reaction (S(N)2) in solution is described using the empirical valence bond (EVB) method. The model includes a generalization to three dimensions of a collinear gas phase EVB model developed by Mathis et al. [J. Mol. Liq. 61, 81 (1994)] and a parametrization of solute-solvent interactions of four different solvents (water, ethanol, chloroform, and carbon tetrachloride). The model is used to compute (in these four solvents) reaction free energy profiles, reaction and solvent dynamics, a two-dimensional reaction/solvent free energy map, as well as a number of other properties that in the past have mostly been estimated.


Progesterone receptor agonists and antagonists as anticancer agents.
Progesterone is a major female steroid hormone produced by the ovarian corpus luteum and by the placental syncytiotrophoblast during the second trimester. The biological effects of this steroid hormone are mediated by the ubiquitously expressed progesterone receptor. The exact link between progesterone and female reproductive organ cancer is a controversial issue with various cross-talks. The present review summarizes recent trends in the development of some (anti)progestagen in the cure and management of breast and uterine cancers.


Low-complexity clustered polynomial nonlinear filter-based electrical dispersion pre-compensation scheme in IM/DD transmission systems.
A polynomial nonlinear filter (PNLF)-based electrical dispersion pre-compensation (pre-EDC) scheme assisted with Gerchberg-Saxton (GS) algorithm is proposed to compensate the chromatic dispersion (CD) for intensity-modulation and direct-detection (IM/DD) optical transmission systems, where PNLF is utilized to fit the nonlinear transfer function of the iterative GS algorithm-based pre-EDC scheme to realize a low-complexity non-iterative CD pre-compensation. The capability of PNLF to fit the nonlinear iterative process enables the PNLF-based pre-EDC scheme to compensate for CD-induced linear distortions and address CD-induced nonlinear distortions, which are typically captured through iterative approaches. Additionally, to further reduce the computational complexity, we also introduce the k-means clustering algorithm to eliminate the weight redundancy and propose a lower-complexity clustered PNLF-based pre-EDC scheme. Simulation results show that PNLF-based and clustered PNLF-based pre-EDC schemes save 76.0% and 97.5% complexity with only 0.3 dB receiver sensitivity penalty at 20% forward error correction (FEC) threshold, compared with GS-based pre-EDC scheme in C-band 56 GBaud 80-km on-off keying (OOK) system. Furthermore, the effectiveness of PNLF-based and clustered PNLF-based pre-EDC schemes is also evaluated through the experimental demonstration. Experimental results show that under C-band 32 GBaud 80-km OOK system, bit error ratio (BER) satisfying 20% FEC threshold is achieved by applying PNLF-based and clustered PNLF-based pre-EDC schemes, which save 78.3% and 94.2% complexity with only 0.4 dB receiver sensitivity penalty compared with GS-based pre-EDC scheme, respectively. The research results indicate that the (clustered) PNLF-based pre-EDC scheme has the great application potential for CD compensation in high-performance and low-cost IM/DD optical transmission systems.


A Flexible Traffic Signal Coordinated Control Approach and System on Complicated Transportation Control Infrastructure.
The transportation control infrastructure serves as the foundation for regional traffic signal control. However, in practice, this infrastructure is often imperfect and complex, characterized by factors such as heterogeneity and uncertainty, which pose significant challenges to existing methods and systems. Therefore, this paper proposes a novel approach to coordinated traffic signal control that emphasizes flexibility. To achieve this flexibility, we combine the flexible model of complex networks with robust fuzzy control methods. This approach enables us to overcome the complexity of the transportation control infrastructure and ensure efficient management of traffic signals. Additionally, to ensure long-term operational ease, we develop a regional traffic signal control system using steam computing technology, which provides high scalability and compatibility. Finally, computational experiments are performed to validate adaptability and performance of our proposed approach.


Do Transit-Oriented Developments (TODs) and Established Urban Neighborhoods Have Similar Walking Levels in Hong Kong?
A sharp drop in physical activity and skyrocketing obesity rate has accompanied rapid urbanization in China. The urban planning concept of transit-oriented development (TOD) has been widely advocated in China to promote physical activity, especially walking. Indeed, many design features thought to promote walking-e.g., mixed land use, densification, and well-connected street network-often characterize both TODs and established urban neighborhoods. Thus, it is often assumed that TODs have similar physical activity benefits as established urban neighborhoods. To verify this assumption, this study compared walking behaviors in established urban neighborhoods and transit-oriented new towns in Hong Kong. To address the limitation of self-selection bias, we conducted a study using Hong Kong citywide public housing scheme, which assigns residents to different housing estates by flat availability and family size rather than personal preference. The results show new town residents walked less for transportation purpose than urban residents. New town residents far from the transit station (800-1200 m) walked less for recreational purpose than TOD residents close to a rail transit station (<400 m) or urban residents. The observed disparity in walking behaviors challenges the common assumption that TOD and established urban neighborhoods have similar impact on walking behavior. The results suggest the necessity for more nuanced planning strategies, taking local-level factors into account to promote walking of TOD residents who live far from transit stations.


Maternal control of male-gamete delivery in Arabidopsis involves a putative GPI-anchored protein encoded by the LORELEI gene.
In Angiosperms, the male gametes are delivered to the female gametes through the maternal reproductive tissue by the pollen tube. Upon arrival, the pollen tube releases the two sperm cells, permitting double fertilization to take place. Although the critical role of the female gametophyte in pollen tube reception has been demonstrated, the underlying mechanisms remain poorly understood. Here, we describe lorelei, an Arabidopsis thaliana mutant impaired in sperm cell release, reminiscent of the feronia/sirène mutant. Pollen tubes reaching lorelei embryo sacs frequently do not rupture but continue to grow in the embryo sac. Furthermore, lorelei embryo sacs continue to attract additional pollen tubes after arrival of the initial pollen tube. The LORELEI gene is expressed in the synergid cells prior to fertilization and encodes a small plant-specific putative glucosylphosphatidylinositol-anchored protein (GAP). These results provide support for the concept of signaling mechanisms at the synergid cell membrane by which the female gametophyte recognizes the arrival of a compatible pollen tube and promotes sperm release. Although GAPs have previously been shown to play critical roles in initiation of fertilization in mammals, flowering plants appear to have independently evolved reproductive mechanisms that use the unique features of these proteins within a similar biological context.


1 alpha-hydroxyvitamin D3 treatment of three patients with 1,25-dihydroxyvitamin D-receptor-defect rickets and alopecia.
Three patients with clinically different severities of vitamin D-dependent rickets, type II, with alopecia, which is 1,25-dihydroxyvitamin D-receptor-defect rickets and is particularly resistant to treatment with calciferol analogues, were treated with large doses of 1 alpha-hydroxyvitamin D3 (1 alpha-(OH)D3) and 2 g of calcium lactate. Except for the alopecia, all of the abnormalities of patients 1 and 2 were reversed by treatment with 3 micrograms/kg/d of 1 alpha-(OH)D3, and those of patient 3, who had the severest manifestations, were reversed by treatment with 6 micrograms/kg/d. The serum 24,25-dihydroxyvitamin D concentrations of the three patients were low before treatment and those of patients 1 and 2 increased during treatment. These findings suggest that in patients 1 and 2, 25-hydroxyvitamin D-24-hydroxylase was stimulated via a 1,25-dihydroxyvitamin D-receptor-mediated system by treatment with 1 alpha-(OH)D3.


Meta-analysis of glyphosate contamination in surface waters and dissipation by biofilms.
One consequence of the intensive use of glyphosate is the contamination of rivers by the active substance and its metabolites aminomethyl phosphonic acid (AMPA) and sarcosine, inducing river eutrophication. Biofilms are the predominant lifestyle for microorganisms in rivers, providing pivotal roles in ecosystem functioning and pollutant removal. The persistence of glyphosate in these ecosystems is suspected to be mostly influenced by microbial biodegradation processes. The present study aimed to investigate the tripartite relationship among biofilms, phosphorus and glyphosate in rivers. The first part consists of a co-occurrence analysis among glyphosate, AMPA and phosphorus using an extensive dataset of measurements (n = 56,198) from French surface waters between 2013 and 2017. The second part investigated the capacity of natural river biofilms to dissipate glyphosate, depending on phosphorus availability and the exposure history of the biofilm, in a microcosm study. A strong co-occurrence among glyphosate, AMPA and phosphorus was found in surface waters. More than two-thirds of samples contained phosphorous with glyphosate, AMPA or both compounds. Seasonal fluctuations in glyphosate, AMPA and phosphorus concentrations were correlated, peaking in spring/summer shortly after pesticide spreading. Laboratory experiments revealed that natural river biofilms can degrade glyphosate. However, phosphorus availability negatively influenced the biodegradation of glyphosate and induced the accumulation of AMPA in water. An increase in alkaline phosphatase activity and phosphorus uptake was observed in glyphosate-degrading biofilms, evidencing the tight link between phosphorus limitation and glyphosate degradation by biofilms. The results of the present study show that phosphorus not only is a key driver of river eutrophication but also can reduce complete glyphosate degradation by biofilms and favour the accumulation of AMPA in river water. The predominant role of biofilms and the trophic status of rivers must therefore be considered in order to better assess the fate and persistence of glyphosate.


Myelin basic protein gene transcription. Identification of proximal and distal cis-acting regulatory elements.
Myelin basic proteins (MBPs) represent a major component of the myelin membrane which are exclusively expressed by glial cells in the nervous system. The cell type-specific expression of MBP is controlled preferentially at the level of RNA synthesis. To investigate the mechanisms by which the MBP gene is regulated, we analyzed transcriptional regulation of this gene in glial and non-glial cells. We have demonstrated that the 320 base pairs upstream of the MBP transcriptional start site contain regulatory elements that preferentially stimulate transcription of MBPs in glial cells. Using a test vector containing the simian virus 40 (SV40) early promoter placed upstream of the bacterial chloramphenicol acetyltransferase gene, we localized three major promoter elements within the 5'-upstream sequence. These elements, designated MB1, MB4, and MB7, spanning proximal (-14 to -50) and distal (-130 to -169 and -249 to -288) positions with respect to the RNA initiation site, activated SV40 promoter transcription more than 40-fold in glial cells. The promoter distal elements, MB4 and MB7, enhanced SV40 promoter activity 2- and 8-fold, respectively, in L cells. Using the gel mobility shift assay, we have demonstrated that the MBP activators (MB1, MB4, and MB7) interact with multiple proteins derived from glial and L cell extract and result in the formation of several complexes. Comparison of band intensity of these complexes implies that these cells contain both unique and ubiquitous DNA binding proteins that recognize the DNA sequences within these activators. These studies suggest that the MBP promoter consists of several regulatory sequences in which the proximal element, MB1, and one of the distal elements, MB4, are selectively more active in glial cells than in L cells. Thus, these novel regulatory elements, in concert with other sequences, appear to stimulate MBP promoter transcription in glial cells.


Syringomyelia in hereditary multiple exostosis.
We describe five children with Hereditary Multiple Exostosis (HME) who also had syringomyelia. Of these, four had a tethered cord/fibrolipoma. No spinal osteochondromas were found in these patients. All had antecedent neurological signs or symptoms that prompted spinal imaging with MRI. Of all patients with HME seen in the Midwest Regional Bone Dysplasia Clinic from 1982 to present, 44% (17/39) of patients had signs or symptoms concerning for possible cord-related neurological findings. However, only 10 of 39 had spinal imaging. Assuming that all individuals with syringomyelia were identified, then 5/39 (13%) were in that way affected. This, of course, is a minimal estimate given that many were not imaged. The incidence of syringomyelia appears to be increased in this population, and seems to be unrelated to spinal osteochondromas. A low threshold for obtaining spinal MRI in patients with Hereditary Multiple Exostosis seems rational. © 2016 Wiley Periodicals, Inc.


Using machine learning to uncover the relation between age and life satisfaction.
This study applies a machine learning (ML) approach to around 400,000 observations from the German Socio-Economic Panel to assess the relation between life satisfaction and age. We show that with our ML-based approach it is possible to isolate the effect of age on life satisfaction across the lifecycle without explicitly parameterizing the complex relationship between age and other covariates-this complex relation is taken into account by a feedforward neural network. Our results show a clear U-shape relation between age and life satisfaction across the lifespan, with a minimum at around 50 years of age.


Partner abuse among women whose children have been sexually abused: an exploratory study.
To explore partner abuse among women in families in which a child has disclosed child sexual abuse, 102 mothers completed a measure of partner abuse and the Coping Responses Inventory. Results suggest that, like women in the general population, mothers of children who have been sexually abused have often experienced partner abuse. As expected, physical abuse in a current relationship was found to be related to the use of avoidance strategies in dealing with the sexual abuse disclosure. The implications for practitioners and for future research are discussed.


Chitinase Chi1 from Myceliophthora thermophila C1, a Thermostable Enzyme for Chitin and Chitosan Depolymerization.
A thermostable Chitinase Chi1 from Myceliophthora thermophila C1 was homologously produced and characterized. Chitinase Chi1 shows high thermostability at 40 °C (>140 h 90% activity), 50 °C (>168 h 90% activity), and 55 °C (half-life 48 h). Chitinase Chi1 has broad substrate specificity and converts chitin, chitosan, modified chitosan, and chitin oligosaccharides. The activity of Chitinase Chi1 is strongly affected by the degree of deacetylation (DDA), molecular weight (Mw), and side chain modification of chitosan. Chitinase Chi1 releases mainly (GlcNAc)2 from insoluble chitin and chito-oligosaccharides with a polymerization degree (DP) ranging from 2 to 12 from chitosan, in a processive way. Chitinase Chi1 shows higher activity toward chitin oligosaccharides (GlcNAc)4-6 than toward (GlcNAc)3 and is inactive for (GlcNAc)2. During hydrolysis, oligosaccharides bind at subsites -2 to +2 in the enzyme's active site. Chitinase Chi1 can be used for chitin valorisation and for production of chitin- and chito-oligosaccharides at industrial scale.


Profile of Gut Microbiota of Adults with Diabetes Mellitus Type 1: A Systematic Review.
Type 1 diabetes mellitus (T1DM) is a chronic disease of clinical importance, whose prevalence has increased in Brazil and worldwide. Among the possible factors involved in the genesis and control of the disease, the intestinal microbiota (IM) deserves to be highlighted, but studies that report differences between the IM of patients with T1DM and those who are healthy are still contradictory and scarce. The objective of this paper was to evaluate the IM profile of T1DM and healthy patients, in order to verify possible differences and to evaluate the possibility of the influence of IM on glycemic control in T1DM. Of the 2716 articles found, nine were included in this review, and all of which were randomized, observational, cross-sectional, cohort and case-control studies that characterized the composition of IM in adults with T1DM and healthy adults. Studies are very diverse, which makes it difficult to associate the IM profile with T1DM etiology and control, however it was found that there was a prevalence of the phylum Firmicutes in the IM of individuals with T1DM and that there was no significant difference in the relative abundance of Bacteroidetes in both populations. It was also possible to identify an inverse relationship of the genus Bifidobacterium and a positive relationship of the genera Bacteroidetes and Prevotella with the concentration ofglycated hemoglobin. More studies are needed to contemplate the characterization of IM in healthy and T1DM individuals.


Evaluation of the effects of aluminium, ethanol and their combination on rat brain synaptosomal integral proteins in vitro and after 90-day oral exposure.
The effects of aluminium lactate (Al-lactate) on the rat cerebral synaptosome integral proteins adenosinetriphosphatase (ATPase) and acetylcholinesterase(AChE) were studied in vitro and in vivo. Coexposure with ethanol (EtOH) was studied in both situations. Isolation of synaptosomes was carried out using isoosmotic Percoll gradients. In in vitro experiments, the synaptosomes were exposed to different concentrations of Al-lactate in the incubation mixture. Al-lactate caused decreases in total ATPase and AChE activities concentration dependently. The decrease in ATP activity started at 0.2 mM concentration, and concentration for the 50% decrease of the enzyme activity (EC50 ) was 1.1 mM. The decrease in AChE activity started at 5-10 mM concentration, and the EC50 value was 15.8 mM. Coexposure with ethanol (2 mM) increased the EC50 values similarly in both cases. After 90-day oral exposure of rats to Al-lactate (91.8 mg/kg/day), the serum aluminium level was 0.9-1.3 ptM/l. Coexposure with EtOH(3.0 g/kg/day) did not significantly increase the blood Al(0.7 2.2 pM/l). Aluminium exposure caused a decrease in the blood EtOH concentration (0.6 mM/1) compared with blood EtOH (12.3 mM/1) in the rats exposed to ethanol only. In the rats studied 2 weeks after the Al exposure, the activities of ATPase and AChE were significantly lower than in the rats studied immediately after the exposure. Correspondingly, a significant decrease in AChE activity was found in Al and EtOH-exposed rats, but in the control rats there were no differences between the study groups. Immediately after the 90-day dosing, the exposed rats did not differ significantly from the control rats. Based on the in vitro results, the neural membrane integral proteins ATPase and AChE may be considered as targets for the effects of aluminium and ethanol. Ninety-day in vivo exposure of rats to aluminium caused decrease in ATPase and AChE activities, detectable 2 weeks after the exposure.


[Dual Left Anterior Descending Coronary Artery;Report of a Case].
A 77-year-old male presented with angina pectoris. On coronary angiography, the left anterior descending artery(LAD) was obstructed after branching the second septal branch. Three-dimensional (3D) images constructed with 64-slice computed tomography (CT) showed type I dual LAD. The short LAD, which had been erroneously recognized as a septal branch on coronary angiography, ran on the anterior interventricular sulcus (AIVS) where it then terminated. The long LAD, which was obstructed at its origin, ran on the left ventricular side of the AIVS, and entered the distal part of the AIVS. Coronary artery bypass grafting including a bypass to the long LAD was successfully performed. Recognition of the dual LAD, a rare coronary artery anomaly regarding its origin and course, is import ant in performing successful myocardial revascularization procedures. The 3D-CT images are extremely useful in demonstrating dual LAD, especially in cases where there is occlusion of the LAD.


Effects of Coenzyme Q10 Supplementation on Serum Values of Gamma-glutamyl transferase, Pseudocholinesterase, Bilirubin, Ferritin, and High-Sensitivity C-Reactive Protein in Women with Type 2 Diabetes.
Type 2 diabetes mellitus (T2DM) is a disease associated with increased oxidative stress which results from mitochondrial dysfunction. Coenzyme Q10 (CoQ10) is an essential antioxidant for energy production in mitochondria. The purpose of this randomized double-blind clinical trial study was to evaluate the effects of CoQ10 supplementation on serum values of gamma-glutamyl transferase (GGT), pseudocholinesterase (PchE), bilirubin, ferritin, and high-sensitivity c-reactive protein (hs-CRP) and metabolic syndrome biomarkers in women with T2DM. Eighty women with T2DM enrolled in this study. Thirty six of them were randomized in the drug group (receiving 100 mg/day of CoQ10) and 44 women were randomized in placebo group. Intervention was continued for 12 weeks. In both groups 35 subjects finished the study and were included in the analysis. Serum levels of the variables were measured before and after supplementation. Serum values of FBS (P=0.039), HOMA-IR (P=0.01), ferritin (P<0.001), total cholesterol (TC) (P=0.006), LDL-C (P=0.007) decreased and HDL-C (P=0.02) increased significantly in the drug group after intervention. Serum levels of triglyceride (P=0.09) decreased marginally in CoQ10 group. The results of the current study had shown that after supplementation with 100 mg/day of CoQ10 for 12 weeks, serum values of FBS, HOMA-IR, TC, LDL-C and ferritin were decreased and values of HDL-C were increased in women with T2DM.


Late Endocrine Side Effects in Children with Acute Leukemia.
This study was carried out in 28 patients (10 female, 18 male) diagnosed with acute leukemia, and aimed to investigate the abnormalities of endocrine system. Twenty-five of 28 patients were acute lymphoblastic leukemia and 3 were acute non-lymphocytic leukemia. Sixteen children were treated using BFM-90 chemotherapy protocol, and the rest with various regimens. Two patients were exposed to 12-13 Gy of total body irradiation followed by bone marrow transplantation. All patients were in remission at least five years. One (3%) of 28 patients had short stature and 4 (14%) had obesity. Pubertal status was retarded in 2 (7%) patients. Glucose intolerance, secondary hypothyroidism and hypergonadotropic hypogonadism were detected in 2, 1 and 2 patients, respectively. TSH response to TRH test was exaggerated in 1 and blunted in 3 patients.


Role of NEAT1/MiR-9-5p/SLC26A2 Pathway on Human Airway Smooth Muscle Cell.
Asthma is a serious inflammatory disease of the respiratory system in which airway smooth muscle cells (ASMCs) play a key role. This study aimed to investigate the expression of SLC26A2 in human ASMCs (HASMCs) and the regulatory mechanism of SLC26A2 in the proliferation and inflammatory factor production of HASMCs. We obtained the asthma-associated differential mRNA SLC26A2 by bioinformatics analysis in childhood acute asthma samples. To investigate its role in airway inflammation and airway remodeling, we treated HASMCs with platelet-derived growth factor (PDGF) in an in vitro model and determined SLC26A2 expression in cells using western blotting. Cell proliferation was detected by MTT and EdU assays, and cell contractile phenotype marker proteins were measured. Cell migration and production of inflammatory factors were determined by Transwell and ELISA assays. Additionally, the upstream regulatory miRNA and LncRNA of SLC26A2 were identified by bioinformatics, luciferase reporter gene, and RIP analyses. SLC26A2 was significantly upregulated in bioinformatics analysis of pediatric asthma-related sample. PDGF treatment up-regulated SLC26A2 expression in HASMCs, whereas the knockdown of SLC26A2 inhibited PDGF-stimulated proliferation, migration, and production of inflammatory factors, and enhanced the expression of cell contractile phenotype marker proteins in HASMCs. Luciferase reporter and RIP experiments validated that NEAT1 targeted miR-9-5p to regulate SLC26A2, thereby influencing the biological function of PDGF-induced HASMCs. These findings indicate that NEAT1-mediated miR-9-5p targeting of SLC26A2 inhibits the PDGF-induced proliferation and production of inflammatory factors in HASMCs. These findings highlight potential therapeutic targets for asthma and airway inflammation.


Identifying typical pre-crash scenarios based on in-depth crash data with deep embedded clustering for autonomous vehicle safety testing.
Choosing appropriate scenarios is critical for autonomous vehicles (AVs) safety testing. Real-world crash scenarios can be used as critical scenarios to test the safety performance of AVs. As one of the dominant types of traffic crashes, the car to powered-two-wheelers (PTWs) crash results in a higher possibility of fatality than ordinary car-to-car crashes. Generally, typical testing scenarios are chosen according to the subjective understanding of the safety experts with limited static features of crashes (e.g., geometric features, weather). This study introduced a novel method to identify typical car-to-PTWs crash scenarios based on real-world crashes with dynamic pre-crash features investigated from the China In-depth Mobility Safety Study-Traffic Accident (CIMSS-TA) database. First, we present crash data collection and construction methods of the CIMSS-TA database to construct testing scenarios. Second, the stacked autoencoder methods are used to learn and obtain embedded features from the high-dimensional data. Third, the extracted features are clustered using k-means clustering algorithm, and then the clustering results are interpreted. Six typical car-to-PTWs scenarios are obtained with the proposed processes. This study introduces a typical high-risk scenario construction method based on deep embedded clustering. Unlike existing researches, the proposed method eliminates the negative impacts of manually selecting clustering variables and provides a more detailed scenario description. As a result, the typical scenarios obtained from AV testing are more robust.


beta-Lactamase-producing Moraxella catarrhalis may prevent the emergence of penicillin-resistant Streptococcus pneumoniae in children with recurrent acute otitis media.
We studied the effect of concomitant nasopharyngeal carriage of beta-lactamase producing Moraxella catarrhalis and Haemophilus influenzae on the occurrence of penicillin resistance of Streptococcus pneumoniae. We took nasopharyngeal samples from 306 children with recurrent otitis media and a history of several antibiotic treatments. We could isolate at least one of the pathogens in 89 subjects. Of these children 13% carried more than one pathogen. Of the isolated M. catarrhalis and H. influenzae strains 93% and 43% produced beta-lactamase, respectively. Of the S. pneumoniae strains 25% were non-susceptible (I/R) to penicillin. However, in patients carrying beta-lactamase-producing M. catarrhalis together with pneumococci all strains were susceptible to penicillin (P=0.0353). This finding suggests that beta-lactamase producing M. catarrhalis may hinder the emergence of penicillin resistance of S. pneumoniae in children with recurrent acute otitis media.


Novel antipsychotics specificity profile: A clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone.
Second generation antipsychotics (SGAs) are effective options in the treatment of schizophrenia and mood disorders, each with characteristic efficacy and safety features. In order to optimize the balance between efficacy and side effects, it is of upmost importance to match compound specificity against patient clinical profile. As the number of SGAs increased, this review can assist physicians in the prescription of three novel SGAs already on the market, namely lurasidone, brexpiprazole, cariprazine, and lumateperone, which is in the approval phase for schizophrenia treatment at the FDA. Besides schizophrenia, EMA and/or FDA approved lurasidone for bipolar depression, brexpiprazole as augmentation in major depressive disorder and cariprazine for the acute treatment of manic or mixed episodes associated with bipolar I disorder. These new antipsychotics were developed with the aim of improving efficacy on negative and depressive symptoms and reducing metabolic and cardiovascular side effects compared to prior SGAs, while keeping the risk of extrapyramidal symptoms low. They succeeded quite well in containing these side effects, despite weight gain during acute treatment remains a possible concern for brexpiprazole, while cariprazine and lurasidone show higher risk of akathisia compared to placebo and other SGAs such as olanzapine. The available studies support the expected benefits on negative symptoms, cognitive dysfunction and depressive symptoms, while the overall effect on acute psychotic symptoms may be similar to other SGAs such as quetiapine, aripiprazole and ziprasidone. The discussed new antipsychotics represent useful therapeutic options but their efficacy and side effect profiles should be considered to personalize prescription.


Dynamic changes in mucus thickness and ion secretion during Citrobacter rodentium infection and clearance.
Citrobacter rodentium is an attaching and effacing pathogen used as a murine model for enteropathogenic Escherichia coli. The mucus layers are a complex matrix of molecules, and mucus swelling, hydration and permeability are affected by many factors, including ion composition. Here, we used the C. rodentium model to investigate mucus dynamics during infection. By measuring the mucus layer thickness in tissue explants during infection, we demonstrated that the thickness changes dynamically during the course of infection and that its thickest stage coincides with the start of a decrease of bacterial density at day 14 after infection. Although quantitative PCR analysis demonstrated that mucin mRNA increases during early infection, the increased mucus layer thickness late in infection was not explained by increased mRNA levels. Proteomic analysis of mucus did not demonstrate the appearance of additional mucins, but revealed an increased number of proteins involved in defense responses. Ussing chamber-based electrical measurements demonstrated that ion secretion was dynamically altered during the infection phases. Furthermore, the bicarbonate ion channel Bestrophin-2 mRNA nominally increased, whereas the Cftr mRNA decreased during the late infection clearance phase. Microscopy of Muc2 immunostained tissues suggested that the inner striated mucus layer present in the healthy colon was scarce during the time point of most severe infection (10 days post infection), but then expanded, albeit with a less structured appearance, during the expulsion phase. Together with previously published literature, the data implies a model for clearance where a change in secretion allows reformation of the mucus layer, displacing the pathogen to the outer mucus layer, where it is then outcompeted by the returning commensal flora. In conclusion, mucus and ion secretion are dynamically altered during the C. rodentium infection cycle.


Traumatic brain injury: methodological approaches to estimate health and economic outcomes.
The effort to standardize the methodology and adherence to recommended principles for all economic evaluations has been emphasized in medical literature. The objective of this review is to examine whether economic evaluations in traumatic brain injury (TBI) research have been compliant with existing guidelines. Medline search was performed between January 1, 1995 and August 11, 2012. All original TBI-related full economic evaluations were included in the study. Two authors independently rated each study's methodology and data presentation to determine compliance to the 10 methodological principles recommended by Blackmore et al. Descriptive analysis was used to summarize the data. Inter-rater reliability was assessed with Kappa statistics. A total of 28 studies met the inclusion criteria. Eighteen of these studies described cost-effectiveness, seven cost-benefit, and three cost-utility analyses. The results showed a rapid growth in the number of published articles on the economic impact of TBI since 2000 and an improvement in their methodological quality. However, overall compliance with recommended methodological principles of TBI-related economic evaluation has been deficient. On average, about six of the 10 criteria were followed in these publications, and only two articles met all 10 criteria. These findings call for an increased awareness of the methodological standards that should be followed by investigators both in performance of economic evaluation and in reviews of evaluation reports prior to publication. The results also suggest that all economic evaluations should be made by following the guidelines within a conceptual framework, in order to facilitate evidence-based practices in the field of TBI.


An evidence based approach to the first unprovoked seizure.
The objective is to illustrate the creation and structure of a particular type of Evidence Based Care (EBC) summary that has direct clinical relevance, the Critically Appraised Topic (CAT). The process consists of a step-by-step application of the EBC principles to a common neurological problem, i.e., a patient presenting with a first, unprovoked generalized seizure. This includes asking a focused clinical question about prognosis for recurrence and the role of antiepileptic drugs; searching the literature to answer the question; selecting the relevant evidence (a meta-analysis about prognosis and a randomized controlled trial about therapy); appraising the literature for its validity and usefulness; and applying the results to the clinical scenario. The result is a one-page, user friendly CAT whose title states a declarative answer to the clinical question. It also contains a description of the literature search and of the evidence, the clinical bottom lines derived from the evidence, and general comments.


Risk Factors Related with Retroperitoneal Laparoscopic Converted to Open Nephrectomy for Nonfunctioning Renal Tuberculosis.
The present study was designed to investigate the risk factors affecting the conversion to open surgery in retroperitoneal laparoscopic nephrectomy of nonfunctioning renal tuberculosis (TB). The records of 144 patients who underwent a retroperitoneal laparoscopic nephrectomy procedure by a single surgeon were retrospectively reviewed. The following factors, including age, sex, body mass index (BMI), diabetes status, hypertension status, side of kidney, size of kidney, degree of calcification, mild perirenal extravasation, contralateral hydronephrosis, the time of anti-TB, and surgeon experience were analyzed. Univariate and multivariate logistic regression analyses were used for statistical assessment. Twenty-three patients were converted to open surgery and the conversion rate was 15.97%. In univariate analysis, BMI ≥35 kg/m2 (p = 0.023), hypertension (p = 0.011), diabetes (p = 0.003), and kidney size (p = 0.032) were the main factors of conversion to open surgery. Sex, age, side, anti-TB time, calcification, mild extravasation, and surgeon experience were not significantly related. In multivariate regression analysis, BMI ≥35 kg/m2, hypertension, diabetes, and enlargement of kidney were the most important factors for conversion to open surgery. Depending on the results achieved by a single surgeon, BMI ≥30 kg/m2, diabetes, hypertension, and enlargement of kidney significantly increased the conversion risk in retroperitoneal laparoscopic nephrectomy for nonfunctioning renal TB.


Genome-wide analyses of amphioxus microRNAs reveal an immune regulation via miR-92d targeting C3.
Recently, amphioxus has served as a model for studying the origin and evolution of vertebrate immunity. However, little is known about how microRNAs (miRNAs) are involved in the immune defense in amphioxus. In this article, we present a systematic study of amphioxus miRNAs in the acute-phase response to bacterial infection; miR-92d was found to regulate the complement pathway in this basal chordate. We identified all 155 possible miRNAs present in the amphioxus Branchiostoma belcheri genome by bioinformatics analyses, including 57 newly identified miRNAs (called bbe-miRNAs), and characterized the miRNA expression pattern. Four miRNAs (bbe-miR-7, bbe-miR-4868a, bbe-miR-2065, and bbe-miR-34b) were upregulated and bbe-miR-92d was downregulated under the challenge of both Vibrio anguillarum and Staphylococcus aureus bacteria. We further predicted miRNA targets and identified mRNA targets of immune-related miRNA using the hybrid PCR method. We propose that miR-92d regulates the complement pathway through targeting C3 for controlling the acute immune response to bacterial infections. This study provides evidence for the complex immune regulation of miRNAs in the acute-phase response in basal chordates.


T serotypes and antimicrobial susceptibilities of group A streptococcus isolates from pediatric pharyngotonsillitis.
Group A streptococcus (GAS) is a major cause of pediatric pharyngotonsillitis. In this study we determined the T serotype and antimicrobial susceptibility of GAS isolates from Japanese children. From January to December 2006, a total of 438 isolates of GAS were obtained from pharyngeal swabs of 438 children with pharyngotonsillitis. The commonest T serotype was type 1 (110 strains, 25.1%), followed by type 12 (107, 24.4%) and type 4 (77, 17.6%). All GAS isolated from pharyngeal swabs were susceptible to beta-lactams (benzylpenicillin, amoxicillin, cefotaxime, ceftriaxone, imipenem, panipenem, and cefditoren) and vancomycin, but 19.6, 19.6, 3.2, 11.6, and 27.6% were resistant to erythromycin, clarithromycin, clindamycin, minocycline, and norfloxacin, respectively. Resistance varied considerably with the T serotype. In particular, type 4 isolates had the highest resistance (67.5, 67.5, 26.0, and 53.2% were resistant to erythromycin, clarithromycin, minocycline, and norfloxacin, respectively).


Individualization of controlled ovarian stimulation in vitro fertilization using ovarian reserve markers.
In assisted reproduction technologies (ART) the controlled ovarian stimulation (COS) therapy is the starting point from which a good oocytes retrieval depends. Treatment individualization is based on ovarian response prediction, which largely depends on a woman's ovarian reserve. Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are considered the most accurate and reliable markers of ovarian reserve. A literature search was carried out for studies that addressed the ability of AMH and AFC to predict poor and/or excessive ovarian response in IVF cycles. According to the predicted response to ovarian stimulation (poor- normal- or high-response) is today possible not only to personalize pre-treatment counseling with the couple, but also to individualize the ovarian stimulation protocol, choosing among GnRH-agonists or antagonists for endogenous follicle-stimulating hormone (FSH) suppression and formulating the FSH starting dose most adequate for the single patients. In this review we discuss how to choose the best COS therapy for the single patient, on the basis of the markers-guided ovarian response prediction.


Liposome-mediated enhancement of the sensitivity in immunoassay based on surface-enhanced Raman scattering at gold nanosphere array substrate.
A novel immunoassay based on surface-enhanced Raman scattering (SERS) has been developed. The method exploits the SERS-derived signal from reporter molecules (crystal violet, CV) encapsulated in antibody-modified liposome particles. The antigen is firstly captured by the primary antibody immobilized in microwell plates and then sandwiched by secondary antibody-modified liposome. The CV molecules are released from the liposome and transferred to specially designed substrate of gold nanosphere arrays with sub-10-nm gaps. The concentration of the antigen is indirectly read out by the SERS intensity of the CVs. The substrate used could substantially improve the sensitivity and reproducibility of SERS measurement. The SERS intensity responses are linearly correlated to logarithm of antigen concentration in the range of 1.0 x 10(-8) to 1.0 x 10(-4) gm L(-1) with a detection limit of 8 ng mL(-1). To our knowledge, this is the first report describing liposome-mediated enhancement of the sensitivity in immunoassay based on surface-enhanced Raman scattering. Experimental results show that the proposed method illustrates a potential prospect of applications in immunoassay.


[Toxin-infections and toxin-related diseases due to Clostridia other than Clostridium difficile].
Clostridia cause severe diseases. Tetanus is rare in Switzerland because of vaccine coverage and the application of guidelines for the management of contaminated wounds. Tetanus requires wound debridement and the administration of antibiotics and anti-tetanus immune. Besides gastroenteritis, infections due to C. perfringens most often require surgery, in addition to antibiotic treatment with penicillin and clindamycin. Botulism is a rare disease caused by a toxin produced by C. botulinum that causes flaccid paralysis. The clinical syndrome must be recognized early in order to administer the antitoxin and improve the prognosis. The other, rarer species of Clostridia require surgical and antibiotic management, but their prognosis remains poor.


Picturing the nurse-person/family/community process in the year 2050.
How will nurses relate with persons in the year 2050? And, how might technology enable or limit the nursing process with persons, families, and communities? These are the questions addressed in this column. Imaging practice in light of the technological imaginings and projections is facilitated by a possible scenario that includes robotics that not only monitor human biological processes, they also emote compassion and caring that may one day be dosed according to the latest diagnostic prescription. Three nurses in this column present their views of how nursing might evolve. Karnick, aligned with the human becoming school of thought, imagines a practice anchored in respect for humanity and quality of life and an accompanying respect for nursing knowledge and nursing work. Senesac and Sato, aligned with Roy's adaptation model, call for nurses to envision and choose the future they want to have. Clear in both perspectives is a reverence for human values and human experience and for the critical role of nursing knowledge as we move toward the not-yet of 2050.


Hepatic sexual dimorphism - implications for non-alcoholic fatty liver disease.
The liver is often thought of as a single functional unit, but both its structural and functional architecture make it highly multivalent and adaptable. In any given physiological situation, the liver can maintain metabolic homeostasis, conduct appropriate inflammatory responses, carry out endobiotic and xenobiotic transformation and synthesis reactions, as well as store and release multiple bioactive molecules. Moreover, the liver is a very resilient organ. This resilience means that chronic liver diseases can go unnoticed for decades, yet culminate in life-threatening clinical complications once the adaptive capacity of the liver is overwhelmed. Non-alcoholic fatty liver disease (NAFLD) predisposes individuals to cirrhosis and increases liver-related and cardiovascular disease-related mortality. This Review discusses the accumulating evidence of sexual dimorphism in NAFLD, which is currently rarely considered in preclinical and clinical studies. Increased awareness of the mechanistic causes of hepatic sexual dimorphism could lead to improved understanding of the biological processes that are dysregulated in NAFLD, to the identification of relevant therapeutic targets and to improved risk stratification of patients with NAFLD undergoing therapeutic intervention.


Comparing Theory of Mind Development in Children with Autism Spectrum Disorder, Developmental Language Disorder, and Typical Development.
Theory of mind (ToM) is the ability to recognize, comprehend, and consider oneself's and others' mental states and perspectives to predict and explain behaviors and motivations. It is widely accepted that children with autism spectrum disorder (ASD) experience difficulties with ToM. However, there are also findings suggesting that ToM abilities might also be compromised in children with Developmental Language Disorders (DLD). To assess ToM abilities in three groups of children: 1. ASD with no language difficulties; 2. DLD, known for their language disorder; and 3. TD with no language issues. A total of 41 preschool children aged 5-to-6 were examined and assigned to one of the three groups based on previous clinical reports and a standardized Hebrew language assessment tool. Nonverbal IQ was established with a standardized test to verify within average range placement (>75 IQ). ToM skills were examined with a Hebrew version of the ToM Task Battery and parent's questionnaire (ToMI). Children with ASD had significantly lower ToM scores compared to the children with DLD, and TD. The ToM scores of the children with DLD were similar to the scores of the TD children. According to the parents' questionnaires, both the ASD children and the DLD children had less developed ToM skills compared to their TD peers. The present findings suggest that children with ASD have a fundamental difficulty in ToM that is independent of their language abilities. Children with DLD show difficulties in everyday social interactions that involve ToM. It is possible that both ASD and language disorders influence ToM development, suggesting that different developmental routes affect the acquisition of ToM.


In vivo optical molecular imaging of vascular endothelial growth factor for monitoring cancer treatment.
Vascular endothelial growth factor (VEGF) expression is a critical component in tumor growth and metastasis. Capabilities to monitor VEGF expression in vivo can potentially serve as a useful tool for diagnosis, prognosis, treatment planning, monitoring, and research. Here, we present the first report of in vivo hyperspectral molecular imaging strategy capable of monitoring treatment-induced changes in VEGF expression. VEGF was targeted with an anti-VEGF antibody conjugated with a fluorescent dye and was imaged in vivo using a hyperspectral imaging system. The strategy was validated by quantitatively monitoring VEGF levels in three different tumors as well as following photodynamic treatment. Specificity of the molecular imaging strategy was tested using in vivo competition experiments and mathematically using a quantitative pharmacokinetic model. The molecular imaging strategy successfully imaged VEGF levels quantitatively in three different tumors and showed concordance with results from standard ELISA. Changes in tumoral VEGF concentration following photodynamic treatment and Avastin treatment were shown. Immunohistochemistry shows that (a) the VEGF-specific contrast agent labels both proteoglycan-bound and unbound VEGF in the extracellular space and (b) the bound VEGF is released from the extracellular matrix in response to photodynamic therapy. In vivo competition experiments and quantitative pharmacokinetic model-based analysis confirmed the high specificity of the imaging strategy. This first report of in vivo quantitative optical molecular imaging-based monitoring of a secreted cytokine in tumors may have implications in providing tools for mechanistic investigations as well as for improved treatment design and merits further investigation.


Smoking as a Risk or Protective Factor in Developing and Severity of COVID-19?
Background: Many studies have discussed the relationship between COVID-19 and smoking, but they include many contradictory findings. This study evaluates the relationship between smoking and the incidence and severity of COVID-19 patients in Shahroud City, Iran. Methods: We conducted a cross-sectional analytical study using COVID-19 data. All suspected cases were referred to the registered centers at Shahroud University of Medical Sciences from 21 January 2020 to 20 March 2021. Multivariable logistic regression was conducted to evaluate the relationship between smoking and SARS-COV 2 confirmed cases, and its severity. Results: Overall, it was confirmed that 22.6% of smokers had positive COVID-19 PCR tests compared to 42.1% of non-smokers. COVID-19 is a public health problem, and the results showed that there was a relationship between smoking and COVID-19 confirmed cases and severity. The results showed that smoking, adjusting for other related factors, reduces the odds of COVID-19 by 58%, but increases the odds of severe disease by 89%. Conclusions: In this study, smoking was significantly associated with a low chance of developing COVID-19 disease but higher odds of severity. These significant results were reported even in the presence of under-reporting of smoking by patients, which underestimates the association. These results should not be ignored, and further studies are needed.


Neuropsychology pilot: Dr. Carlos Porges.
This article is an interview that explores Dr. Carlos Porge's atypical job as a neuropsychologist and active airline pilot. The article aims to educate about the path and costs that go into having an atypical career in psychology. Additionally, this interview with Dr. Porges explores the challenges, considerations, and limitations of working as a neuropsychology pilot. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Intrauterine growth restriction (IUGR): biometric and Doppler assessment.
Intrauterine growth restriction (IUGR) is a common complication in pregnancy and influences morbidity and mortality at all stages of life. Historically, the management of IUGR has been dependent on antenatal biophysical testing and umbilical artery Doppler studies. With recent Doppler studies of the fetal central circulation, including intracardiac flows and the ductus venosus, better timing of delivery to minimize morbidity may be possible. This review will provide the reader with tools to diagnose IUGR, more accurately date the IUGR pregnancy with poor dating criteria, and better assess the condition of the IUGR fetus. A brief review of animal models of IUGR is presented to demonstrate research directions for answering human clinical questions and potentially carrying therapeutic intervention from the bench to the bedside.


[Work overload in the perception of nurses working at hospitals].
This article presents the first part of a qualitative research in which we interviewed ten nurses that were burnout with work and ten that were not. The objective was to comprehend how they experience burnout situations. The interviews were analysed according to Content Analysis Technique. The "overload of work" category was the most frequent in the participants' speeches. All the nurses with burnout made reference to this category about tem times, while relating the situations they consider to cause burnout. In the other hand, nurses without burnout only related to it once or twice. The overload of work appears as a consequence of "accumulated functions" on their daily activities and from the consequent "time pressure" they suffer. The speeches reflect the nurse's work organization which, frequently, is difficult to practice in a strict way, leading some professionals to make decisions sometimes considered contradictory.


Protective effects of hydrogen sulfide against angiotensin II-induced endoplasmic reticulum stress in HUVECs.
The inhibitory effects of hydrogen sulfide (H2S) on angiotensin II (AngII)-stimulated human umbilical vein endothelial cell (HUVEC) dysfunction remain to be elucidated. Endoplasmic reticulum (ER) stress has been detected in endothelial dysfunction (ED). The present study aimed to determine whether H2S may exert an inhibitory effect on AngII‑induced ER stress. Using HUVECs as a model system, the present study used western blotting to detect protein expression, intracellular reactive oxygen species (ROS) levels were determined by oxidative conversion of cell permeable DCFH‑DA to fluorescent dichlorofluorescein, CCK‑8 assay was used to investigate the cell viability, methylene blue was used to investigate the CSE activity, TUNEL was used to investigate the cells apoptosis. The present study demonstrated that AngII not only upregulated the expression levels of inducible nitric oxide synthase (iNOS), stimulated ROS production and increased cell apoptosis, but also downregulated the expression levels of phosphorylated‑endothelial nitric oxide synthase, decreased the expression and activity of cystathionine‑c‑lyase (CSE) and decreased cell viability. Furthermore, hydrogen peroxide (H2O2; an exogenous ROS) downregulated the expression and activity of CSE, and had similar effects as AngII, whereas the inhibitory effects of AngII were completely suppressed by N-acetyl-L-cysteine (a ROS scavenger). In addition, AngII induced the expression of glucose‑regulated protein 78 (GRPP78) and C/EBP homologous protein (CHOP), which are markers of ER stress. Conversely, the stimulatory effects of AngII were completely inhibited by sodium hydrosulfide (NaHS; a H2S donor). Treatment with NaHS attenuated ROS production, inhibited CHOP and GRP78 expression, and decreased cell apoptosis. The present study indicated that AngII induced ED via the activation of ER stress in HUVECs. In addition, the effects of AngII on ER stress could be suppressed by H2S.


Iron chelation: inhibition of key signaling pathways in the induction of the epithelial mesenchymal transition in pancreatic cancer and other tumors.
Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide in both men and women. It presents late with non-specific symptoms, which makes it difficult to diagnose until the cancer has progressed and metastasized. Metastasis is facilitated by the epithelial-to-mes-enchymal transition (EMT), which is promoted via the oncogenic transforming growth factor beta (TGFβ), Wnt, and nuclear factor kappa B (NFκB) signaling pathways. However, recent studies have demonstrated that the EMT can be inhibited by novel anti-cancer agents known as thiosemicarbazone iron chelators. These novel agents also up-regulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which can restore normal signaling to the cell and suppresses metastasis via inhibition of the EMT. Through the ability of iron chelators to up-regulate NDRG1 expression and affect multiple molecular targets, these agents have the potential to maintain the epithelial phenotype of cancer cells and may lead to improved survival rates for patients with late-stage disease.


An adaptive filter for suppression of cardiac and respiratory noise in MRI time series data.
The quality of MRI time series data, which allows the study of dynamic processes, is often affected by confounding sources of signal fluctuation, including the cardiac and respiratory cycle. An adaptive filter is described, reducing these signal fluctuations as long as they are repetitive and their timing is known. The filter, applied in image domain, does not require temporal oversampling of the artifact-related fluctuations. Performance is demonstrated for suppression of cardiac and respiratory artifacts in 10-minute brain scans on 6 normal volunteers. Experimental parameters resemble a typical fMRI experiment (17 slices; 1700 ms TR). A second dataset was acquired at a rate well above the Nyquist frequency for both cardiac and respiratory cycle (single slice; 100 ms TR), allowing identification of artifacts specific to the cardiac and respiratory cycles, aiding assessment of filtering performance. Results show significant reduction in temporal standard deviation (SD(t)) in all subjects. For all 6 datasets with 1700 ms TR combined, the filtering method resulted in an average reduction in SD(t) of 9.2% in 2046 voxels substantially affected by respiratory artifacts, and 12.5% for the 864 voxels containing substantial cardiac artifacts. The maximal SD(t) reduction achieved was 52.7% for respiratory and 55.3% for cardiac filtering. Performance was found to be at least equivalent to the previously published RETROICOR method. Furthermore, the interaction between the filter and fMRI activity detection was investigated using Monte Carlo simulations, demonstrating that filtering algorithms introduce a systematic error in the detected BOLD-related signal change if applied sequentially. It is demonstrated that this can be overcome by combining physiological artifact filtering and detection of BOLD-related signal changes simultaneously. Visual fMRI data from 6 volunteers were analyzed with and without the filter proposed here. Inclusion of the cardio-respiratory regressors in the design matrix yielded a 4.6% t-score increase and 4.0% increase in the number of significantly activated voxels.


Increased extracellular dopamine and 5-hydroxytryptamine levels contribute to enhanced subthalamic nucleus neural activity during exhausting exercise.
The purpose of the study was to explore the mechanism underlying the enhanced subthalamic nucleus (STN) neural activity during exhausting exercise from the perspective of monoamine neurotransmitters and changes of their corresponding receptors. Rats were randomly divided into microdialysis and immunohistochemistry study groups. For microdialysis study, extracellular fluid of the STN was continuously collected with a microdialysis probe before, during and 90 min after one bout of exhausting exercise. Dopamine (DA) and 5-hydroxytryptamine (5-HT) levels were subsequently detected with high-performance liquid chromatography (HPLC). For immunohistochemistry study, the expression of DRD2 and HT2C receptors in the STN, before, immediately after and 90 min after exhaustion was detected through immunohistochemistry technique. Microdialysis study results showed that the extracellular DA and 5-HT neurotransmitters increased significantly throughout the procedure of exhausting exercise and the recovery period (P<0.05 or P<0.01). Immunohistochemistry study results showed that the expression levels of DRD2 and HT2C in the rat STN immediately after exhausting exercise and at the time point of 90 min after exhaustion were both higher than those of the rest condition, but the difference was not significant (P>0.05). Our results suggest that the increased extracellular DA and 5-HT in the STN might be one important factor leading to the enhanced STN neural activity and the development of fatigue during exhausting exercise. This study may essentially offer useful evidence for better understanding of the mechanism of the central type of exercise-induced fatigue.