The ADAMTS metalloproteinases.
The ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are a group of proteases that are found both in mammals and invertebrates. Since the prototype ADAMTS-1 was first described in 1997, there has been a rapidly expanding body of literature describing this gene family and the proteins they encode. The complete human family has 19 ADAMTS genes, together with three members of a newly identified subgroup, the ADAMTSL (ADAMTS-like) proteins, which have several domains in common with the ADAMTSs. The ADAMTSs are extracellular, multidomain enzymes whose known functions include: (i) collagen processing as procollagen N-proteinase; (ii) cleavage of the matrix proteoglycans aggrecan, versican and brevican; (iii) inhibition of angiogenesis; and (iv) blood coagulation homoeostasis as the von Willebrand factor cleaving protease. Roles in organogenesis, inflammation and fertility are also apparent. Recently, some ADAMTS genes have been found to show altered expression in arthritis and various cancers. This review highlights progress in understanding the structural organization and functional roles of the ADAMTSs in normal and pathological conditions.


Synthesis, antimycobacterial and cytotoxic activity of α,β-unsaturated amides and 2,4-disubstituted oxazoline derivatives.
The synthesis of six α,β,-unsaturated amides and six 2,4-disubstituted oxazolines derivatives and their evaluation against two Mycobacterium tuberculosis strains (sensitive H37Rv and a resistant clinical isolate) is reported. 2,4-Disubstituted oxazolines (S)-3b,d,e were the most active in the sensitive strain with a MIC of 14.2, 13.6 and 10.8μM, respectively, and the compounds (S)-3d,f were the most active against resistant strain with a MIC of 6.8 and 7.4μM. The ex-vivo evaluation of hepatotoxicity on precision-cut rat liver slices was also tested for the α,β-unsaturated amides (S)-2b and (S)-2d,f and for the oxazolines (S)-3b and (S)-3d,f at different concentrations (5, 15 and 30μg/mL). The results indicate that these compounds possess promising antimycobacterial activity and at the same time are not hepatotoxic. These findings open the possibility for development of new drugs against tuberculosis.


Inhibition of neurogenic inflammation as a novel treatment for ischemic stroke.
Each year, 15 million people suffer a stroke, of which 5 million die and 5 million are left permanently disabled. Cerebral swelling is of particular concern following stroke as it accounts for much of the death and disability. However, the mechanisms leading to cerebral swelling are not yet fully understood. Recent studies from our laboratory suggest that neuropeptides, and specifically substance P, may be involved in the injury processes that occur following acute insults to the brain such as stroke and trauma, and may be responsible, in part, for edema formation. Levels of substance P are increased following CNS injury, indicative of neurogenic inflammation, and this is associated with injury to the blood-brain barrier, the development of cerebral edema, cell death and functional deficits. Subsequent studies inhibiting neuropeptide release have consistently shown decreased cerebral edema and improved neurological outcome, while substance P antagonists administered after the insult are efficacious in reducing post-stroke cerebral edema and neurological deficits. The current review summarizes the evidence supporting the benefits of inhibiting neurogenic inflammation to treat ischemic stroke.


The release of genetically modified crops into the environment. Part I. Overview of current status and regulations.
In the past 6 years, the global area of commercially grown, genetically modified (GM) crops has increased more than 30-fold to over 52 million hectares. The number of countries involved has more than doubled. Especially in developing countries, the GM crop area is anticipated to increase rapidly in the coming years. Despite this high adoption rate and future promises, there is a multitude of concerns about the impact of GM crops on the environment. Regulatory approaches in Europe and North America are essentially different. In the EU, it is based on the process of making GM crops; in the US, on the characteristics of the GM product. Many other countries are in the process of establishing regulation based on either system or a mixture. Despite these differences, the information required for risk assessment tends to be similar. Each risk assessment considers the possibility, probability and consequence of harm on a case-by-case basis. For GM crops, the impact of non-use should be added to this evaluation. It is important that the regulation of risk should not turn into the risk of regulation. The best and most appropriate baseline for comparison when performing risk assessment on GM crops is the impact of plants developed by traditional breeding. The latter is an integral and accepted part of agriculture.


Glucocorticoids and appearance of 1,25-dihydroxyvitamin D3 receptor in rat intestine.
The ontogenesis of the 1,25-dihydroxyvitamin D3 specific binding activity in intestine was examined in vitamin D-deficient and replete rats. The absence of binding activity in intestines during the first two postnatal weeks was not influenced by vitamin D supplementation. The concentration of binding sites peaked on day 18 in vitamin D-replete rats and preceded that in the deficient group by approximately 1 wk. The influence of glucocorticoids on 1,25-dihydroxyvitamin D3-binding protein levels was examined by sequential hydrocortisone administration and adrenalectomy. Subcutaneous hydrocortisone administration before day 14 postpartum did not induce binding activity. The concentration of binding sites was significantly increased to 369 +/- 60 fmol/mg of protein by hydrocortisone injections from days 15 to 17 postpartum when compared with an average of 182 +/- 16 fmol/mg of protein in littermate controls. Hydrocortisone administration did not further increase receptor levels in rats injected from days 19 to 21. Bilateral adrenalectomy on day 17 postpartum significantly decreased the concentration of binding sites. It is concluded that adrenal glucocorticoids play an important role in the developmental appearance of 1,25-dihydroxyvitamin D3 specific binding activity in the postnatal rat intestine.


Mutational signatures in squamous cell carcinoma of the lung.
Tumor mutational burden (TMB) has been identified as one of the predictors for the response to anti-programmed cell death-1 (anti-PD-1) antibody therapy and reported to correlate with smoking history in lung adenocarcinoma. However, in squamous cell carcinoma of the lung, the association between TMB and clinicopathological background factors, such as smoking history, has not been reported, including in our previous study. The mutational signature is a tool to identify the mutagens that are contributing to the mutational spectrum of a tumor by investigating the pattern of DNA changes. Here, we analyzed the mutational signature in lung squamous cell carcinoma to identify mutagens affecting the TMB. Seven representative mutational signatures including signature 7 (SI7) [ultraviolet (UV)-related], SI4 (smoking), SI6/15 [mismatch repair (MMR)], SI2/13 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)], and SI5 (clock-like) were analyzed in Japanese patients with lung squamous cell carcinoma (n=67) using data generated by next-generation sequencing consisting of a 415-gene panel. The relationships between signatures and clinico-pathological data including TMB and programmed death-ligand 1 (PD-L1) expression were analyzed. Although the reconstructed mutational counts were small with targeted sequencing (median: 30.1, range: 13.3-98.7), the distributions of signatures were comparable among samples, with 56 cases containing more than four signatures. The smoking-related SI4 was found in 45 cases and was significantly related with pack-year index (PYI) (P=0.026). The reconstructed mutation counts were highly correlated with SI4 (r=0.51, P<0.0001), whereas the correlation was weak with SI6/15 (MMR-related) and SI2/13 (APOBEC-related). There was no mutational signature related with PD-L1 expression. Some patients exhibited unique signatures; the patient with the highest mutational counts had a MMR signature, and another patient with a prominent UV signature had occupational exposure to UV, as he was employed as a neon sign engineer. Mutational signatures can predict the cause of lung squamous cell carcinoma. Tobacco smoking is the mutagen most related with TMB.


Peroxide derivatives as SARS-CoV-2 entry inhibitors.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Host cell invasion is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, bio-layer interferometry (BLI) was used to screen a series of fifty-two peroxides, including aminoperoxides and bridged 1,2,4 - trioxolanes (ozonides), with the aim of identifying small molecules that interfere with the RBD-ACE2 interaction. We found that two compounds, compound 21 and 29, exhibit the activity to inhibit RBD-ACE2. They are further demonstrated to inhibit SARS-CoV-2 cell entry, as shown in pseudovirus assay and experiment with authentic SARS-CoV-2. A comprehensive in silico analysis was carried out to study the physicochemical and pharmacokinetic properties, revealing that both compounds have good physicochemical properties as well as good bioavailability. Our results highlight the potential of small molecules targeting RBD inhibitors as potential therapeutic drugs for COVID-19.


When Does the IC50 Accurately Assess the Blocking Potency of a Drug?
Preclinical assessment of drug-induced proarrhythmicity is typically evaluated by the potency of the drug to block the potassium human ether-à-go-go-related gene (hERG) channels, which is currently quantified by the IC50. However, channel block depends on the experimental conditions. Our aim is to improve the evaluation of the blocking potency of drugs by designing experimental stimulation protocols to measure the IC50 that will help to decide whether the IC50 is representative enough. We used the state-of-the-art mathematical models of the cardiac electrophysiological activity to design three stimulation protocols that enhance the differences in the probabilities to occupy a certain conformational state of the channel and, therefore, the potential differences in the blocking effects of a compound. We simulated an extensive set of 144 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and we also experimentally validated our key predictions. Our results show that the IC50 protocol dependency relied on the tested compounds. Some of them showed no differences or small differences on the IC50 value, which suggests that the IC50 could be a good indicator of the blocking potency in these cases. However, others provided highly protocol dependent IC50 values, which could differ by even 2 orders of magnitude. Moreover, the protocols yielding the maximum IC50 and minimum IC50 depended on the drug, which complicates the definition of a "standard" protocol to minimize the influence of the stimulation protocol on the IC50 measurement in safety pharmacology. As a conclusion, we propose the adoption of our three-protocol IC50 assay to estimate the potency to block hERG in vitro. If the IC50 values obtained for a compound are similar, then the IC50 could be used as an indicator of its blocking potency, otherwise kinetics and state-dependent binding properties should be accounted.


Ultrasound-guided percutaneous microwave ablation of sporadic renal angiomyolipoma: preliminary results.
Microwave ablation (MWA) has been developed as one of the most commonly used local oncologic treatments. However, there is still a dearth of studies concerning MWA in the treatment of renal angiomyolipomas (AML). To evaluate the efficacy and safety of ultrasound (US)-guided percutaneous MWA when treating AML. Nineteen lesions with pathologically confirmed AML in 14 patients (5 men, 9 women; mean age, 49.2 ± 14 years) were treated with US-guided percutaneous MWA with one or two cooled-shaft needle antennae. A power output of 45 W or 50 W for 300-1140 s was emitted to achieve complete tumor necrosis. Contrast-enhanced ultrasound (CEUS) was performed to observe the treatment efficacy 3 days later. Patients were followed up with CEUS, computed tomography (CT), and/or magnetic resonance imaging (MRI) after 1, 3, and 6 months, and long-term ablation efficacy was evaluated every 6 months thereafter. Among the 19 renal lesions, 17 achieved complete ablation as monitored by US after one session of MWA, and two patients required a second session of MWA. Postoperative evaluation with CEUS showed that complete ablation was obtained in 15 lesions; however, in four lesions, complete ablation could not be attained. During the follow-up period of 6-36 months (median, 10 months), a fistula to the descending colon was found in one patient and local infection around the ablation zone was found in another. Neither injury to the renal pelvis nor damage to renal function was observed. None of the patients exhibited hematuria or abnormalities in routine urine tests during the hospitalization period or during follow-up. Minor complications, such as subcapsular bleeding, mild to moderate pain, and fever were eliminated after appropriate treatment. MWA is an effective and minimally invasive technique for the management of AML that can preserve renal function with acceptable complication rates.


The acquisition of b-cell competence and diversity.
The in vitro splenic focus technique has been used to establish the characteristics of the repertoire of B cells in adult BALB/c mice, its stimulation and development. Evidence is presented that the technique yields an accurate estimate of the precursor cell frequency by providing monoclonal responses of a constant portion (4%) of transferred B cells. Since the monoclonally derived antibodies can be analyzed, it has also been possible to determine the isotype and clonotype of many of the resultant antibodies. The adult spleen can be shown to contain a vast repertoire (over 10(7) clonotypes) of primary B cells, each clonotype represented by from less than ten to as many as 10(4) responsive cells. Antigenic stimulation of these primary B cells is highly specific and apparently affinity dependent and leads to both antibody-forming cell clone formation and a population of secondary B cells. Secondary B cells, though derived from the same clonotypes, differ from primary B cell in several characteristics, including a lower degree of secificity of antigenic stimulation. In addition, secondary B cells can be stimulated in collaboration with allogeneic antigen-specific T cells to yield clones producing antibody of the IgG1 isotope, whereas primary B cells similarly stimulated produce only IgM antibodies. Analyses of neonatal B cells indicate that the acquisition of the adult repertoire is a highly patterned process. Thus, whereas 10(4) clonotypes are present at birth, more and more clonotypes are acquired in a highly ordered pattern during the first few weeks of life. It is concluded that this process is probably evolutionarily determined, since antigen-driven events appear to play no role. However, since developing B cells can be shown to be exquisitely sensitive to tolerance induction, negative antigenic selection may play an important role, particularly in eliminating clonotypes recognizing self-determinants for which the species is polymorphic.


Is the Oncological Outcome of Early Stage Uterine Carcinosarcoma Different from That of Grade 3 Endometrioid Adenocarcinoma?
The clinicopathologic characteristics, recurrence patterns, and survival of patients with grade 3 endometrial cancer (G3-EAC) and uterine carcinosarcoma (UCS) were compared. The medical records of patients treated for G3-EAC and UCS between January 1996 and December 2016 at 11 gynecologic oncology centers in Turkey and Germany were analyzed. Of all patients included in the study, 161 (45.1%) were diagnosed with UCS and 196 (54.9%) with G3-EAC at FIGO stage I-II (early stage) disease. The recurrence rate was higher in patients with UCS than in those with G3-EAC (17.4 vs. 9.2%, p = 0.02). The 5-year disease-free survival (DFS; 75.2 and 80.8%, respectively; p = 0.03) and overall survival (OS; 79.4 and 83.4%, respectively; p = 0.04) rates were significantly lower in the UCS group compared to the G3-EAC group. UCS histology was an independent prognostic factor for decreased 5-year DFS (HR 1.8, 95% CI 1.2-3.2; p = 0.034) and OS (HR 2.7, 95% CI 1.3-6.9; p = 0.041) rates. The recurrence rate was higher in UCS patients than in G3-EAC patients, regardless of disease stage. DFS and OS were of shorter duration in UCS than in G3-EAC patients. Adequate systematic lymphadenectomy and omentectomy were an independent prognostic factor for increased 5-year DFS and OS rates.


Endocytosis, intracellular transport, and cytotoxic action of Shiga toxin and ricin.
Protein toxins such as ricin and Shiga toxin with intracellular targets have to be endocytosed and translocated to the cytosol to inhibit the protein synthesis and thereby kill the cell. Ricin is internalized by both clathrin-dependent and -independent endocytic mechanisms, whereas Shiga toxin seems to be taken up exclusively from clathrin-coated pits. After endocytosis, internalized membrane and content are delivered to endosomes, where sorting for further routing in the cell takes place. Toxins that remain membrane bound at low endosomal pH can be recycled to the cell surface or transcytosed in polarized epithelia. A large proportion of internalized toxin is transported to lysosomes for degradation. Most importantly, a fraction of the internalized ricin and Shiga toxin molecules is delivered to the trans-Golgi network (TGN). Shiga toxin can, in some very sensitive cells, be transported retrogradely through the Golgi cisterns all the way back to the endoplasmic reticulum (ER), and it is possible that also ricin is transported retrogradely to the ER. In this review, a cell biological overview of these intracellular transport steps is presented, and evidence is provided that the delivery to the TGN and the subsequent retrograde transport to the ER are required for optimal intoxication. Moreover, it is argued that knowledge of this transport is important for targeted drug delivery such as the application of immunotoxins in cancer therapy.


Crambe (Crambe abyssinica) and sunflower (Helianthus annuus) protein concentrates: production methods and nutritional properties for use in fish feed.
The purpose of this study was to develop and improve protein concentration techniques for two industrial by-products with the potential for use in fish feed. In particular, we chemically characterized crambe meal and sunflower meal and their protein concentrates. Three different protein concentration methods were tested: isoelectric pH (pHi), acid pH and alkaline pH. For crambe and sunflower meals extraction using the pHi method was most efficient in terms of protein yield and crude protein content in the concentrates; this method also increased lysine and methionine content in the concentrates. The water holding capacity of the sunflower protein concentrate was greater than that of the crambe protein concentrate. The crambe protein concentrate had a foam-formation capacity of 15%, which stabilized at 6% after 90 minutes. The protein concentration method also reduced total phenolic content by approximately 50% in the concentrates compared with the meals. Therefore, we conclude that protein concentration using the pHi method is the most efficient technique for crambe and sunflower meals, and the use of this technique can decrease total phenolic compounds while improving meal quality for fish feeding.


Energetics and electronic structures of perylene confined in carbon nanotubes.
The energetics and geometries of perylene encapsulated in carbon nanotubes (CNTs) have been investigated employing density functional theory using the generalized gradient approximation combined with the van der Waals correction. Our calculations show that the encapsulated perylene molecules possess two metastable molecular conformations with respect to the CNT wall, which are almost degenerate with each other. A standing conformation, with respect to the CNT wall, is the ground state conformation for a semiconducting (19,0)CNT, while a lying conformation is the ground state for a metallic (11,11)CNT. Cooperation and competition between perylene-perylene and perylene-CNT interactions cause these possible perylene conformations inside CNTs. However, the electronic structure of the CNT encapsulating the perylene molecules is found to be insensitive to the molecular conformation.


STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers.
Fatty liver is an important cause of morbidity in humans and is linked to impaired liver regeneration after liver injury, but the mechanisms for impaired liver regeneration remain unknown. In the normal liver, the interleukin (IL)-6/STAT-3 pathway is thought to play a central role in regeneration because this pathway is disrupted in IL-6-deficient mice that exhibit impaired liver regeneration after 70% partial hepatectomy (PH). To determine whether inhibition of STAT-3 is involved in fatty liver-related mitoinhibition, regenerative induction of STAT-3 was compared in normal mice and leptin-deficient ob/ob mice that have fatty livers and markedly impaired liver regeneration after PH. In both groups, two waves of STAT-3 activation were observed, the first in endothelia and the second in hepatocytes. Before PH, a significantly higher percentage of ob/ob endothelial and hepatocyte nuclei expressed phosphorylated (activated) STAT-3. After PH, phospho-STAT-3 accumulated in liver nuclei of lean mice and this response was markedly exaggerated in ob/ob mice. Moreover, a striking inverse correlation was noted between hepatocyte nuclear accumulation of phospho-STAT-3 and DNA synthesis (as assessed by bromodeoxyuridine labeling), as well as cyclin D1 mRNA induction and protein expression. In contrast, STAT-3 activation was positively correlated with p21 protein expression in both groups of mice. Because these results link exaggerated STAT-3 activation with impaired hepatocyte proliferation, STAT-3 inhibition cannot be a growth-arrest mechanism in ob/ob fatty livers. Rather, hyperinduction of this factor may promote mitoinhibition by up-regulating mechanisms that impede cell cycle progression.


Stapled aortic anastomoses: a minimally invasive, feasible alternative to videoscopic aortic suturing?
Widespread applications of totally laparoscopic aortic reconstructions have been limited by the long cross-clamp time required to suture the aortic anastomosis despite improvement in instrumentation. The authors' hypothesis was that a "one-step anastomosis concept" using an intraluminal stapler would allow shorter cross-clamp time but similar patency and imperviousness as videoscopic suturing techniques. An intraluminal stapler (Endopath-ILS, Ethicon) with a modified anvil was used to perform videoscopic-assisted thoracic aorta-to-iliac artery bypass with a 21 mm by 8 mm polytetrafluoroethylene (PTFE) graft in 22 sheep through a minimally invasive approach using a 5 cm thoracotomy. The graft-to-iliac artery anastomoses were hand sutured through a flank incision. Twelve sheep were used to establish the technique and 10 subsequent animals constituted the study group. Aortic cross-clamp time, imperviousness, and need for additional sutures were recorded and compared to previously reported data using videoscopic suturing in pigs. Patency was assessed by comparing lower limb arterial pressures. Macroscopic and microscopic examinations of the anastomoses were performed at different time-points within the first 3 months. Videoscopic-assisted stapled anastomoses were also performed on atherosclerotic aortas of 3 human cadavers. Stapled anastomoses between the thoracic aorta and PTFE graft were completed in 8 of 10 animals. Two animals were euthanized after stapler failure and anastomotic bleeding. Sutures to strengthen the anastomosis had to be used in 4 cases. Mean aortic cross-clamp time in 8 successful cases was 4.3 +/-2.9 minutes (range 2-11 minutes) and was significantly shorter than clamp time of videoscopic suturing technique (48.7 +/-9.4 minutes, p < 0.0001). Imperviousness was good or excellent in 4 animals and fair in 4 animals. All anastomoses were patent at the end of the procedure. Examination of the anastomosis of the 2 failed interventions showed medial aortic tear surrounding the anastomosis in 1 case and misfired staples in the other. No graft occlusion was noted during follow-up ranging from 0 to 12 weeks. At the time of harvest, no bleeding was noted after epinephrine and volume infusion to increase mean arterial pressure to 200 mm Hg for 15 minutes. Macroscopic examination of the anastomoses revealed adequate healing with circumferential stapling of the prosthesis to the aortic wall and no stenosis or thrombus except in 1 false aneurysm (1/7, 14%). Surface electron microscopy showed cells coverage of the anastomosis surface. When applied on human cadaver thoracic and abdominal aorta with atherosclerotic changes, clamping times of less than 5 minutes were achieved. However, imperviousness tested with saline was poor. An automatic stapling device allows performance of a graft-to-aorta anastomosis through a minimally invasive approach with shorter clamping time than a videoscopic suturing technique. However, the current technique of aortic stapling is unreliable and further improvements are needed.


Synovial sarcoma: from genetics to genetic-based animal modeling.
Synovial sarcomas are highly aggressive mesenchymal cancers that show modest response to conventional cytotoxic chemotherapy, suggesting a definite need for improved biotargeted agents. Progress has been hampered by the lack of insight into pathogenesis of this deadly disease. The presence of a specific diagnostic t(X;18) translocation leading to expression of the unique SYT-SSX fusion protein in effectively all cases of synovial sarcoma suggests a role in the etiology. Other nonspecific anomalies such as overexpression of Bcl-2, HER-2/neu, and EGFR have been reported, but their role in the pathogenesis remains unclear. Using gene targeting, we recently generated mice conditionally expressing the human SYT-SSX2 fusion gene from mouse endogenous ROSA26 promoter in chosen tissue types in the presence of Cre recombinase. These mice develop synovial sarcoma when SYT-SSX2 is expressed within myoblasts, thereby identifying a source of this enigmatic tumor and establishing a mouse model of this disease that recapitulates the clinical, histologic, immunohistochemical, and transcriptional profile of human synovial sarcomas. We review the genetics of synovial sarcoma and discuss the usefulness of genetics-based mouse models as a valuable research tool in the hunt for key molecular determinants of this lethal disease as well as a preclinical platform for designing and evaluating novel treatment strategies.


Human serum albumin adsorption on hydrogel contact lenses in vitro.
To improve the understanding of the formation of protein deposits on hydrogel lenses. A study of protein adsorption on three commercial hydrogel contact lenses of different materials, Etafilcon A (2-hydroxyethyl methacrylate [HEMA] polymer with sodium methacrylate and 2-ethyl-2-hydroxymethyl-1,3-propanediol trimethacrylate), tefilcon (poly[HEMA] cross-linked and copolymerized with ethylene glycol dimethacrylate), and vifilcon A (methacrylic acid polymer with ethylene glycol dimethacrylate, HEMA and N-vinyl pyrrolidone) was undertaken by using a single protein solution, human serum albumin (HSA), and a radiolabel-tracer technique. Static adsorption leading to multilayer adsorption was observed. Complete reversibility for adsorbed HSA on lenses did not exist. Some was tightly bound, whereas most was loosely bound and could be removed easily by rinsing in phosphate-buffered saline. Irreversible adsorption of HSA on the lenses was found to be time dependent and did not reach a maximum value even after 48 hours of adsorption. The amount of HSA adsorbed on the lenses-irreversibly as well as totally adsorbed protein-was in the order of vifilcon A > tefilcon > etafilcon A. Adsorption of HSA on the lenses increases with decreasing pH (range, 7.4 to 4) but always follows the above trend with respect to the different types of lenses. Irreversible binding of HSA on lenses is governed by the kinetics of protein denaturation. Electrostatic interactions may not play a major role in HSA adsorption on hydrogel lenses. Some other factors, such as hydrophobic dehydration, and special monomer units, such as N-vinyl pyrrolidone in the lens materials, may favor adsorption of HSA.


Detection of airborne genetically modified maize pollen by real-time PCR.
The cultivation of genetically modified (GM) crops has raised numerous concerns in the European Union and other parts of the world about their environmental and economic impact. Especially outcrossing of genetically modified organisms (GMO) was from the beginning a critical issue as airborne pollen has been considered an important way of GMO dispersal. Here, we investigate the use of airborne pollen sampling combined with microscopic analysis and molecular PCR analysis as an approach to monitor GM maize cultivations in a specific area. Field trial experiments in the European Union and South America demonstrated the applicability of the approach under different climate conditions, in rural and semi-urban environment, even at very low levels of airborne pollen. The study documents in detail the sampling of GM pollen, sample DNA extraction and real-time PCR analysis. Our results suggest that this 'GM pollen monitoring by bioaerosol sampling and PCR screening' approach might represent an useful aid in the surveillance of GM-free areas, centres of origin and natural reserves.


Spectacle Compliance among Adolescents: A Qualitative Study from Southern India.
To understand the perceptions of adolescents and their parents about spectacle compliance of adolescents in Southern India. Using a qualitative snapshot design, three focus group discussions were conducted each with parents and adolescents studying in schools located in and around Chennai, Tamil Nadu. Purposive sampling technique was used in the selection of participants. Separate focus group guides were developed for parents and adolescents. All focus group discussions were conducted in the school premises and audio recorded. These audio files were then transcribed verbatim and then translated into English. A framework analytical approach was used for data analysis that involved gaining familiarity with the data to identify a thematic framework. Two major themes that emerged were (1) perceptions on barriers to spectacle compliance that was further subdivided into physical, psychological, and societal barriers; and (2) solutions to improve spectacle use. Barriers identified included scars on the nose, unattractive frames contributing to poor appeal, adolescents feeling discriminated and set apart, fears of injury to eyes, lack of parental involvement, and negative attitudes of society toward those wearing spectacles. Solutions given by the stakeholders included provision of lightweight, well-fitting, trendy frames of adolescents' choice, importance and need for periodical eye examinations, including teachers in encouraging spectacle use and preventing bullying and teasing by other adolescents, provision of free spectacles along with periodic replacement, and inclusion of awareness sessions on spectacle use for both parents and adolescents. The study has identified both barriers and solutions for improving spectacle compliance among school adolescents from the viewpoint of the stakeholders involved. Implementing the solutions suggested by the stakeholders through planned intervention programs could possibly help in ensuring better compliance of spectacle use among school adolescents.


A rural general surgeon's thoughts on surgery in South African rural areas.
A brief description of the old missionary era of rural surgery is given and this is followed by a description of the present situation. Problem areas relating both to medical staffing and infrastructure are identified. The characteristics required of a rural surgeon are described, and some thoughts are given to outline the establishment of long-term career paths in rural surgery.


Effects of any epoxymethano stable analogue of prostaglandin endoperoxides (U-46619) on human platelets.
U-46619 is a stable epoxymethano analogue of cyclic endoperoxide PGH2. We studied platelet aggregation, 14C-5HT release, LDH extrusion and prostaglandin and thromboxane production induced by this compound in platelet-rich plasma samples from 15 healthy volunteers. Each subject was tested both before and 90 min after aspirin (500 mg) ingestion. The threshold aggregating concentration (TAC) of U-44619 ranged between 0.18 and 0.90 micro M. Aggregation was maximal between 40 and 60 min after venipuncture and was concentration-dependent. At concentrations below the TAC, U-44619 induced primary reversible aggregation with minimal 14C-5HT release. At TAC or higher concentrations aggregation and release proceeded as parallel events. Neither prostaglandin or thromboxane production nor LDH loss could be detected in any of the situations tested. Aspirin ingestion did not modify the pattern of platelet responses. In unstirred, not aggregated platelet samples 14C-5HT release by U-46619 occurred to a similar extent as in stirred, aggregated platelet samples. Addition to citrated PRP of 0.3 mM Na2 EDTA blocked both aggregation and release induced by U-46619. This compound, however, aggregated washed platelets resuspended in Ca++-free-tyrode-albumin containing fibrinogen. The mechanism by which U-46619 activates platelets differs from that of all other common aggregating agents.


Helping by siblings of children with mental retardation.
Our purpose for conducting this investigation was to extend the research on the help that siblings of children with mental retardation give to their brothers and sisters to include not only custodial care, but also other forms of helping behavior, such as emotional support, tangible aid, and information giving. We compared 100 siblings (50 with and 50 without a brother or sister with mental retardation) in terms of their perceived helping behavior. Siblings of brothers and sisters with mental retardation engaged in higher levels of perceived emotional support and custodial care but not information giving or tangible aid. Perceived custodial care and emotional support were associated with gender, the child's need for assistance, and self-esteem.


Antimicrobial peptides protect coho salmon from Vibrio anguillarum infections.
Fish losses from infectious diseases are a significant problem in aquaculture worldwide. Therefore, we investigated the ability of cationic antimicrobial peptides to protect against infection caused by the fish pathogen Vibrio anguillarum. To identify effective peptides for fish, the MICs of certain antimicrobial peptides against fish pathogens were determined in vitro. Two of the most effective antimicrobial peptides, CEME, a cecropin-melittin hybrid peptide, and pleurocidin amide, a C-terminally amidated form of the natural flounder peptide, were selected for in vivo studies. A single intraperitoneal injection of CEME did not affect mortality rates in juvenile coho salmon infected with V. anguillarum, the causative agent of vibriosis. Therefore, the peptides were delivered continuously using miniosmotic pumps placed in the peritoneal cavity. Twelve days after pump implantation, the fish received intraperitoneal injections of V. anguillarum at a dose that would kill 50 to 90% of the population. Fish receiving 200 microg of CEME per day survived longer and had significantly lower accumulated mortalities (13%) than the control groups (50 to 58%). Fish receiving pleurocidin amide at 250 microg per day also survived longer and had significantly lower accumulated mortalities (5%) than the control groups (67 to 75%). This clearly shows the potential for antimicrobial peptides to protect fish against infections and indicates that the strategy of overexpressing the peptides in transgenic fish may provide a method of decreasing bacterial disease problems.


The Neural Correlates of Chronic Symptoms of Vertigo Proneness in Humans.
Vestibular signals are of significant importance for variable functions including gaze stabilization, spatial perception, navigation, cognition, and bodily self-consciousness. The vestibular network governs functions that might be impaired in patients affected with vestibular dysfunction. It is currently unclear how different brain regions/networks process vestibular information and integrate the information into a unified spatial percept related to somatosensory awareness and whether people with recurrent balance complaints have a neural signature as a trait affecting their development of chronic symptoms of vertigo. Pivotal evidence points to a vestibular-related brain network in humans that is widely distributed in nature. By using resting state source localized electroencephalography in non-vertiginous state, electrophysiological changes in activity and functional connectivity of 23 patients with balance complaints where chronic symptoms of vertigo and dizziness are among the most common reported complaints are analyzed and compared to healthy subjects. The analyses showed increased alpha2 activity within the posterior cingulate cortex and the precuneues/cuneus and reduced beta3 and gamma activity within the pregenual and subgenual anterior cingulate cortex for the subjects with balance complaints. These electrophysiological variations were correlated with reported chronic symptoms of vertigo intensity. A region of interest analysis found reduced functional connectivity for gamma activity within the vestibular cortex, precuneus, frontal eye field, intra-parietal sulcus, orbitofrontal cortex, and the dorsal anterior cingulate cortex. In addition, there was a positive correlation between chronic symptoms of vertigo intensity and increased alpha-gamma nesting in the left frontal eye field. When compared to healthy subjects, there is evidence of electrophysiological changes in the brain of patients with balance complaints even outside chronic symptoms of vertigo episodes. This suggests that these patients have a neural signature or trait that makes them prone to developing chronic balance problems.


Multiple sites of purinergic control of insulin secretion in mouse pancreatic beta-cells.
In mouse pancreatic beta-cells, extracellular ATP (0.1 mmol/l) effectively reduced glucose-induced insulin secretion. This inhibitory action resulted from a direct interference with the secretory machinery, and ATP suppressed depolarization-induced exocytosis by 60% as revealed by high-resolution capacitance measurements. Suppression of Ca2+-dependent exocytosis was mediated via binding to P2Y1 purinoceptors but was not associated with inhibition of the voltage-dependent Ca2+ currents or adenylate cyclase activity. Inhibition of exocytosis by ATP resulted from G-protein-dependent activation of the serine/threonine protein phosphatase calcineurin and was abolished by cyclosporin A and deltamethrin. In contrast to the direct inhibitory action on exocytosis, ATP reduced the whole-cell ATP-sensitive K+ (K(ATP)) current by 30% (via activation of cytosolic phospholipase A2), leading to membrane depolarization and stimulation of electrical activity. The stimulatory effect of ATP also involved mobilization of Ca2+ from thapsigargin-sensitive intracellular stores. We propose that the inhibitory action of ATP, by interacting with the secretory machinery at a level downstream to an elevation in [Ca2+]i, is important for autocrine regulation of insulin secretion in mouse beta-cells.


Current and Novel Techniques for Metal Artifact Reduction at CT: Practical Guide for Radiologists.
Artifacts caused by metallic implants appear as dark and bright streaks at computed tomography (CT), which severely degrade the image quality and decrease the diagnostic value of the examination. When x-rays pass through a metal object, depending on its size and composition, different physical effects negatively affect the measurements in the detector, most notably the effects of photon starvation and beam hardening. To improve image quality and recover information about underlying structures, several artifact reduction methods have been introduced in modern CT systems. Projection-based metal artifact reduction (MAR) algorithms act in projection space and replace corrupted projections caused by metal with interpolation from neighboring uncorrupted projections. MAR algorithms primarily suppress artifacts that are due to photon starvation. The dual-energy CT technique is characterized by data acquisition at two different energy spectra. Dual-energy CT provides synthesized virtual monochromatic images at different photon energy (kiloelectron volt) levels, and virtual monochromatic images obtained at high kiloelectron volt levels are known to reduce the effects of beam hardening. In clinical practice, although MAR algorithms can be applied after image acquisition, the decision whether to apply dual-energy CT for the patient usually needs to be made before image acquisition. Radiologists should be more familiar with the clinical and technical features of each method and should be able to choose the optimal method according to the clinical situation. ©RSNA, 2018.


Inhibition of in vitro myogenic differentiation by a polyomavirus early function.
In the present work we report on the role of a polyomavirus (Py) early function in interfering with both morphological and biochemical differentiation of the myogenic C2 cell line. The analysis of cell clones stably transfected with a plasmid carrying an ORI- Py genome showed that in the presence of the whole viral early region myogenesis is blocked and a transformed phenotype is evident. By using a plasmid that only encodes large-T function, the involvement of this individual early viral gene product was determined. Inhibition of myogenic differentiation by Py large T is proportional to the level of its expression. This inhibition does not appear to require alteration of cell growth properties. The analysis of muscle-specific functions expressed at different steps in the myogenic pathway showed that Py large T blocks the expression of terminal differentiation markers without altering the expression of the regulatory gene MyoD.


Effect of Sinotubular Junction Size on TAVR Leaflet Thrombosis: A Fluid-structure Interaction Analysis.
TAVR has emerged as a standard approach for treating severe aortic stenosis patients. However, it is associated with several clinical complications, including subclinical leaflet thrombosis characterized by Hypoattenuated Leaflet Thickening (HALT). A rigorous analysis of TAVR device thrombogenicity considering anatomical variations is essential for estimating this risk. Clinicians use the Sinotubular Junction (STJ) diameter for TAVR sizing, but there is a paucity of research on its influence on TAVR devices thrombogenicity. A Medtronic Evolut® TAVR device was deployed in three patient models with varying STJ diameters (26, 30, and 34mm) to evaluate its impact on post-deployment hemodynamics and thrombogenicity, employing a novel computational framework combining prosthesis deployment and fluid- structure interaction analysis. The 30 mm STJ patient case exhibited the best hemodynamic performance: 5.94 mmHg mean transvalvular pressure gradient (TPG), 2.64 cm 2 mean geometric orifice area (GOA), and the lowest mean residence time (T R ) - indicating a reduced thrombogenic risk; 26 mm STJ exhibited a 10 % reduction in GOA and a 35% increase in mean TPG compared to the 30 mm STJ; 34 mm STJ depicted hemodynamics comparable to the 30 mm STJ, but with a 6% increase in T R and elevated platelet stress accumulation. A smaller STJ size impairs adequate expansion of the TAVR stent, which may lead to suboptimal hemodynamic performance. Conversely, a larger STJ size marginally enhances the hemodynamic performance but increases the risk of TAVR leaflet thrombosis. Such analysis can aid pre- procedural planning and minimize the risk of TAVR leaflet thrombosis.


[Curable forms of sensorineural hearing loss].
Upon the analysis of the literature data and original investigations the author makes the conclusion on the existance of several etiopathogenetic forms of neurosensory hypoacusis. One of the forms is caused by defective conduction of the sound wave energy to senso-neural elements of the receptor. This form can be diagnostically differentiated from the others and is sensitive to treatment, with low-frequency aperiodic pulse current, in particular.


Causes of chronic renal failure in children in a single hospital in jordan: a 10 years retrospective study.
Case records of patients aged 13 years or below with chronic renal failure (CRF), seen during the last 10 years at the King Hussein Medical Center, Amman, Jordan were reviewed. There were 46 patients with CRF, (25 males and 21 females), aged 1/2 to 13 years. Chronic pyelonephritis was the major cause of CRF seen in 23 cases (50%), followed by glomerulonephritis in eight (17.4%), congenital hypodysplasia in six (13%), hereditary nephritis in five (10.9%) and unknown etiology in four (8.7%). Of the study patients, 17.3% were below the age of five years at first presentation. Twenty one patients progressed to end-stage renal disease and among them chronic glomerulonephritis was the most common primary renal disease. The higher incidence of chronic pyelonephritis causing CRF in our series in comparison to 23.9% incidence reported in the developed countries shows that our infants and young children probably are not investigated early enough nor do they receive adequate treatment at the time of their first urinary tract infection. Prevention of renal failure, availability of replacement therapy, and extension of treatment opportunities to more children are the main problems concerning CRF in children in our country.


Plasma malondialdehyde increases transiently after ischemic forearm exercise.
Exercise and ischemia-reperfusion (I-R) have previously been shown to induce oxidative stress in skeletal muscle. Previous studies have demonstrated conflicting results when exercise-induced oxidative stress has been measured using plasma carbonyls, specifically malondialdehyde (MDA). These conflicting results likely stem from the timing and method utilized to measure plasma carbonyls. To determine the concentration and timing of aldehyde and ketone generation after ischemic forearm exercise utilizing HPLC analysis. Plasma carbonyls, including MDA, 17-beta-estradiol, and lactate, were measured after a forearm ischemic exercise test (FIT) in males and females (in both phases of their menstrual cycle). Blood flow was occluded to the forearm, and six cycles of maximal isometric handgrip exercise were executed using a 9:1, duty:rest cycle, for 60 s. Blood samples were collected pre, immediately post, and 1, 3, and 10 min post-FIT. Plasma MDA increased similarly for both males and females immediately post and 1 min post-FIT (P<0.05) and returned to baseline levels by 3 min post-FIT. Ischemic exercise did not alter plasma concentrations of other measured carbonyls, and gender and menstrual cycle did not influence any measured variable (P>0.05), except for lactate concentrations, which increased more for males (P<0.05). Force was higher for males at all time points (P<0.05); however, there was no effect of gender on percent fatigue. Future studies must consider sampling times after metabolic stress in order to quantify changes in MDA concentration.


Effects of antidepressants on IP-10 production in LPS-activated THP-1 human monocytes.
Major depressive disorder and cardiovascular disease are common serious illnesses worldwide. Selective serotonin reuptake inhibitors and norepinephrine-dopamine reuptake inhibitors may reduce the mortality of cardiovascular disease patients with comorbid depression. Interferon-γ-inducible protein 10 (IP-10), a type 1 T helper cell (Th1)-related chemokine, contributes to manifestations of atherosclerosis during cardiovascular inflammations; however, the pathophysiological mechanisms linking cardiovascular disease and effective antidepressants have remained elusive. We investigated the in vitro effects of six different classes of antidepressants on the IP-10 chemokine expression in lipopolysaccharide (LPS)-stimulated monocytes, and their detailed intracellular mechanisms. The human monocytes were pretreated with antidepressants (10⁻⁸-10⁻⁵ M) before LPS-stimulation. IP-10 was measured by enzyme-linked immunosorbent assay (ELISA) and then intracellular signaling was investigated using Western blotting and chromatin immunoprecipitation. Fluoxetine and bupropion suppressed LPS-induced IP-10 expression in monocytes, and they had no cytotoxic effects. Furthermore, fluoxetine inhibited LPS-induced IP-10 expression via the mitogen-activated protein kinase (MAPK)-p38 pathway. Fluoxetine and bupropion could not only treat depression but also reduce Th1-related chemokine IP-10 production in human monocytes. Our results may indicate a possible mechanism related to how particular antidepressants reduce the risk of cardiovascular disease.


Metabolically favorable remodeling of human adipose tissue by human adenovirus type 36.
Experimental infection of rats with human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as a therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue. We determined whether Ad-36 increases glucose uptake in human adipose tissue explants. Cell-signaling pathways targeted by Ad-36 to increase glucose uptake were determined in the explants and human adipose-derived stem cells. Ad-2, a nonadipogenic human adenovirus, was used as a negative control. As a proof of concept, nondiabetic and diabetic subjects were screened for the presence of Ad-36 antibodies to ascertain if natural Ad-36 infection predicted improved glycemic control. Ad-36 increased glucose uptake by adipose tissue explants obtained from nondiabetic and diabetic subjects. Without insulin stimulation, Ad-36 upregulated expressions of several proadipogenic genes, adiponectin, and fatty acid synthase and reduced the expression of inflammatory cytokine macrophage chemoattractant protein-1 in a phosphotidylinositol 3-kinase (PI3K)-dependent manner. In turn, the activation of PI3K by Ad-36 was independent of insulin receptor signaling but dependent on Ras signaling recruited by Ad-36. Ad-2 was nonadipogenic and did not increase glucose uptake. Natural Ad-36 infection in nondiabetic and diabetic subjects was associated with significantly lower fasting glucose levels and A1C, respectively. Ad-36 proteins may provide novel therapeutic targets that remodel human adipose tissue to a more metabolically favorable profile.


Divergent functions of angiotensin II receptor isoforms in the brain.
The renin-angiotensin system (RAS) plays a critical role in cardiovascular and fluid homeostasis. The major biologically active peptide of the RAS is angiotensin II, which acts through G protein-coupled receptors of two pharmacological classes, AT(1) and AT(2). AT(1) receptors, expressed in brain and peripheral tissues, mediate most classically recognized actions of the RAS, including blood pressure homeostasis and regulation of drinking and water balance. In rodents, two highly homologous AT(1) receptor isoforms, termed AT(1A) and AT(1B) receptors, are expressed at different levels in major forebrain cardiovascular and fluid regulatory centers, with AT(1A) expression generally exceeding AT(1B) expression, but the relative contributions of these receptor subtypes to central angiotensin II responses are not known. We used gene targeting in combination with a unique system for maintaining catheters in the cerebral ventricles of conscious mice to test whether there are differential roles for AT(1A) and AT(1B) receptors in responses elicited by angiotensin II in the brain. Here we show that the blood pressure increase elicited by centrally administered angiotensin II can be selectively ascribed to the AT(1A) receptor. However, the drinking response requires the presence of AT(1B) receptors. To our knowledge, this is the first demonstration of a primary and nonredundant physiological function for AT(1B) receptors.


Nocturnal non-invasive positive pressure ventilation for stable chronic obstructive pulmonary disease.
Non-invasive positive pressure ventilation (NIPPV) is effective in treating acute exacerbations of chronic obstructive pulmonary disease (COPD). Nocturnal non-invasive positive pressure ventilation (nocturnal-NIPPV) has been proposed as an intervention for stable hypercapnic patients with COPD. To assess the effects of nocturnal-NIPPV at home via nasal mask or face mask in people with COPD by using a meta-analysis based on individual patient data (IPD). We searched the Cochrane Airways Group Specialised Register. We performed the latest search in August 2012. Randomised controlled trials in people with stable COPD that compared nocturnal-NIPPV at home for at least five hours per night, for at least three consecutive weeks plus standard therapy with standard therapy alone. IPD were collected and two review authors assessed risk of bias independently. This update of the systematic review on nocturnal-NIPPV in COPD (Wijkstra 2002), has led to the inclusion of three new studies, leading to seven included studies on 245 people. We obtained IPD for all participants in all included studies. The 95% confidence interval (CI) of all outcomes included zero. These included partial pressure of CO2 and O2 in arterial blood, six-minute walking distance (6MWD), health-related quality of life (HRQoL), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), maximal inspiratory pressure (PImax) and sleep efficiency. The mean effect on 6MWD was small at 27.7 m and not statistically significant. Given the width of the 95% CI (-28.1 to 66.3 m), the real effect of NIPPV on 6MWD is uncertain and we cannot exclude an effect that is clinically significant (considering that the minimal clinically difference on 6MWD is around 26 m). Nocturnal-NIPPV at home for at least three months in hypercapnic patients with stable COPD had no consistent clinically or statistically significant effect on gas exchange, exercise tolerance, HRQoL, lung function, respiratory muscle strength or sleep efficiency. Meta-analysis of the two new long-term studies did not show significant improvements in blood gases, HRQoL or lung function after 12 months of NIPPV. However, the small sample sizes of these studies preclude a definite conclusion regarding the effects of NIPPV in COPD.


Severe hemodynamic instability in a patient with suspected hepatoadrenal syndrome during liver transplantation -A case report-.
Adrenal insufficiency, which is related to hemodynamic instability and increased mortality, has been reported in patients with advanced liver disease regardless of the presence of septic conditions. In this regard, the hepatoadrenal syndrome has been recently proposed as adrenal insufficiency in critically ill patients with liver disease. We describe here a 67-year-old female patient with hepatic failure and adrenal insufficiency. The patient showed stable vital signs and no evidence of sepsis preoperatively. Despite hydrocortisone replacement and inotropics administration, severe intraoperative hemodynamic instability was observed. Hydrocortisone administration was continued postoperatively, nevertheless inotropics could not be tapered. On postoperative day 11, the patient died due to pneumonia and septic shock. Hepatoadrenal syndrome may have played a key role in her severe hemodynamic fluctuation and poor outcome, reinforcing the importance of adrenal function in the liver transplantation surgery.


A Systematic Review of Prenatally Diagnosed Intra-abdominal Enteric Duplication Cysts.
With improvements in prenatal ultrasound, more abdominal enteric duplication cysts (EDCs) are diagnosed prenatally. The optimal time for operative intervention is unclear. We aimed to review the evidence supporting the indication and timing of surgery for prenatally diagnosed EDCs. A systematic review was performed using a defined search strategy identifying articles with inclusion criteria of prenatal diagnosis of histologically confirmed EDCs. Outcomes included (1) indications for resection (symptoms vs. prophylactic) and (2) time from birth to operative intervention. Of 1,590 articles screened, prenatal diagnosis of histologically confirmed EDCs was made in 68 articles, detailing indications and timing for resection for 86 patients. Thirty-five patients (41%) became symptomatic early and were resected promptly at a median of 2 days of age. Indications for intervention included bowel obstruction, volvulus, bleeding, recurrent pain and diagnostic dilemma (concern for cystic neuroblastoma). There were 51 patients (59%) who were resected prophylactically at a median of 90 days of age without interval symptoms. Symptomatic cysts had a larger mean cyst diameter. There was a difference in the anatomic distribution of asymptomatic or symptomatic EDCs-gastric duplications were more frequently asymptomatic while jejunal, proximal ileal and colonic duplications were more frequently symptomatic. The optimal approach to EDCs diagnosed prenatally is not supported by strong evidence in the literature. Our systematic review indicates that almost half of the infants diagnosed prenatally become symptomatic early and are resected. In asymptomatic patients, close observation and delayed prophylactic resection in infancy can be considered.


Clinical characteristics and survival of extranodal natural killer/T-cell lymphoma: a single-center 12-year retrospective analysis.
The characteristics and survival of 218 patients with extranodal natural killer/T-cell lymphoma (ENKTCL) were analyzed in this retrospective study. The median progression-free survival (PFS) and overall survival (OS) were 10.9 months and 50.5 months, respectively. Sequential chemoradiotherapy achieved a 74.5% overall response rate (ORR) and a 30.9% 5-year PFS rate in patients with localized stage. Asparaginase-containing protocols demonstrated superior prognosis in advanced cases, with a median FPS at 5.7 months, compared to 1.9 months without asparaginase. Initial treatment with P-GEMOX regimens showed superior ORR and PFS compared to the SMILE regimen, with lower toxicities. Hematopoietic stem cell transplantation (HSCT) improved the PFS and OS of refractory or relapsed (R/R) cases. PD-1/PD-L1 antibody could achieve a median PFS at 4.0 months and a median OS at 14.6 months in R/R patients for whom salvage therapies failed. High-risk PINK-E score was the only independent adverse prognostic factor for PFS and OS.


A convolution algorithm for brachytherapy dose computations in heterogeneous geometries.
Currently-available brachytherapy dose computation algorithms ignore heterogeneities such as tissue-air interfaces, shielded gynecological colpostats, and tissue-composition variations in 125I implants despite dose computation errors as large as 40%. To calculate dose in the presence of tissue and applicator heterogeneities, a computer code has been developed that describes scatter dose as a 3-D spatial integral which convolves primary photon fluence with a dose-spread array. The dose-spread array describes the distribution of dose due to multiple scattering about a single primary interaction site and is precomputed by the Monte Carlo method. To correct for heterogeneities traversed by the primary photons, the dose-spread array is renormalized to reflect the density and composition of the element, and the distance to the point of interest is scaled by the path-length of the intervening medium. Convolution calculations for 125I and 137Cs point sources in the presence of finite phantoms, air voids and high-density shields have been compared to the corresponding Monte Carlo calculations. The convolution code absolute and relative dose rate predictions are shown to agree with Monte Carlo calculations within 3%. Direct evaluation of the 3-D spatial convolution integral using 1-D adaptive integration reveals efficiency gains of 20-50 relative to Monte Carlo photon-transport calculations.


The water balance questionnaire: design, reliability and validity of a questionnaire to evaluate water balance in the general population.
There is a need to develop a questionnaire as a research tool for the evaluation of water balance in the general population. The water balance questionnaire (WBQ) was designed to evaluate water intake from fluid and solid foods and drinking water, and water loss from urine, faeces and sweat at sedentary conditions and physical activity. For validation purposes, the WBQ was administrated in 40 apparently healthy participants aged 22-57 years (37.5% males). Hydration indices in urine (24 h volume, osmolality, specific gravity, pH, colour) were measured through established procedures. Furthermore, the questionnaire was administered twice to 175 subjects to evaluate its reliability. Kendall's τ-b and the Bland and Altman method were used to assess the questionnaire's validity and reliability. The proposed WBQ to assess water balance in healthy individuals was found to be valid and reliable, and it could thus be a useful tool in future projects that aim to evaluate water balance.


Ultraviolet confocal fluorescence microscopy of the in vitro cornea: redox metabolic imaging.
A laser scanning microscope was fitted with two argon-ion lasers that provided wavelengths in the regions of 364, 488, and 514 nm. A Zeiss water objective of 25 x , with a numerical aperture of 0.8, corrected for the UV, was used to measure the fluorescence from optical sections of freshly enucleated rabbit eyes. The confocal microscope was used in both the reflected and fluorescent modes to image in situ epithelial and endothelial cells. An excitation wavelength of 364 nm and emission at 400-500 nm were used to image the fluorescence from reduced pyridine nucleotides. We demonstrate the feasibility of two-dimensional fluorescent confocal imaging of reduced pyridine nucleotides in corneal epithelial and endothelial cells.


Small mine size is associated with lung function abnormality and pneumoconiosis among underground coal miners in Kentucky, Virginia and West Virginia.
To describe the prevalence of lung function abnormality and coal workers' pneumoconiosis (CWP) by mine size among underground coal miners in Kentucky, Virginia and West Virginia. During 2005-2012, 4491 miners completed spirometry and chest radiography as part of a health surveillance programme. Spirometry was interpreted according to American Thoracic Society and European Respiratory Society guidelines, and radiography per International Labour Office standards. Prevalence ratios (PR) were calculated for abnormal spirometry (obstructive, restrictive or mixed pattern using lower limits of normal derived from National Health and Nutrition Examination Survey (NHANES) III) and CWP among workers from small mines (≤50 miners) compared with those from large mines. Among 3771 eligible miners, those from small mines were more likely to have abnormal spirometry (18.5% vs 13.8%, p<0.01), CWP (10.8% vs 5.2%, p<0.01) and progressive massive fibrosis (2.4% vs 1.1%, p<0.01). In regression analysis, working in a small mine was associated with 37% higher prevalence of abnormal spirometry (PR 1.37, 95% CI 1.16 to 1.61) and 2.1 times higher prevalence of CWP (95% CI 1.68 to 2.70). More than one in four of these miners had evidence of CWP, abnormal lung function or both. Although 96% of miners in the study have worked exclusively under dust regulations implemented following the 1969 Federal Coal Mine Safety and Health Act, we observed high rates of respiratory disease including severe cases. The current approach to dust control and provision of safe work conditions for central Appalachian underground coal miners is not adequate to protect them from adverse respiratory health effects.


Neural Mechanisms of Overt Attention Shifts to Emotional Faces.
Emotional faces draw attention and eye-movements towards them. However, the neural mechanisms of attention have mainly been investigated during fixation, which is uncommon in everyday life where people move their eyes to shift attention to faces. Therefore, the current study combined eye-tracking and Electroencephalography (EEG) to measure neural mechanisms of overt attention shifts to faces with happy, neutral and angry expressions, allowing participants to move their eyes freely towards the stimuli. Saccade latencies towards peripheral faces did not differ depending on expression and early neural response (P1) amplitudes and latencies were unaffected. However, the later occurring Early Posterior Negativity (EPN) was significantly larger for emotional than for neutral faces. This response appears after saccades towards the faces. Therefore, emotion modulations only occurred after an overt shift of gaze towards the stimulus had already been completed. Visual saliency rather than emotional content may therefore drive early saccades, while later top-down processes reflect emotion processing.


Accurate alignment of functional EPI data to anatomical MRI using a physics-based distortion model.
Mapping of functional magnetic resonance imaging (fMRI) to conventional anatomical MRI is a valuable step in the interpretation of fMRI activations. One of the main limits on the accuracy of this alignment arises from differences in the geometric distortion induced by magnetic field inhomogeneity. This paper describes an approach to the registration of echo planar image (EPI) data to conventional anatomical images which takes into account this difference in geometric distortion. We make use of an additional spin echo EPI image and use the known signal conservation in spin echo distortion to derive a specialized multimodality nonrigid registration algorithm. We also examine a plausible modification using log-intensity evaluation of the criterion to provide increased sensitivity in areas of low EPI signal. A phantom-based imaging experiment is used to evaluate the behavior of the different criteria, comparing nonrigid displacement estimates to those provided by a imagnetic field mapping acquisition. The algorithm is then applied to a range of nine brain imaging studies illustrating global and local improvement in the anatomical alignment and localization of fMRI activations.


New Opportunities and Cautionary Insights about Decentralizing and Deglobalizing Clinical Trials During the Great Lockdown.
The 2020s began with a rare coronavirus (COVID-19) disaster, which led to a pandemic-induced recession and Great Lockdown. In response, there has been a worldwide mobilization of resources to detect, treat, and cure the virus. Some policymakers are advocating for the repatriation of globally distributed healthcare know-how. Without a cure for COVID-19, the ambiguity concerning how coronavirus-related policies will impact international business remains unclear. Through a multi-method approach, our study sheds light on two key healthcare industry trends: decentralization and deglobalization of clinical trials. We offer actionable strategies to not only mitigate these challenges, but also to take advantage of their new opportunities.


Emerging aspects of rabies infection: with a special emphasis on children.
Increased awareness of the long-neglected rabies virus could promote the highly effective methods of preventing human deaths. Rabies and rabies-related lyssaviruses have recently been appearing in unexpected places, sometimes with dire consequences. Although rabies of canine origin remains 100% fatal in human beings, should the surprising recovery of a single unvaccinated child influence treatment now? Evidence of rabies-related lyssavirus infection of bats is increasing across continents and with new virus types. Human rabies has been misdiagnosed as cerebral malaria, or even drug abuse. Organ transplant recipients have been infected. The first unvaccinated patient, a teenager, bitten by a bat, recovered from rabies encephalitis, but why might this be? Highly effective control and prevention of infection is possible. Preexposure prophylaxis for schoolchildren could now become routine. Improved economical intradermal postexposure vaccine regimens could increase the availability of affordable treatment in developing countries. Controlling dog rabies could prevent 95% of human deaths, but education and resources are lacking. The risks and problems of rabies and other lyssaviruses vary greatly across the world. Knowledge of epidemiology and prevention could save the lives of victims of animal bites and promote efforts to control and even eliminate dog rabies.


Geologic controls on phytoplankton elemental composition.
Planktonic organic matter forms the base of the marine food web, and its nutrient content (C:N:Porg) governs material and energy fluxes in the ocean. Over Earth history, C:N:Porg had a crucial role in marine metazoan evolution and global biogeochemical dynamics, but the geologic history of C:N:Porg is unknown, and it is often regarded constant at the "Redfield" ratio of ∼106:16:1. We calculated C:N:Porg through Phanerozoic time by including nutrient- and temperature-dependent C:N:Porg parameterizations in a model of the long-timescale biogeochemical cycles. We infer a decrease from high Paleozoic C:Porg and N:Porg to present-day ratios, which stems from a decrease in the global average temperature and an increase in seawater phosphate availability. These changes in the phytoplankton's growth environment were driven by various Phanerozoic events: specifically, the middle to late Paleozoic expansion of land plants and the Triassic breakup of the supercontinent Pangaea, which increased continental weatherability and the fluxes of weathering-derived phosphate to the oceans. The resulting increase in the nutrient content of planktonic organic matter likely impacted the evolution of marine fauna and global biogeochemistry.


Disseminated intravascular coagulation in spine surgery: illustrative case review and the paradigms of management.
Disseminated intravascular coagulation (DIC) is rarely encountered by spine surgeons outside of deformity or severe trauma cases. The authors report an extraordinarily unique case of refractory DIC after elective resection of multiple en plaque thoracic meningiomas in a patient with neurofibromatosis type 1. A 49-year-old man underwent T1-3 laminoplasty and expansile duraplasty for resection of multiple en plaque meningiomas for thoracic myelopathy. Intraoperatively, the patient was found to be in a state of DIC that did not resolve postoperatively despite massive transfusions of blood products. He required subsequent returns to the operating room due to recurrent epidural hematomas with resulting paraplegia. Ultimately, the wound was left open, and a wound vacuum-assisted closure (VAC) was placed to prevent further returns to the operating room. DIC persisted until the administration of recombinant factor VIIa. In this report, the authors review the mechanisms, subtypes, and approaches to treatment of DIC with a focus on the bleeding subtype. If this subtype is refractory to blood product administration (> 24 hours), recombinant factor VIIa is a safe and effective option. A wound VAC can be safely utilized with exposed dura if deemed necessary by the surgeon; however, the volume and characteristics of the output should be closely monitored. The use of unconventional surgical solutions may provide options to mitigate the morbidity associated with refractory DIC in spine surgery.


A method to assess concomitant cardiac phosphodiesterase inhibition and positive inotropy.
The ability of positive inotropic drugs to inhibit phosphodiesterase was assessed by observance of the potentiation of inotropic responses to the low intrinsic efficacy beta-adrenoceptor partial agonist prenalterol. Previous studies have shown that an increase in tissue stimulus response capability, as is produced for beta-adrenoceptors by blockade of phosphodiesterase, produces an increase in the maximal response to beta-adrenoceptor partial agonists. Using this principle, we tested cardiotonic drugs on normal and prenalterol-pretreated guinea pig left atria and compared the resulting inotropic responses statistically. Prenalterol pretreatment did not potentiate inotropic responses to methoxamine and CaCl2 and blocked (in accordance with beta-adrenoceptor occupation by a low-efficacy partial agonist) responses to norepinephrine (NE), tyramine, and to a certain extent ouabain. This latter finding was attributed to a low-level catecholamine-release by ouabain in this tissue. The inotropic responses to the phosphodiesterase inhibitors isobutylmethylxanthine (IBMX), theophylline, and enprophylline were greatly potentiated. Similarly, the responses to the cardiotonic drugs (known also to be inhibitors of phosphodiesterase) milrinone, amrinone, and fenoximone were potentiated. Positive inotropy to the cardiotonic drug sulmazole was not significantly potentiated by this procedure, indicating that in this tissue sulmazole may produce inotropic responses by other mechanisms as well. In general, this simple assay may be useful to detect blockade of cardiac phosphodiesterase concomitant with positive inotropy. Although a causal relationship between the PDE inhibition and positive inotropy may not be made from these data, knowledge of PDE blockade may still be useful in the assessment of inotropic mechanism and propensity for toxic side effects.


[Partial pericardial tamponade immediately after cardiac surgery].
Partial pericardial tamponade is a critical situation frequently misdiagnosed. We describe five patients with this entity during an urgent surgical reintervention performed few hours after the initial one. We found clots compressing cardiac cavities in all, usually in the right atrium. In one of them we found also a clot compressing the left atrium. None of the patients studied had the classical clinical features of cardiac tamponade (Kussmaul's sign: pulsus paradoxus) and we found no difference in blood pressure, quantity of bleeding or pulmonary capillary pressure, considering the reinterventional moment in comparison to the values taken immediately after the initial surgery and the ones registered during the surgical reintervention. There was significative increase in the central venous pressure value, decreased urine output and drop in the cardiac index. Based on this observation, we believe it is possible to have a presumptive diagnosis of partial pericardial tamponade by bidimensional echocardiographic studies just before the surgical reintervention.


Association of blood pressure with dietary intake, physical activity, and anthropometric measurements in Turkish adolescents.
Determining high blood pressure in childhood is an important step to reduce the risk of occurrence of high blood pressure-related diseases in adulthood. This study aimed to assess the association of blood pressure with dietary intake, physical activity, and anthropometric measurements in Turkish adolescents. This cross-sectional study included 370 students (202 females, 168 males) aged 14 to 18 years from one private and one public school in Kayseri, Turkey. Some anthropometric measurements and 24-hour dietary recall of the students were obtained. Their blood pressures were measured, and the International Physical Activity Questionnaire and the Mediterranean Diet Quality Index (KIDMED) were used. The body mass index (BMI) mean and waist/height ratio of the hypertensive group were significantly higher than those of the prehypertensive group, whereas their daily potassium, calcium, and magnesium intakes were significantly lower than those of the normotensive group. The percentage of individuals with very low diet quality was higher in the hypertensive group than in the normotensive group (P > 0.05). The percentage of participants with sufficient physical activity was higher in the normotensive group than in the prehypertensive and hypertensive groups. Factors such as high BMI and waist/height rates; low calcium, magnesium, and potassium intakes with diet; insufficient physical activity; and low quality of diet might cause an increase in the blood pressure.


Improved prognosis of postoperative hepatocellular carcinoma patients when treated with functional foods: a prospective cohort study.
Active hexose correlated compound (AHCC) is a newly developed functional food. In vitro experiments have shown that AHCC enhances natural killer cell activity, and may be considered a potent biological response modifier in the treatment of cancer patients. However, the effects of AHCC in a clinical setting have not been reported. We seek to determine whether AHCC can improve the prognosis of hepatocellular carcinoma (HCC) patients following surgical treatment. A prospective cohort study was performed from February 1, 1992 to December 31, 2001. A total of 269 consecutive patients with histologically confirmed HCC were studied. All of the patients underwent resection of a liver tumor. Time to treatment failure (disease recurrence or death) and ten parameters related to liver function after surgery were examined. Of the 269 patients, 113 received AHCC orally after undergoing curative surgery (AHCC group). The AHCC group had a significantly longer no recurrence period (hazard ratio (HR), 0.639; 95% confidence interval (CI), 0.429-0.952; P=0.0277) and an increased overall survival rate (HR, 0.421; 95% CI, 0.253-0.701; P=0.0009) when compared to the control group by Cox's multivariate analysis. This study suggests that AHCC intake can improve the prognosis of postoperative HCC patients.


A robust nanofluidic membrane with tunable zero-order release for implantable dose specific drug delivery.
This manuscript demonstrates a mechanically robust implantable nanofluidic membrane capable of tunable long-term zero-order release of therapeutic agents in ranges relevant for clinical applications. The membrane, with nanochannels as small as 5 nm, allows for the independent control of both dosage and mechanical strength through the integration of high-density short nanochannels parallel to the membrane surface with perpendicular micro- and macrochannels for interfacing with the ambient solutions. These nanofluidic membranes are created using precision silicon fabrication techniques on silicon-on-insulator substrates enabling exquisite control over the monodispersed nanochannel dimensions and surface roughness. Zero-order release of analytes is achieved by exploiting molecule to surface interactions which dominate diffusive transport when fluids are confined to the nanoscale. In this study we investigate the nanofluidic membrane performance using custom diffusion and gas testing apparatuses to quantify molecular release rate and process uniformity as well as mechanical strength using a gas based burst test. The kinetics of the constrained zero-order release is probed with molecules presenting a range of sizes, charge states, and structural conformations. Finally, an optimal ratio of the molecular hydrodynamic diameter to the nanochannel dimension is determined to assure zero-order release for each tested molecule.


Dampness in buildings and health (DBH): Report from an ongoing epidemiological investigation on the association between indoor environmental factors and health effects among children in Sweden.
With the aim of identifying health-relevant exposures in buildings, an epidemiological study "Dampness in Buildings and Health" (DBH) started in the year 2000 in Sweden. The health focus of the study is on asthma and allergic symptoms among small children and their parents. The first step in the study was an epidemiological cross-sectional questionnaire on housing and health involving 14,077 preschool children in the county of Värmland in Sweden (March-April 2000). Self-reported moisture-related problems in the building were strongly associated with asthma, allergic symptoms, and airway infections among children and adults. Other factors associated with symptoms among the children were allergic heredity, smoking in the family, male sex, urban living, short breast feeding, pet keeping, daycare attendance, non-farming life and some food habits. The second step in the study was a nested case-control study including 198 children with symptoms and 202 healthy controls. A detailed clinical examination by physicians in parallel with extensive inspections and measurements in the subjects' homes were conducted from October 2001 to April 2002. The influence of selection bias in case-control studies has been studied, and questionnaires on self-reported symptoms and building characteristics have been validated. Identified risk factors for allergic symptoms are, e.g., inspector-observed dampness, a low ventilation rate, endotoxin, Penicillium and phthalates in dust. In the third phase, a 5-year follow-up study will be carried out during 2005. The same questionnaire as used in DBH-phase 1 will be distributed to the 10,852 children/parents who responded to the first questionnaire in 2000. Finally, in a fourth phase, controlled experimental studies in climate chambers and in vitro tests regarding findings from DBH-Phase 2 are planned to be conducted during 2004-08. Asthma and allergies among small children are associated with a number of risk factors in the indoor environment. In investigations of building-related health problems many factors have to be considered, including "dampness" emissions from building materials, and ventilation rates.


CoreDetector: a flexible and efficient program for core-genome alignment of evolutionary diverse genomes.
Whole genome alignment of eukaryote species remains an important method for the determination of sequence and structural variations and can also be used to ascertain the representative non-redundant core-genome sequence of a population. Many whole genome alignment tools were first developed for the more mature analysis of prokaryote species with few current tools containing the functionality to process larger genomes of eukaryotes as well as genomes of more divergent species. In addition, the functionality of these tools becomes computationally prohibitive due to the significant compute resources needed to handle larger genomes. In this research, we present CoreDetector, an easy-to-use general-purpose program that can align the core-genome sequences for a range of genome sizes and divergence levels. To illustrate the flexibility of CoreDetector, we conducted alignments of a large set of closely related fungal pathogen and hexaploid wheat cultivar genomes as well as more divergent fly and rodent species genomes. In all cases, compared to existing multiple genome alignment tools, CoreDetector exhibited improved flexibility, efficiency, and competitive accuracy in tested cases. CoreDetector was developed in the cross platform, and easily deployable, Java language. A packaged pipeline is readily executable in a bash terminal without any external need for Perl or Python environments. Installation, example data, and usage instructions for CoreDetector are freely available from https://github.com/mfruzan/CoreDetector.


Effects of prior concentric training on eccentric exercise induced muscle damage.
Exercise induced muscle damage (EIMD) from strenuous unaccustomed eccentric exercise is well documented. So too is the observation that a prior bout of eccentric exercise reduces the severity of symptoms of EIMD. This has been attributed to an increase in sarcomeres in series. Recent studies have suggested that prior concentric training increases the susceptibility of muscle to EIMD following eccentric exercise. This has been attributed to a reduction of sarcomeres in series, which decreases muscle compliance and changes the length-tension relation of muscle contraction. To assess the effects of prior concentric training on the severity of EIMD. Four men and four women (mean (SD) age 21.1 (0.8) years) followed a four week concentric training programme. The elbow flexor musculature of the non-dominant arm was trained at 60% of one repetition maximum dynamic concentric strength performance, three times a week, increasing to 70% by week 3. After three days of rest, participants performed 50 maximal isokinetic eccentric contractions on both arms. All participants gave written informed consent before taking part in this study, which was approved by the school ethics committee. Strength, relaxed arm angle (RAA), arm circumference, and soreness on active extension and flexion were recorded immediately before eccentric exercise, one hour after, and at 24 hour intervals for three days. Data were analysed with fully repeated measures analyses of variance. Strength retention was significantly (p<0.01) greater in the control arm than the trained arm (84.0 (13.7)%, 90.4 (14.7)%, 95.2 (10.5)%, 103.5 (7.6)% v 75.5 (11.3)%, 77.6 (15.3)%, 80.1 (13.9)%, 80.9 (12.5)%) at one, 24, 48, and 72 hours respectively. Similarly, soreness was greater in the trained arm (0.7 (0.6), 3.1 (1.4), 3.0 (1.5), 1.9 (2.3)) than in the untrained arm (0 (0.2), 1.6 (1.3), 1.4 (0.6), 0.6 (0.4)) at one, 24, 48, and 72 hours respectively (p<0.05). Concentric training induced a significant reduction in RAA (165.2 (6.7) degrees v 157.3 (4.9) degrees ) before the eccentric exercise bout (p<0.01). This was further reduced and remained lower in the trained arm at all time points after the eccentric exercise (p<0.01). The arm circumference of the concentrically trained arm was significantly greater than baseline (p<0.05) at 72 hours (30.3 (2.9) v 29.8 (3.3) cm). These findings extend the understanding of the effects of prior concentric training in increasing the severity of EIMD to an upper limb exercise model. The inclusion of concentric conditioning in rehabilitation programmes tends to exacerbate the severity of EIMD in subsequent unaccustomed exercise. However, where concentric conditioning is indicated clinically, the net effect of conditioning outcome and EIMD may still confer enhanced strength performance and capability to dynamically stabilise a joint system.


Antibody against an Anaplasma marginale MSP5 epitope common to tick and erythrocyte stages identifies persistently infected cattle.
A protein epitope of major surface protein 5 (MSP5), defined by monoclonal antibody (MAb) ANAF16C1, is conserved among Anaplasma species (E. S. Visser, T. C. McGuire, G. H. Palmer, W. C. Davis, V. Shkap, E. Pipano, and D. P. Knowles, Jr., Infect. Immun. 60:5139-5144, 1992) and is expressed in the salivary glands of infected ticks. A competitive inhibition ELISA (cELISA) for the detection of bovine anti-MSP5 antibodies was developed by using purified recombinant MSP5 fusion protein and MAb ANAF16C1. The specificity of the recombinant-MSP5 cELISA within North America was established by using 261 serum samples from cattle in the regions of Hawaii and Northern Ontario where anaplasmosis is not endemic and from cattle proven by splenectomy or subinoculation of whole blood into susceptible splenectomized recipients to be uninfected. The maximum percent inhibition by these sera was 18%. Sera known to be positive were obtained from 35 cattle either experimentally inoculated with infected erythrocytes or exposed to infected Dermacentor andersoni ticks. Thirty-four of the 35 serum samples inhibited MAb ANAF16C1 binding by > or = 25%. During acute infection, the MSP5 cELISA detected antibodies prior to or concomitantly with the appearance of rickettsiae in erythrocytes. Antibodies were detectable in sera from persistently infected cattle inoculated as long as 6 years previously.


[Sickle cell disease: A diagnosis to keep in mind].
Sickle cell disease (SCD) is an autosomal recessive genetic disorder. It is the most frequent structural hemoglobinopathy worldwide, and it is produced by an alteration in the globin chain genes. In Chile, there is no data on the prevalence of SCD since it is considered a very rare condition. The incidence of this disease has been increasing due to migration of people from areas with greater presence of SCD. It is important to know and consider this diagnosis in a selected group of patients with anemia, in order to prevent and treat the different complications of this disease. This article reviews the most recent information that shows new concepts in the knowledge of the physiopathology, and especially publications of guidelines and consensus in relation to the diagnosis and management of this con dition.


Cognitive Style as Environmentally Sensitive Individual Differences in Cognition: A Modern Synthesis and Applications in Education, Business, and Management.
The key aims of this article are to relate the construct of cognitive style to current theories in cognitive psychology and neuroscience and to outline a framework that integrates the findings on individual differences in cognition across different disciplines. First, we characterize cognitive style as patterns of adaptation to the external world that develop on the basis of innate predispositions, the interactions among which are shaped by changing environmental demands. Second, we show that research on cognitive style in psychology and cross-cultural neuroscience, on learning styles in education, and on decision-making styles in business and management all address the same phenomena. Third, we review cognitive-psychology and neuroscience research that supports the validity of the concept of cognitive style. Fourth, we show that various styles from disparate disciplines can be organized into a single taxonomy. This taxonomy allows us to integrate all the well-documented cognitive, learning, and decision-making styles; all of these style types correspond to adaptive systems that draw on different levels of information processing. Finally, we discuss how the proposed approach might promote greater coherence in research and application in education, in business and management, and in other disciplines.


Assembly of the LongSHOT cohort: public record linkage on a grand scale.
Virtually all existing evidence linking access to firearms to elevated risks of mortality and morbidity comes from ecological and case-control studies. To improve understanding of the health risks and benefits of firearm ownership, we launched a cohort study: the Longitudinal Study of Handgun Ownership and Transfer (LongSHOT). Using probabilistic matching techniques we linked three sources of individual-level, state-wide data in California: official voter registration records, an archive of lawful handgun transactions and all-cause mortality data. There were nearly 28.8 million unique voter registrants, 5.5 million handgun transfers and 3.1 million deaths during the study period (18 October 2004 to 31 December 2016). The linkage relied on several identifying variables (first, middle and last names; date of birth; sex; residential address) that were available in all three data sets, deploying them in a series of bespoke algorithms. Assembly of the LongSHOT cohort commenced in January 2016 and was completed in March 2019. Approximately three-quarters of matches identified were exact matches on all link variables. The cohort consists of 28.8 million adult residents of California followed for up to 12.2 years. A total of 1.2 million cohort members purchased at least one handgun during the study period, and 1.6 million died. Three steps taken early may be particularly useful in enhancing the efficiency of large-scale data linkage: thorough data cleaning; assessment of the suitability of off-the-shelf data linkage packages relative to bespoke coding; and careful consideration of the minimum sample size and matching precision needed to support rigorous investigation of the study questions.


Investigation of food products containing garlic or onion for a false positive sulphite response by LC-MS/MS.
In the US, sulphites must be declared on the label if they are present in concentrations greater than 10 mg/kg (determined as) SO2 because an allergic-like response has been reported in a small subset of the population upon consumption of sulphite-containing products. The most widely used method for sulphite determination, the optimised Monier-Williams (OMW), produces false positive results with vegetables from the Allium (garlic) and Brassica (cabbage) genera due to extraction conditions that are thought to cause endogenous sulphur compounds to release SO2. Recently, an LC-MS/MS method was developed for sulphites but has only been tested with samples that are 100% Allium or Brassica. Since regulatory samples may contain these vegetables as ingredients, additional investigations were necessary to determine the potential extent of false positives. Four blank matrices, chips, phyllo shells, hummus, and quinoa were spiked with various concentrations of onion and garlic powders. The sulphite concentrations were determined using an LC-MS/MS method. The matrix is extracted with a buffered formaldehyde solution, converting free and reversibly bound sulphite to the stable formaldehyde adduct, hydroxymethylsulfonate (HMS). It was determined that even at concentrations up to 8% garlic powder or 2% onion powder, the measured sulphite concentration was below the 10 mg/kg SO2 labelling threshold. Commercial dried garlic powders were evaluated to determine the variation in responses that might be encountered in future regulatory samples. Recovery studies were conducted to determine if these methods would detect added sulphite. The ability to eliminate false positives due to these ingredients will result in a greater reliability in the accurate determination of added sulphite to ensure compliance with labelling requirements.


Exosomal miR-182 derived from bone marrow mesenchymal stem cells drives carfilzomib resistance of multiple myeloma cells by targeting SOX6.
Multiple myeloma (MM) is a common hematological malignancy. Drug resistance remains to be a major clinical challenge in MM therapy. In this study, we aim to investigate the functional roles of bone marrow mesenchymal stem cells (BMSC)-derived exosomal miR-182 on the carfilzomib resistance of MM and its underlying mechanism. qRT-PCR and Western blot methods were utilized to confirm the gene or protein expressions. CCK-8 and transwell assays were performed to measure the capabilities of proliferation, migration, and invasion. The molecular interactions were validated through ChIP and Dual luciferase assay. Our findings indicated that miR-182 expression was upregulated in serum, BMSCs and BMSC-derived exosomes from MM patients. Hypoxia-inducible factor-1α (HIF-1α), a key transcriptional factor in tumor microenvironment, could boost miR-182 expression by directly binding to its promoter, thus favoring exosomal secretion. Moreover, exosomal miR-182 from BMSCs could be transferred to MM cells and was able to promote malignant proliferation, metastasis, and invasion, as well as decrease the sensitivity of MM cells against carfilzomib. Additionally, SOX6 was identified as a downstream target of miR-182 in MM cells, and its expression was negatively regulated by miR-182. Rescue experiments proved that loss of SOX6 in MM cells dramatically reversed the promoting roles of BMSC-secreted exosomal miR-182 on proliferation, metastasis, and carfilzomib resistance in MM cells. Collectively, our findings indicated that exosomal miR-182 derived from BMSCs contributed to the metastasis and carfilzomib resistance of MM cells by targeting SOX6. This study sheds light on the pathogenesis of the BMSC-derived exosome containing miR-182 in the malignant behaviors of MM cells and carfzomib resistance.


Are household firearms stored less safely in homes with adolescents?: Analysis of a national random sample of parents.
To examine whether firearms are more frequently stored loaded, unlocked, or both in households with adolescents only (aged 13-17 years) compared with households with younger children only (aged 0-12 years). Random-digit-dial survey on firearms (n = 2770). We computed bivariate associations between the presence of adolescents and firearm storage practices. Statistical significance was assessed using prevalence ratios with 95% confidence intervals. United States. Survey respondents with children (aged <18 years) who reported the presence of a household firearm. Prevalence of firearms in the home stored loaded and/or unlocked. Of the 392 respondents, 22% had a loaded firearm, 32% had an unlocked firearm, and 8% had a firearm stored loaded and unlocked. Compared with households with younger children, households with adolescents only were somewhat more likely to store a firearm unlocked (42% vs 29%; prevalence ratio, 1.48; 95% confidence interval, 1.04-2.02), loaded (26% vs 20%; prevalence ratio, 1.25; 95% confidence interval, 0.82-1.91), or both (10% vs 8%; prevalence ratio, 1.43; 95% confidence interval, 0.64-3.19). Parents of adolescents appear to be more likely to keep household firearms stored unsafely, especially with regard to keeping firearms unlocked. This is of concern because most youth firearm injuries happen to adolescents. Firearm injury prevention programs should directly target parents of adolescents to promote safe firearm storage.