Genome-Wide Association Study Reveals Complex Genetic Architecture of Cadmium and Mercury Accumulation and Tolerance Traits in Medicago truncatula.
Heavy metals are an increasing problem due to contamination from human sources that and can enter the food chain by being taken up by plants. Understanding the genetic basis of accumulation and tolerance in plants is important for reducing the uptake of toxic metals in crops and crop relatives, as well as for removing heavy metals from soils by means of phytoremediation. Following exposure of Medicago truncatula seedlings to cadmium (Cd) and mercury (Hg), we conducted a genome-wide association study using relative root growth (RRG) and leaf accumulation measurements. Cd and Hg accumulation and RRG had heritability ranging 0.44 - 0.72 indicating high genetic diversity for these traits. The Cd and Hg trait associations were broadly distributed throughout the genome, indicated the traits are polygenic and involve several quantitative loci. For all traits, candidate genes included several membrane associated ATP-binding cassette transporters, P-type ATPase transporters, oxidative stress response genes, and stress related UDP-glycosyltransferases. The P-type ATPase transporters and ATP-binding cassette protein-families have roles in vacuole transport of heavy metals, and our findings support their wide use in physiological plant responses to heavy metals and abiotic stresses. We also found associations between Cd RRG with the genes CAX3 and PDR3, two linked adjacent genes, and leaf accumulation of Hg associated with the genes NRAMP6 and CAX9. When plant genotypes with the most extreme phenotypes were compared, we found significant divergence in genomic regions using population genomics methods that contained metal transport and stress response gene ontologies. Several of these genomic regions show high linkage disequilibrium (LD) among candidate genes suggesting they have evolved together. Minor allele frequency (MAF) and effect size of the most significant SNPs was negatively correlated with large effect alleles being most rare. This is consistent with purifying selection against alleles that increase toxicity and abiotic stress. Conversely, the alleles with large affect that had higher frequencies that were associated with the exclusion of Cd and Hg. Overall, macroevolutionary conservation of heavy metal and stress response genes is important for improvement of forage crops by harnessing wild genetic variants in gene banks such as the Medicago HapMap collection.


Correlation of MR diffusion tensor imaging parameters with ASIA motor scores in hemorrhagic and nonhemorrhagic acute spinal cord injury.
This study investigated correlations between American Spinal Injury Association (ASIA) clinical injury motor scores in patients with traumatic cervical cord injury and magnetic resonance (MR) diffusion tensor imaging (DTI) parameters. Conventional imaging and DTI were performed to evaluate 25 patients (age, 39.7±13.9 years; 4 women, 21 men) with blunt spinal cord injury and 11 volunteers (age, 31.5±10.7 years; 3 women, 8 men). Cord contusions were hemorrhagic (HC) in 13 and non-hemorrhagic (NHC) in 12 patients. The spinal cord was divided into three regions to account for spatial and pathological variation in DTI parameters. Comparisons of regional and injury site mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity ( λ(⊥)), and longitudinal diffusivity ( λ(‖)) were made with control subjects. ASIA motor scores were correlated with DTI using linear regression analysis. HC and NHC patients showed significant reduction (p<0.001) in MD and λ(‖) in all three regions. At the injury site, significant decreases in FA and λ(‖) were seen for both injury groups (p<0.001). λ(⊥) values were significantly increased only for patients with NHC (p<0.05). Significant reduction in FA and λ(‖) (p<0.0001) was observed at the whole cord level between the injured (NH and NHC) and control groups. Within the NHC group, strong correlations were observed between ASIA motor scores and average MD, FA, λ(⊥), and λ(‖) at the injury site. However, no correlation was observed within the HC group between any of the DTI parameters and ASIA motor scores. DTI parameters reflect the severity of spinal cord injury and correlate well with ASIA motor scores in patients with NHC.


Position of teeth on the edentulous atrophic maxilla.
For prosthetic treatment of strongly atrophic alveolar wall, some biometric methods have been developed. The measurements taken from plaster cast models of 230 edentulous, average 29.9 years, and 125 dentulous post-menopausal women were correlated. In the edentulous maxilla the sagittal position of canine teeth can be determined by the oral edge of incisive papilla. The transverse position of canine teeth was on the outer edge of the alveolar wall because of the extensive loss of buccal alveolar bone. On the incisor area the facial surfaces of the central incisors were determined by the oral edge of incisive papilla and the distance was about twice the length of the papilla. The sagittal position of the first premolars was one-third and the first molars two-thirds the length of the palate from the plane of the labial edge of incisive papilla. The transverse position of the premolars and molars was determined by the scar-line, which is a cord-like elevation or track on the alveolar mucosa after extractions of the teeth. According to the comparative method, the position of the scar-line differed from the lingual gingival margin line and was situated about half breadth of the tooth in a buccal direction from it. The transverse position of premolar and molar in the edentulous maxilla is about the middle of the scar-line in a facio-buccal direction. In the setting of the artificial teeth, the facial surfaces of these teeth should be on average 5.0-6.0 mm sideways from the scar-line, whilst the total bilateral breadth of the alveolar wall in the sulcus area was on average 1.0-2.0 mm larger.


Textile Display for Electronic and Brain-Interfaced Communications.
Textile displays are poised to revolutionize current electronic devices, and reshape the future of electronics and related fields such as biomedicine and soft robotics. However, they remain unavailable due to the difficulty of directly constructing electroluminescent devices onto the textile-like substrate to really display desired programmable patterns. Here, a novel textile display is developed from continuous electroluminescent fibers made by a one-step extrusion process. The resulting displaying textile is flexible, stretchable, three-dimensionally twistable, conformable to arbitrarily curved skins, and breathable, and can dynamically display a series of desired patterns, making it useful for bioinspired electronics, soft robotics, and electroluminescent skins, among other applications. It is demonstrated that these displaying textiles can also communicate with a computer and mouse brain for smart display and camouflage applications. This work may open up a new direction for the integration of wearable electroluminescent devices with the human body, providing new and promising communication platforms.


Postoperative delirium in the elderly: diagnosis and management.
Delirium is a common but often undiagnosed complication in the elderly following a major operation. Recognizing the presentation of delirium and the criteria to establish the diagnosis of delirium will improve a clinician's ability to detect this complication. Treating delirium with environmental, supportive, and pharmacologic interventions reduces the incidence and side effects of postoperative delirium. The purpose of this review is to describe the diagnosis and treatment of postoperative delirium.


Prognostic and diagnostic significance of Cavin 2 in lung adenocarcinoma.
Cavin 2 down-regulation is reported in several malignant tumors and is associated with tumor progression. However, the role of Cavin 2 in lung adenocarcinoma is unknown. This study aimed to investigate the prognostic and diagnostic significance of Cavin 2 in lung adenocarcinoma. Cavin 2 expression levels were examined in 150 cases of lung adenocarcinoma and matched adjacent normal lung tissues using RNA extraction and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting and immunohistochemistry (IHC) assays. Then, the relationship of Cavin 2 expression with clinicopathological characteristics and patients' survival was further evaluated in lung adenocarcinoma. QPCR and Western blotting analysis indicated that Cavin 2 expression levels were significantly lower in lung adenocarcinoma tissues compared with those in adjacent normal lung tissues (p < 0.0001). The IHC results showed that positive expression of Cavin 2 was mainly located in cytoplasm as brown, but was hard to detect in lung adenocarcinoma tissues. The low-expression rates of Cavin 2 in lung adenocarcinoma and adjacent normal lung tissues were 62.0% and 20.0%, respectively, and the difference was significant (p < 0.0001). Lower expression of Cavin 2 was significantly associated with tumor size, TNM stage and lymph node metastasis (p < 0.05). Cavin 2 has low expression in lung adenocarcinoma, which might be regarded as a potential prognostic and diagnostic biomarker.


[Use of ultrasonography in the bladder neck suspension].
From 1988 to 1992, 78 patients with genuine stress urinary incontinence underwent bladder neck suspension under ultrasonic monitoring. Tightness of suspension was adjusted by setting posterior urethrovesical angle to approximately 90 degree by transrectal ultrasonography during operation. Urinary continence was achieved in 68 of 78 patients. In the remaining 10 patients, slight incontinence recurred within 6 months after operation. In 60 patients undergoing postoperative chain cystourethrogram, the posterior urethrovesical angles set during operation were about the same as those after operation. In 39 patients undergoing uroflowmetry under the condition that micturition volume was 200 ml or more, urinary flow rate did not decrease after operation. In 20 patients whose posterior urethrovesical angles were measured by transperineal and transabdominal as well as transrectal ultrasonography, angles measured by each ultrasonography were almost identical and neither manipulation could change the configuration of the bladder neck. The posterior urethrovesical angles set during operation were kept postoperatively and provided proper tightness of the suspension suture to achieve urinary continence without any difficulty of urination. Therefore, a posterior urethrovesical angle can be set by transperineal and transabdominal ultrasonography as well as transrectal ultrasonography. While transrectal approach provides the clearest image among the three approaches, transperineal and transabdominal approach carried out with a transabdominal convex or sectorial probe are more convenient than transrectal approach which needed a special probe.


Optimization of Meloxicam Solid Dispersion Formulations for Dissolution Enhancement and Storage Stability Using 33 Full Factorial Design Based on Response Surface Methodology.
This study aimed to formulate and optimize solid-dispersion of meloxicam (MX) employing response-surface-methodology (RSM). RSM allowed identification of the main effects and interactions between studied factors on MX dissolution and acceleration of the optimization process. 33 full factorial design with 27 different formulations was proposed. Effects of drug loading percentage (A), carriers' ratio (B), method of preparation (C), and their interactions on percent MX dissolved after 10 and 30 min (Q10min & Q30min) from fresh and stored samples were studied in distilled water. The considered levels were 2.5%, 5.0%, and 7.5% (factor A), three ratios of Soluplus®/Poloxamer-407 (factor B). Physical mixture (PM), fusion method (FM), and hot-melt-extrusion (HME) were considered factor (C). Stability studies were carried out for 3 months under stress conditions. The proposed optimization design was validated by 3-extra checkpoints formulations. The optimized formulation was selected via numerical optimization and investigated by DSC, XRD, PLM, and in vitro dissolution study. Results showed that HME technique gave the highest MX dissolution rate compared to other techniques (FM & PM). At constant level of factor (C), the amount of MX dissolved increased by decreasing MX loading and increasing Soluplus in carriers' ratio. Actual responses of the optimized formulation were in close consistency with predicted data. Amorphous form of MX in the optimized formulation was proved by DSC, XRD, and PLM. Selected factors and their levels of the optimization design were significantly valuable for demonstrating and adapting the expected formulation characteristics for rapid dissolution of MX (Q10min= 89.09%) from fresh and stored samples.


Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection.
As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.


The calmodulin pathway and evolution of elongated beak morphology in Darwin's finches.
A classic textbook example of adaptive radiation under natural selection is the evolution of 14 closely related species of Darwin's finches (Fringillidae, Passeriformes), whose primary diversity lies in the size and shape of their beaks. Thus, ground finches have deep and wide beaks, cactus finches have long and pointed beaks (low depth and narrower width), and warbler finches have slender and pointed beaks, reflecting differences in their respective diets. Previous work has shown that even small differences in any of the three major dimensions (depth, width and length) of the beak have major consequences for the overall fitness of the birds. Recently we used a candidate gene approach to explain one pathway involved in Darwin's finch beak morphogenesis. However, this type of analysis is limited to molecules with a known association with craniofacial and/or skeletogenic development. Here we use a less constrained, complementary DNA microarray analysis of the transcripts expressed in the beak primordia to find previously unknown genes and pathways whose expression correlates with specific beak morphologies. We show that calmodulin (CaM), a molecule involved in mediating Ca2+ signalling, is expressed at higher levels in the long and pointed beaks of cactus finches than in more robust beak types of other species. We validated this observation with in situ hybridizations. When this upregulation of the CaM-dependent pathway is artificially replicated in the chick frontonasal prominence, it causes an elongation of the upper beak, recapitulating the beak morphology of the cactus finches. Our results indicate that local upregulation of the CaM-dependent pathway is likely to have been a component of the evolution of Darwin's finch species with elongated beak morphology and provide a mechanistic explanation for the independence of beak evolution along different axes. More generally, our results implicate the CaM-dependent pathway in the developmental regulation of craniofacial skeletal structures.


Sulfurtransferases and cyanide detoxification in mouse liver, kidney, and brain.
The activity of rhodanese, 3-mercaptopyruvate sulfurtransferase (MPST) and cystathionase in mouse liver, kidney, and four brain regions: tele-, meso-, di- and rhombencephalon was studied 30 min and 2 h following a sublethal dose of cyanide (4 mg/ kg body weight) intraperitoneal injection. Simultaneously, sulfane sulfur levels and total sulfur content, a direct or indirect source of sulfur for CN(-) conversion to SCN(-), were also investigated in these tissues. In the liver this dose of cyanide seemed to impair the process of cyanide detoxification by MPST, as well as rhodanese inhibition. The effects of cyanide administration to mice proved to be totally different in the liver and kidney. In the kidney, a significant increase in the rhodanese activity was observed as early as 30 min following cyanide intoxication, and an elevated cystathionase activity after 2 h was detected. This suggests the involvement of cystathionase in cyanide detoxification in the kidney. The activity of MPST remained at the same level as in the control group. In the rhombencephalon, similarly as in the kidney, L-cysteine desulfuration pathways, which generate sulfane sulfur and sulfurtransferases that transfer sulfane sulfur atoms to CN(-), seemed to play an important role as a defense system against cyanide. The stable level of sulfane sulfur and total sulfur content was accompanied in the rhombencephalon by an increased activity of MPST, cystathionase and rhodanese. In other brain regions the role of these three sulfurtransferases was not so clear and it seemed that in the telencephalon, where the total sulfur content, but not the sulfane sulfur level, was significantly increased, some sulfur-containing compounds, such as GSH and/or cysteine, appeared in response to cyanide.


Severe Acute Respiratory Syndrome Coronavirus-2 Infections in Critical Care Staff: Beware the Risks Beyond the Bedside.
Critical care workers were considered to be at high risk of severe acute respiratory syndrome coronavirus-2 infection from patients during the first wave of the pandemic. Staff symptoms, previous swab testing, and antibody prevalence were correlated with patient admissions to investigate this assumption. Cross-sectional study. A large critical care department in a tertiary-care teaching hospital in London, United Kingdom. Staff working in critical care. None. Participants completed a questionnaire and provided a serum sample for severe acute respiratory syndrome coronavirus-2 antibody testing over a 3-day period in April 2020. We compared the timing of symptoms in staff to the coronavirus disease 2019 patient admissions to critical care. We also identified factors associated with antibody detection. Of 625 staff 384 (61.4%) reported previous symptoms and 124 (19.8%) had sent a swab for testing. Severe acute respiratory syndrome coronavirus-2 infection had been confirmed in 37 of those swabbed (29.8%). Overall, 21% (131/625) had detectable severe acute respiratory syndrome coronavirus-2 antibody, of whom 9.9% (13/131) had been asymptomatic. The peak onset of symptoms among staff occurred 2 weeks before the peak in coronavirus disease 2019 patient admissions. Staff who worked in multiple departments across the hospital were more likely to be seropositive. Staff with a symptomatic household contact were also more likely to be seropositive at 31.3%, compared with 16.2% in those without (p < 0.0001). Staff who developed coronavirus disease 2019 were less likely to have caught it from their patients in critical care. Other staff, other areas of the hospital, and the wider community are more likely sources of infection. These findings indicate that personal protective equipment was effective at preventing transmission from patients. However, staff also need to maintain protective measures away from the bedside.


The LG3 module of laminin-5 harbors a binding site for integrin alpha3beta1 that promotes cell adhesion, spreading, and migration.
Laminins are a family of extracellular matrix glycoproteins involved in cell adhesion and migration. A major obstacle to understanding their structure-function relationships is the lack of small laminin domains capable of replicating integrin-binding, cell-adhesive, and migratory functions of the intact molecule. Here, we show that the recombinant LG3 (rLG3) module (26 kDa) of laminin-5 (Ln-5) alpha(3) chain replicated key Ln-5 activities. rLG3 but not rLG1 or rLG2 supported cell adhesion and migration of at least two distinct cell lines, in an integrin alpha(3)beta(1)-dependent manner. Cell adhesion to rLG3 was regulated by divalent cations and accompanied by cell spreading and tyrosine phosphorylation of FAK focal adhesion kinase. The integrin binding activity of rLG3 was confirmed by rLG3 affinity chromatography of detergent cell lysates, which resulted in specific purification of integrin alpha(3)beta(1). To our knowledge, this is the first report directly demonstrating that a recombinant laminin LG module is an active domain capable of supporting integrin-dependent cell adhesion and migration.


Effect of Geumgwe-Sinkihwan on Renal Dysfunction in Ischemia/Reperfusion-Induced Acute Renal Failure Mice.
Renal ischemia-reperfusion (I/R) injury is an important cause of acute renal failure (ARF). Geumgwe-sinkihwan (GSH) was recorded in a traditional Chines medical book named "Bangyakhappyeon" in 1884. GSH has been used for treatment for patients with diabetes and glomerulonephritis caused by deficiency of kidney yang and insufficiency of kidney gi. Here we investigate the effects of GSH in mice model of ischemic acute kidney injury. The mice groups are as follows; sham group: C57BL6 male mice, I/R group: C57BL6 male mice with I/R surgery, GSH low group: I/R + 100 mg/kg/day GSH, and GSH high group: I/R + 300 mg/kg/day GSH. Ischemia was induced by clamping both renal arteries and reperfusion. Mice were orally given GSH (100 and 300 mg/kg/day) during 3 days after surgery. Treatment with GSH significantly ameliorated creatinine clearance, creatinine, and blood urea nitrogen levels. Treatment with GSH reduced neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), specific renal injury markers. GSH also reduced the periodic acid-Schiff and picro sirius red staining intensity in kidney of I/R group. Western blot and real-time RT-qPCR analysis demonstrated that GSH decreased protein and mRNA expression levels of the inflammatory cytokines in I/R-induced ARF mice. Moreover, GSH inhibited protein and mRNA expression of inflammasome-related protein including NLRP3 (NOD-like receptor pyrin domain-containing protein 3, cryoprin), ASC (Apoptosis-associated speck-like protein containing a CARD), and caspase-1. These findings provided evidence that GSH ameliorates renal injury including metabolic dysfunction and inflammation via the inhibition of NLRP3-dependent inflammasome in I/R-induced ARF mice.


Effects of early neonatal development and delayed feeding immediately post-hatch on the hepatic lipogenic program in broiler chicks.
The embryo to neonate transition is a critical period of development that has significant impact on broiler production. During this time important genetic programs governing metabolism and growth are established. The goal of this work was to study the effects of early post-hatch (PH) development and the time of initiation of feeding on activation of the genetic program regulating hepatic lipogenesis. A comparison of liver total RNA samples at hatch and 7 days PH was performed using oligonucleotide-based (Affymetrix GeneChip®) chicken genome microarrays. During the first week PH there was significant up-regulation of key lipogenic genes including: ATP citrate lyase (ACL), malic enzyme (ME), fatty acid synthase (FAS), acetyl-CoA carboxylase alpha (ACCα), stearoyl-CoA desaturase-1 (SCD-1), sterol regulatory element binding protein-2 (SREBP-2) and thyroid hormone responsive spot 14α (Spot 14α) among others. These findings were confirmed using gene-specific RT-PCR assays. In a follow-up study, we investigated the effects of withholding feed for the first 48 h PH (delayed feeding, DF) on lipogenic gene expression through 8 days PH. Body weight gain was significantly depressed by DF. Plasma levels of the major metabolic hormones that regulate lipogenic gene expression (insulin, glucagon and T(3)) changed significantly during PH development, but were largely unaffected by DF. Plasma glucose was significantly lower in the DF group at 24h PH but recovered thereafter. In general, DF inhibited the up-regulation of lipogenic genes until feeding was initiated. Delayed up-regulation was also observed for the lipogenic transcription factor genes, SREBP-1, SREBP-2 and peroxisome proliferator-activated receptor gamma (PPARγ), but not for carbohydrate response element binding protein (ChREB) or liver X receptor (LXR). Our results offer additional insight into the transcriptional programming of hepatic lipogenesis in response to the transition from high fat (yolk) to high carbohydrate (feed) nutrition that occurs during early PH development.


Comparison of Time-kill Assay to Evaluate the Antimicrobial Efficacy of Garlic (Allium sativum) and Guava (Psidium guajava) Extracts on Periodontal Pathogens.
The role of Gram-negative anaerobic periodontal pathogens in periodontal diseases has led to the loss of tooth-supporting structures. These diseases can be prevented by the inhibition of bacterial biofilm on the tooth surfaces. Many treatment modalities have been tried to prevent periodontal diseases. With the rise in resistance to synthetic antimicrobials, there is a requirement to develop natural antimicrobials for the control of periodontitis. The aim of the study was to evaluate and compare the efficacy of garlic (Allium sativum) and guava (Psidium guajava) extracts on Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans using time-kill assay. Aqueous garlic extract (AGaE), ethanolic garlic extract (EGaE), aqueous guava extract (AGuE), and ethanolic guava extract (EGuE) were prepared. Time-kill assays were performed on P. gingivalis and A. actinomycetemcomitans. The aqueous and ethanolic extracts of guava and garlic were compared to assess the maximum bactericidal potency. The comparison of time-kill assay of AGaE and AGuE on P. gingivalis showed a statistically significant difference at 2 h (t = 5.29, P < 0.01), 4 h (t = -4.867, P < 0.01), and 6 h (t = -3.647, P < 0.001). The comparison of time-kill assay of EGaE and EGuE on A. actinomycetemcomitans showed a statistically significant difference at 2 h (t = 4.54, P < 0.01) and highly significant difference at 4 h (t = 6.57, P < 0.001). The, judicious use of these phytomedicinal products could be cost-effective and also the adverse effects caused due to the long-term usage of synthetic antimicrobials can be avoided.


[Prevalence of modifiable risk factors in the nursing diagnosis of risk for sudden infant death syndrome].
To measure the prevalence of modifiable risk factors for the nursing diagnosis of risk of sudden infant death syndrome (RSIDS), and to establish the association between the prevalence found and the sociodemographic characteristics of the sample. The sample was composed of 384 mothers (Spaniards, Moroccans and Ecuadorians). Data were collected in the maternity ward of Sta. M del Rosell Hospital in Cartagena (Murcia) from June to November 2007 through a questionnaire containing items on sociodemographic variables and questions about upbringing habits and practices, which are defined as modifiable risk factors by the NANDA-I taxonomy. In the statistical analysis, the Chi-square test was used for qualitative variables and Student's t-test and analysis of variance were used for quantitative variables. A total of 77.1% of newborns were diagnosed with RSIDS related to modifiable risk factors. Notable was the high prevalence of risk factors such as the choice of side-lying position to put the newborn to bed in 39.8% (153) and smoking during pregnancy in 25.7% (99). Statistically significant associations were found (p<0.001) between the diagnosis of RSIDS and the mother's nationality, educational level and household income. The high prevalence of some modifiable risk factors among newborns raises the need to provide more information about upbringing habits and practices for SIDS prevention, not only in Infant Nursing Consulting Rooms but also throughout pregnancy and in the first days of life of the newborn.


Donor human milk and risk of surgical necrotizing enterocolitis: A meta-analysis.
The prevention of necrotizing enterocolitis (NEC) is a primary goal in the care of preterm and low birth-weight infants. Donor-banked milk (DM)-feeding has been reported to have a protective effect towards NEC with respect to formula-feeding. All the meta-analysis published so far, have been focused on the protective effect of DM on the overall risk of NEC, none of them focused on the risk of the most severe cases on NEC only, that are those requiring surgery. We conducted a meta-analysis of available evidences on the risk of developing surgical cases of NEC in DM-fed preterm and/or low birth weight infants with respect to those formula-fed. A search for articles published between January 1960 and January 2018 and addressing the association between DM and surgical NEC was conducted via PubMed, Embase and Cochrane database. We included randomized controlled clinical trials, reporting primary data and involving preterm and/or low birth weight infants fed with preterm formula compared to DM, both as sole diet or complementing own mother's milk. Estimates were pooled using random-effects. Study quality was assessed by GRADE score and risk of bias by the Review Manager software tool. Four papers were included in the meta-analysis. DM did not exert a beneficial effect of DM on the risk of preventing surgical NEC with respect to formula (RR: 0.45; 95% CI: 0.19-1.09). This meta-analysis indicates that DM does not exert a clear protective effect, on the surgical cases of NEC with respect to preterm formula. Since DM feeding implies remarkable extra cost for the preparation, storage and delivery of the milk with respect to preterm formula, stronger evidences are required to recommend this type of feeding as a preventive strategy for surgical NEC. Mother's milk, when available, could represents the best choice. CRD42015020296.


Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: Long-term outcomes in women and men.
To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. This study comprised 69 185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40-79 years at first prescription, treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5 mmol/L) at baseline, plus treatment discontinuation. A total of 48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol vs 41.7% of those with functioning SLCO1B1 (odds ratio 1.31, 95% confidence interval [CI] 1.1-1.55, P = .001). Fewer males had high cholesterol and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (hazard ratio [HR] 1.19, 95% CI 1.03-1.37, P = .01), amounting to five discontinuations per 100 statin-years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3, 95% CI 1.08-1.56, P = .006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year. In this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve the effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype-guided statin selection.


[Familial occurrence of pheochromocytoma].
Familial occurrence of pheochromocytoma in mother and two sons (11 and 14 years old) is described. The diagnosis was based on biochemical tests and localization methods. Bilateral tumors were demonstrated on computerized tomographic scanning in two of our patients. No association with multiple endocrine neoplasma was found. Removal of the tumors resulted in normalization of blood pressure and biochemical parameters. The histopathological examination of the tumor confirmed the diagnosis. A possibility of familial occurrence should be considered in patients with pheochromocytoma and appropriate diagnostic tests must be performed in their near relatives.


The effect of dithiotreitol on thyroid peroxidase and microsomal antigen epitopes recognized by auto and monoclonal antibodies.
The effect of disulphide bridges reduction of the microsomal antigen (Mic-Ag) and thyroid peroxidase (TPO) by dithiotreitol (DTT) has been investigated. The reaction of all 67 tested sera from untreated hyperthyroid Graves' and from 22 Hashimoto's patients with high microsomal antibodies (aAb) titer was diminished by 90-95% by DTT, at pH 9.6. The remaining 5-10% of the activity was not destroyed by DTT. The residual Mic-Ag after DTT reduction was able to inhibit the binding of all 45 Graves' and 22 Hashimoto's tested aAb's to the native microsomal antigen by 100% at high concentration. Reaction of affinity purified TPO with two monoclonal antibodies (mAb) were diminished by 80% to 95% by DTT pretreatment, while the reaction of one mAb with TPO was only slightly affected. The reaction of TPO and Mic-Ag with rabbit polyclonal anti-TPO serum (rabbit a TPO) was diminished by 60% by DTT pretreatment. The immunological reactivity of TPO with aAb's was diminished by 65% after DTT pretreatment. The microsomal antigen-aAb's complex was not destroyed by DTT. Results presented in this paper suggest conformational epitope structure of the Mic-Ag recognized by aAb's in patients with thyroid autoimmune disease (AITD).


Nonlinear absorption and Raman gain in helium-ion-implanted silicon waveguides.
We study whether helium ion implantation can reduce the carrier lifetime and thus reduce the density of two-photon-absorption-generated free carriers. Our experiments and theoretical model show that helium ion implantation into silicon waveguides can successfully reduce the free-carrier losses and allow net gain to be attained by cw-pumped stimulated Raman scattering without requiring reverse bias to remove the photogenerated free carriers.


The Hook1 gene is non-functional in the abnormal spermatozoon head shape (azh) mutant mouse.
In mice carrying the autosomal recessive mutation 'abnormal spermatozoon head shape' (azh) all spermatozoa display a highly abnormal head morphology that differs drastically from the compact and hook-shaped head of the normal murine sperm. Moreover, the azh mutation causes tail abnormalities often resulting in coiled sperm tails or in the decapitation of the sperm head from the flagellum. We have isolated and characterized murine Hook1 cDNA and analyzed the corresponding genomic structure. Furthermore, the Hook1 gene was mapped to the same region on chromosome 4 to which the azh locus was previously linked. The Hook1 gene is predominantly expressed in haploid male germ cells, and immunohistochemical analysis revealed that Hook1 is responsible for the linkage of the microtubular manchette and the flagellum to cellular structures. Here, we report that the azh mutation is due to a deletion of exons 10 and 11 in the murine Hook1 gene leading to a non-functional protein. Our results indicate that loss of Hook1 function results in ectopic positioning of microtubular structures within the spermatid and causes the azh phenotype. Therefore, the human HOOK1 gene could serve as a candidate gene for male infertility due to teratozoospermia or decapitation defects.


The T Cell in Myeloma.
An active role for the immune system in controlling the malignant plasma cell clone in myeloma has been postulated for many years. The clinical states of monoclonal gammopathy of undetermined significance, plateau phase disease, and smoldering myeloma all suggest that a significant host-tumor interaction is taking place. The fundamental role of the cytotoxic T cell in tumor elimination and control has been exemplified by the dramatic efficacy of adoptive T-cell therapies in many hemopoietic malignancies. However, tumor-host cross-talk results in suppression of the endogenous cytotoxic T-cell response against the malignant plasma cell. Whereas patients with myeloma do not clinically exhibit a T-cell immunodeficiency state, with, for example, increased mycobacterial infections, a number of abnormalities of T-cell function are evident. The major abnormalities of T cells include clonal expansions and associated immunosenescence, alterations of regulatory T cells/T helper 17 cells (Treg/Th17 ratio) and acquired membrane abnormalities, due to trogocytosis, which result in acquired Treg cells. Dendritic cell dysfunction associated with impaired antigen processing and presentation caused by abnormalities of the bone marrow microenvironment plays an additional role. In this perspective, we examine the T-cell abnormalities in myeloma and postulate that, whereas cytotoxic T cells interacting with the tumor are dysfunctional, residual T cells still function adequately against external pathogens and thus protect patients from the infections normally associated with a generalized T-cell immunodeficiency state. The so-called 3 E's of host-tumor interaction (elimination, equilibrium, and escape) are clearly reflected in the immune landscape and clinical behavior of myeloma.


Cost-benefit studies of health care programs. Choosing methods for desired results.
This article summarizes the results of a critical review of several cost-benefit analyses (CBA) of health care programs. With pertinent examples, it is demonstrated that the results and conclusions of a study depend upon the assumptions and methods underlying the measurement of costs and benefits in a CBA. Given the incentives for an analyst to comply with desires of his sponsor, and given the scope of the choice available to an analyst among alternative assumptions and methods, it seems quite possible that desired results often dictate the assumptions and methods chosen. It is recommended that a policy maker should suspect an advocacy in the results and conclusions of every CBA. If CBAs are to be a true decision aid, a policy maker ought to obtain several of them, each of which assesses the costs and benefits of a given action plan using assumptions and methods substantially different from the other.


Primaquine for Plasmodium vivax radical cure: What we do not know and why it matters.
Plasmodium vivax radical cure requires the administration of a blood schizonticide for killing blood-stage parasites and the addition of a drug able to kill hypnozoites, the dormant parasite stages residing in the liver of infected patients. All drugs used clinically for killing hypnozoites are 8-aminoquinolines and among them, primaquine has been at the forefront of P. vivax case management for decades. We discuss here the possible factors that could lead to the emergence and selection of P. vivax primaquine resistant parasites and emphasize on how a better understanding of the mechanisms underlying primaquine treatment and hypnozoite biology is needed to prevent this catastrophic scenario from happening.


Optimization for high-energy and high-efficiency broadband optical parametric chirped-pulse amplification in LBO near 800 nm.
In this Letter, we present a study of high-energy and high-conversion-efficiency broadband optical parametric chirped-pulse amplification (OPCPA) system with a 100 mm×100 mm×17 mm LBO crystal near 800 nm. The results showed that the back-conversion was sensitively affected by the pump intensity and the injected signal intensity. It occurred when the injected signal was above 0.82 J with a pump energy of 170 J, and this effect also reshaped the amplified spectrum. After optimization, an amplified energy of 45.3 J was achieved with a conversion efficiency of 26.3% by the OPCPA. The peak power of the hybrid CPA-OPCPA laser system reached 1.02 PW with a compressed duration of 32 fs, which is the first reported OPCPA peak power higher than 1 PW, to the best of our knowledge.


Effectiveness of Invisalign® aligners in the treatment of severe gingival recession: A case report.
In this report, we demonstrate the effectiveness of the InvisalignⓇ system in the treatment of severe gingival recession and bone dehiscence through torque, translation, and intrusion movements in a young woman. Cone-beam computed tomography was used to assess bone parameters and check the teeth during treatment. The root of the mandibular right central incisor, which was buccally positioned and exhibited bone dehiscence of 9.4 mm, was moved toward the center of the alveolar process by using the InvisalignⓇ system and SmartForceⓇ features. The patient was monitored by a periodontist throughout the orthodontic treatment period. Her gingival recession reduced, while the bone dehiscence reduced from 9.40 mm to 3.14 mm. Thus, movement of the root into the alveolus promoted bone neoformation and treated the gingival recession. The findings from this case suggest that orthodontic treatment using the InvisalignⓇ system, along with periodontal monitoring, can aid in the treatment of gingival recession and alveolar defects.


Arthroscopically reduced, irreducible patella dislocation.
Acute patella dislocations account for approximately 2%-3% of knee injuries and are therefore a relatively common presentation in the accident and emergency department. The majority of patella dislocations can be reduced with simple manoeuvres or even spontaneously and can be managed conservatively by bracing and rehabilitation. The aim of this study is to identify and review the main causes of the unique and unexpected event of irreducible patella dislocation and their characteristic presentations. Irreducible patella dislocations can happen but are very rare. Currently, a limited number of case reports are available, prompting for a need for research on this topic. This case study can shed light on the possible pathogenesis and pathognomonic features of irreducible patella dislocations and provide insight on the available therapeutic approaches.


Investigating discharge destinations for schizophrenic patients.
An audit of hospital records of 542 patients diagnosed as having schizophrenia discharged in the years 1986-88 from the Princess Alexandra Hospital, Brisbane, showed that 46% of patients left hospital to live with other family members, usually parents or spouses. Analysis of destination suggested that the extent of patient-family connectedness increases when the patient is younger, has had fewer admissions, or has had the illness for a shorter period of time.


What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care?
Increased awareness of prostate cancer has led to earlier initiation of therapy, and the potential for a longer duration of treatment has led to a stronger emphasis on tolerability. Historically, the mainstay of treatment of hormone-sensitive prostate cancer has been castration-based therapy, but antiandrogens are now emerging as an alternative. This article reviews the tolerability profiles of antiandrogens as well as other existing treatments for prostate cancer and examines their implications on patient care. A search of online literature databases was conducted to identify recent articles and studies (1990-2006) that have reported adverse effects associated with treatment approaches for men with prostate cancer. The therapies reviewed here include castration, antiandrogens, a combination of castration and antiandrogens (CAB), estrogens, and chemotherapy. Castration offers significant clinical benefits when used as monotherapy or as adjuvant therapy; however, it is associated with loss of bone mineral density, and a reduction in physical activity and sexual function, which can have a negative impact on quality of life. Detrimental effects on muscle mass, fat deposition, and cognitive function have also been reported. Recent data suggest that the non-steroidal antiandrogen, bicalutamide, confers a significant overall survival benefit when used as adjuvant to radiotherapy in patients with locally advanced disease. However, the survival data for bicalutamide are not as extensive as those available for LHRH agonists. Although they do not appear to have a significant impact on sexual and physical activity, non-steroidal antiandrogens are frequently associated with gynecomastia and breast pain, and some are associated with diarrhea. Estrogens have been used in patients with androgen-independent prostate cancer; however, cardiovascular toxicity has restricted their use. In patients whose prostate cancer has become hormone-refractory, treatment options include chemotherapeutic agents, such as docetaxel and mitoxantrone. It is important for physicians to discuss the adverse effects of all the available treatment options with patients so that a therapy can be selected to meet their expectations in terms of overall survival and tolerability.


The role of water near cytochrome a in cytochrome c oxidase.
Resonance Raman scattering studies of cytochrome c oxidase reveal that two vibrational modes narrow upon placing the enzyme in D2O. This is interpreted as evidence for the presence of water molecules near cytochrome a that increase the linewidth of the heme modes due to resonance vibrational energy transfer to the H2O bending mode. From the nature of the modes in which the broadening is detected, it is deduced that the water molecules are located near the formyl and the vinyl substituents of the cytochrome a. The change in width in the formyl mode appears quickly, whereas that in the vinyl mode only develops after extended exposure of the enzyme to D2O. On the basis of these results we propose a new mechanism for proton translocation. In this hypothesis water molecules at the active site become activated and are dissociated into protons and hydroxyl groups due to changes in the pKas of residues near the heme when the redox state of the cytochrome a changes. Structural features of the protein stabilize this charge separation and allow directional migration of protons to the cytosolic side of the inner mitochondrial membrane. It is pointed out that this mechanism may be operative in all proton-translocation complexes, and it is observed that in bacteriorhodopsin, also a proton pump, water molecules are detected near the active site lending support to the generality of this mechanism.


Conclusions and recommendations for policies on rural aging in the first decades of the 21st century.
The 2000 Forum on Rural Aging: Policy Debates was one of the main tracks of the first International Conference on Rural Aging held in Charleston, WVa., in June 2000. The 2000 Forum was a follow-up to the Expert Group Meeting on Rural Aging, which met at Shepherdstown, WVa., in May 1999. That group considered policy implications of the 1999 International Year of Older Persons for rural aging in four key areas: the situation of older people, multigenerational relationships, lifelong development, and the development and aging of rural populations. As a direct follow-up of the Shepherdstown Expert Group Meeting, the 2000 Forum on Rural Aging formulated the Conclusions and Recommendations for Policies on Rural Aging through a series of working groups. The Conclusions and Recommendations were endorsed by the Conference Plenary Session on June 11, 2000. The Draft Recommendations for Policies on Rural Aging were availablefor comments on the Internet in the remaining part of the year 2000. Many comments were received. Hana Hermanova and Sally Richardson incorporated the comments into the finalized version.


Hierarchical Passivity Criterion for Delayed Neural Networks via A General Delay-Product-Type Lyapunov-Krasovskii Functional.
This article is concerned with passivity analysis of neural networks with a time-varying delay. Several techniques in the domain are improved to establish the new passivity criterion with less conservatism. First, a Lyapunov-Krasovskii functional (LKF) is constructed with two general delay-product-type terms which contain any chosen degree of polynomials in time-varying delay. Second, a general convexity lemma without conservatism is developed to address the positive-definiteness of the LKF and the negative-definiteness of its time-derivative. Then, with these improved results, a hierarchical passivity criterion of less conservatism is obtained for neural networks with a time-varying delay, whose size and conservatism vary with the maximal degree of the time-varying delay polynomial in the LKF. It is shown that the conservatism of the passivity criterion does not always reduce as the degree of the time-varying delay polynomial increases. Finally, a numerical example is given to illustrate the proposed criterion and benchmark against the existing results.


Phosphoenolpyruvate carboxylase activity and concentration in the endosperm of developing and germinating castor oil seeds.
Monospecific polyclonal antibodies against maize leaf phosphoenolpyruvate carboxylase (PEPC, EC 126.96.36.199) were utilized to examine the subunit composition and developmental profile of endosperm PEPC in developing and germinating castor oil seeds (Ricinus communis L. cv Baker 296). PEPC from developing endosperm consists of a single type of 100-kilodalton subunit, whereas the enzyme from 2- to 5-day germinated endosperm appears to contain equal proportions of immunologically related 103- and 108-kilodalton subunits. The maximal activity of PEPC in developing endosperms (2.67 micromoles oxaloacetate produced per minute per gram fresh weight) is approximately 20-fold and threefold greater than that of fully mature (dry seed) and germinating endosperms, respectively. The most significant increase in the activity and concentration of endosperm PEPC occurs during the middle cotyledon to full cotyledon stage of seed development; this period coincides with the most active phase of storage oil accumulation by ripening castor oil seeds. The data are compatible with the recent proposal (RG Smith, DA Gauthier, DT Dennis, DH Turpin [1992] Plant Physiol 1233-1238) that PEPC plays a fundamental role in vivo in the cytosolic production of an important substrate (malate) for fatty acid biosynthesis by developing castor oil seed leucoplasts. Immediately following seed imbibition, PEPC activity and concentration increase in parallel, with the greatest levels attained by the third day of germination. It is suggested that during this early phase of seed germination PEPC has a critical function to build up cellular dicarboxylic acid pools required to initiate significant activities of both the tricarboxylic acid and glyoxylate cycles.


Osteonecrosis of the jaw as a late complication of herpes zoster infection: a case report.
Occurrences of rare oral complications following herpes zoster (HZ) infection have been reported. In the present case, a 57-year-old man was referred for periodontal evaluation due to gingival bleeding. His medical history included diagnoses of chronic lymphocytic leukemia and HZ infection. Intraoral examination revealed necrosis and alveolar bone exposure around the mandibular left lateral incisor, and the patient reported spontaneous exfoliation of the maxillary and mandibular left central incisors. Conservative surgical and antibiotic therapies were provided to the patient, and a diagnosis of osteonecrosis of the jaw following HZ infection was established. There were no signs of recurrence in 17 months of follow-up. Clinicians should be aware of unusual complications related to a previous HZ infection.


Health insurance and payment systems for severe acute pancreatitis.
The medical insurance system of Japan is based on the Universal Medical Care System guaranteed by the provision of the Article 25 of the Constitution of Japan, which states that "All the people shall have the right to live a healthy, cultural and minimum standard of life." The health insurance system of Japan comprises the medical insurance system and the health care system for the long-lived. Medical care insurance includes the employees' health insurance (Social Insurance) that covers employees of private companies and their families and community insurance (National Health Insurance) that covers the self-employed. Each medical insurance system has its own medical care system for the retired and their families. The health care system for the long-lived covers people of over 75 years of age (over 65 years in people with a certain handicap). There is also a system under which all or part of the medical expenses is reimbursed by public expenditure or the cost of medical care not covered by health insurance is paid by the government. This system is referred to collectively as the "the public payment system of medical expenses." To support the realization of the purpose of this system, there is a treatment research enterprise for specified diseases (intractable diseases). Because of the high mortality rate, acute pancreatitis is specified as an intractable disease for the purpose of reducing its mortality rate, and treatment expenses of patients are paid in full by the government dating back to the day when the application was made for a certificate verifying that he or she has severe acute pancreatitis.


Predictive microRNAs for lymph node metastasis in endoscopically resectable submucosal colorectal cancer.
Accurate prediction of regional lymph node metastasis (LNM) in endoscopically resected T1-stage colorectal cancers (CRCs) can reduce unnecessary surgeries. To identify miRNA markers that can predict LNM in T1-stage CRCs, the study was conducted in two phases; (I) miRNA classifier construction by miRNA-array and quantitative reverse transcription PCR (qRT-PCR) using 36 T1-stage CRC samples; (II) miRNA classifier validation in an independent set of 20 T1-stage CRC samples. The expression of potential downstream target genes of miRNAs was assessed by immunohistochemistry. In the discovery analysis by miRNA microarray, expression of 66 miRNAs were significantly different between LNM-positive and negative CRCs. After qRT-PCR validation, 11 miRNAs were consistently significant in the combined classifier construction set. Among them, miR-342-3p was the most significant one (P=4.3×10-4). Through logistic regression analysis, we developed a three-miRNA classifier (miR-342-3p, miR-361-3p, and miR-3621) for predicting LNM in T1-stage CRCs, yielding the area under the curve of 0.947 (94% sensitivity, 85% specificity and 89% accuracy). The discriminative ability of this system was consistently reliable in the independent validation set (83% sensitivity, 64% specificity and 70% of accuracy). Of the potential downstream targets of the three-miRNAs, expressions of E2F1, RAP2B, and AKT1 were significantly associated with LNM. In conclusion, this classifier can predict LNM more accurately than conventional pathologic criteria and our study results may be helpful to avoid unnecessary bowel surgery after endoscopic resection in early CRC.


The transcriptional response of Saccharomyces cerevisiae to osmotic shock. Hot1p and Msn2p/Msn4p are required for the induction of subsets of high osmolarity glycerol pathway-dependent genes.
We have analyzed the transcriptional response to osmotic shock in the yeast Saccharomyces cerevisiae. The mRNA level of 186 genes increased at least 3-fold after a shift to NaCl or sorbitol, whereas that of more than 100 genes was at least 1.5-fold diminished. Many induced genes encode proteins that presumably contribute to protection against different types of damage or encode enzymes in glycerol, trehalose, and glycogen metabolism. Several genes, which encode poorly expressed isoforms of enzymes in carbohydrate metabolism, were induced. The high osmolarity glycerol (HOG) pathway is required for full induction of many but not all genes. The recently characterized Hot1p transcription factor is required for normal expression of a subset of the HOG pathway-dependent responses. Stimulated expression of the genes that required the general stress-response transcription factors Msn2p and Msn4p was also reduced in a hog1 mutant, suggesting that Msn2p/Msn4p might be regulated by the HOG pathway. The expression of genes that are known to be controlled by the mating pheromone response pathway was stimulated by osmotic shock specifically in a hog1 mutant. Inappropriate activation of the mating response may contribute to the growth defect of a hog1 mutant in high osmolarity medium.


An interdisciplinary workshop to improve palliative care: advanced heart failure--clinical guidelines and healing words.
Effective communication is recognized as an essential process to providing quality care, including palliative and end-of-life care. Discussion of prognosis and support needs of patients with heart failure is particularly challenging given the nature of the condition and care across several settings. The objective was to design, implement, and evaluate an interdisciplinary workshop aimed at improving attitudes and skills related to communication with patients and family, health team communication and documentation, and assessment of physical and emotional symptoms. A pretest, delayed posttest evaluation design was used to evaluate two 4-h workshops offered to nurses, social workers, and other nonphysician clinicians. Although baseline reports of skills were high for the participants, significant improvement was noted for objectives emphasized in the workshop. This project demonstrated the feasibility of designing, marketing a brief workshop, and positively impacting communication and documentation skills.


Efg1-mediated recruitment of NuA4 to promoters is required for hypha-specific Swi/Snf binding and activation in Candida albicans.
Efg1 is essential for hyphal development and virulence in the human pathogenic fungus Candida albicans. How Efg1 regulates gene expression is unknown. Here, we show that Efg1 interacts with components of the nucleosome acetyltransferase of H4 (NuA4) histone acetyltransferase (HAT) complex in both yeast and hyphal cells. Deleting YNG2, a subunit of the NuA4 HAT module, results in a significant decrease in the acetylation level of nucleosomal H4 and a profound defect in hyphal development, as well as a defect in the expression of hypha-specific genes. Using chromatin immunoprecipitation, Efg1 and the NuA4 complex are found at the UAS regions of hypha-specific genes in both yeast and hyphal cells, and Efg1 is required for the recruitment of NuA4. Nucleosomal H4 acetylation at the promoters peaks during initial hyphal induction in an Efg1-dependent manner. We also find that Efg1 bound to the promoters of hypha-specific genes is critical for recruitment of the Swi/Snf chromatin remodeling complex during hyphal induction. Our data show that the recruitment of the NuA4 complex by Efg1 to the promoters of hypha-specific genes is required for nucleosomal H4 acetylation at the promoters during hyphal induction and for subsequent binding of Swi/Snf and transcriptional activation.


Macrophage activation syndrome in juvenile dermatomyositis: a systematic review.
Macrophage activation syndrome (MAS) is a potentially fatal complication of a number of rheumatological conditions, but few studies assessed it in juvenile dermatomyositis (JDM). Indeed, MAS is not considered as a frequent complication of JDM, but its occurrence could be under-estimated. In order to address this issue, we performed a revision of the available medical literature, describing and assessing patients with both MAS and JDM. After retrieving 253 records initially, 11 papers were selected as appropriate for our research objective, which provided a total of 12 patients affected with both MAS and JDM. Our pooled case series suggested that MAS in JDM may not be very rare, even though no final conclusion about its incidence and mortality rate can be made. However, JDM-related MAS seems to be difficult to treat, since methylprednisolone pulse therapy alone was not sufficient in most cases. Moreover, MAS in JDM patients often occurred at the onset of the rheumatic disease, before the final diagnosis of JDM could be established. Finally, MAS criteria validated for systemic Juvenile Idiopathic Arthritis (sJIA) resulted to be a very useful guidance to diagnose MAS in JDM patients as well, but their reliability may not be absolute. Therefore, cohort and multicenter studies are needed to assess the incidence and improve the diagnostic criteria for MAS in JDM patients.


Prevalence, pathophysiological mechanisms and factors affecting urolithiasis.
The formation of urinary stone, urolithiasis, is one the oldest known disease affecting human throughout different civilizations and times. The exact pathophysiological mechanism of urolithiasis is not yet clear, as these calculi are of various types and too complex for simple understanding. A single theory cannot explain its formation; therefore, different theories are presented in various times for its explanation like free particle, fixed particle, Randall's plaque theory. In addition, various factors and components are identified that play an important role in the formation of these urinary calculi. In this review, composition of kidney stones, its prevalence/incidence, explanation of pathophysiological mechanisms and role of various factors; urinary pH, uric acid, parathyroid hormone, citrate, oxalate, calcium and macromolecules; osteopontin, matrix Gla protein, kidney injury molecules, urinary prothrombin fragment-1, Tamm-Horsfall protein, inter-α-inhibitors, have been discussed in detail.


Integrated Analysis to Obtain Potential Prognostic Signature in Glioblastoma.
Glioblastoma multiforme (GBM) is the most malignant and multiple tumors of the central nervous system. The survival rate for GBM patients is less than 15 months. We aimed to uncover the potential mechanism of GBM in tumor microenvironment and provide several candidate biomarkers for GBM prognosis. In this study, ESTIMATE analysis was used to divide the GBM patients into high and low immune or stromal score groups. Microenvironment associated genes were filtered through differential analysis. Weighted gene co-expression network analysis (WGCNA) was performed to correlate the genes and clinical traits. The candidate genes' functions were annotated by enrichment analyses. The potential prognostic biomarkers were assessed by survival analysis. We obtained 81 immune associated differentially expressed genes (DEGs) for subsequent WGCNA analysis. Ten out of these DEGs were significantly associated with targeted molecular therapy of GBM patients. Three genes (S100A4, FCGR2B, and BIRC3) out of these genes were associated with overall survival and the independent test set testified the result. Here, we obtained three crucial genes that had good prognostic efficacy of GBM and may help to improve the prognostic prediction of GBM.


Development of gentamicin resistance in gram-negative bacteria in Czechoslovakia and correlation with its usage.
Widespread use of gentamicin in Czechoslovakia began in 1975 when it became more available, although its use remained restricted until 1986. Starting in 1980 a remarkable increase in gentamicin resistance was observed in Pseudomonas aeruginosa, Klebsiella, Enterobacter and several Proteus species, especially Proteus rettgeri. A large proportion of gentamicin-resistant strains came from the urine of hospitalized patients. In spite of infection control measures and restrictive antibiotic policy, gentamicin resistance has increased over the last years. In 1985 gentamicin resistance of bacteria in Czechoslovakia represented 18.2% and was higher than in Austria or the Federal Republic of Germany, for example, but lower than in Hungary, France, Greece and Italy. The usage of gentamicin has also increased. During the years 1982-1987 gentamicin usage in Czechoslovakia increased by one-half. In a representative collection of 69 gentamicin-resistant Gram-negative strains from seven regions of Czechoslovakia, the mechanisms of resistance to gentamicin, netilmicin, tobramycin and amikacin were studied. Production of acetyltransferases (AAC) and adenylyltransferases (ANT) was observed in 84% of strains. The majority of isolates produced AAC(3) enzymes (55%); production of ANT(2") represented the second most observed resistance mechanism (35%); only 14% of isolates produced AAC(6'). This resistance pattern correlates with patterns reported recently for Central and Southern Europe. Due to dissemination of plasmids coding for the AAC(3)-II enzyme, the majority of Czechoslovak gentamicin-resistant Gram-negative strains were also tobramycin- (87%) and netilmicin-resistant (68%). Amikacin remains the most effective aminoglycoside against multiresistant bacterial strains.


A potential pathway for flippase-facilitated glucosylceramide catabolism in plants.
The Aminophospholipid ATPase (ALA) family of plant lipid flippases is involved in the selective transport of lipids across membrane bilayers. Recently, we demonstrated that double mutants lacking both ALA4 and -5 are severely dwarfed. Dwarfism in ala4/5 mutants was accompanied by cellular elongation defects and various lipidomic perturbations, including a 1.4-fold increase in the accumulation of glucosylceramides (GlcCers) relative to total sphingolipid content. Here, we present a potential model for flippase-facilitated GlcCer catabolism in plants, where a combination of ALA flippases transport GlcCers to cytosolic membrane surfaces where they are degraded by Glucosylceramidases (GCDs). GCDs remove the glucose headgroup from GlcCers to produce a ceramide (Cer) backbone, which can be further degraded to sphingoid bases (Sphs, e.g, phytosphingosine) and fatty acids (FAs). In the absence of GlcCer-transporting flippases, GlcCers are proposed to accumulate on extracytoplasmic (i.e., apoplastic) or lumenal membrane surfaces. As GlcCers are potential precursors for Sph production, impaired GlcCer catabolism might also result in the decreased production of the secondary messenger Sph-1-phosphate (Sph-1-P, e.g., phytosphingosine-1-P), a regulator of cell turgor. Importantly, we postulate that either GlcCer accumulation or reduced Sph-1-P signaling might contribute to the growth reductions observed in ala4/5 mutants. Similar catabolic pathways have been proposed for humans and yeast, suggesting flippase-facilitated GlcCer catabolism is conserved across eukaryotes.


Influence of different LED wavelengths on retinal melatonin levels - A rodent study.
Retinal melatonin is crucial for neuroprotection. Exposure to light-emitting diodes (LEDs) affects retinal neurons, possibly influencing retinal melatonin levels. Hence, we aimed to quantify the retinal melatonin level with different LED wavelengths. A total of 24 Sprague Dawley (SD) male rats were divided into four groups (n = 6 in each group) as normal controls (NC), blue light (BL), white light (WL), and yellow light (YL). The rats in the experimental groups were exposed to different wavelengths of LEDs for 28 days (12:12 h light-dark cycle) with uniform illumination of 450-500 lx. Following exposure, the rats were subjected to behavioral tests such as passive avoidance and elevated plus maze tests. Following the behavior tests, the rats were sacrificed, eyes were enucleated, and retinal tissue was stored at -80 °C. The homogenized retina was used for reactive oxygen species (ROS) and melatonin quantification using an enzyme-linked immunosorbent assay (ELISA) kit. Passive avoidance test revealed a significant difference across the groups (p < 0.0004). The BL exposure group demonstrated increased latency to enter the dark compartment (DC) and impaired motor memory. The elevated plus maze test revealed a significant difference across all the groups (p < 0.012), where the time spent in the closed arm was greater in the BL exposure group. Comparison of ROS levels revealed a significant difference across the groups (p < 0.0001), with increased nitric oxide concentrations in the experimental groups. Melatonin levels were significantly decreased in the light exposure groups (p < 0.0001) compared to the NC group. Cumulative exposure to different LED wavelengths resulted in increased anxiety with impaired motor activity. This was also complemented by the addition of oxidative stress leading to decreased melatonin levels in the retina, which might trigger retinal neuronal damage.


Palliative Care Penetration Among Hospitalizations with Acute Pulmonary Embolism: A Nationwide Analysis.
Background: Integration of palliative care in the management of critical illnesses has been linked with a better quality of life for patients and their families. Yet, there is a paucity of data regarding the role of palliative care for acute pulmonary embolism (PE) hospitalizations which is a leading cause of cardiovascular death in the United States. Methods: Using the Nationwide Inpatient Sample years 2005-2015, acute PE hospitalizations were identified by using ICD-9-codes. The primary outcome was the trends of palliative care penetration during acute PE hospitalizations and the main secondary outcome was the factors associated with palliative care utilization. Results: Among 505,485 acute PE hospitalizations, 15,522 (3.1%) had a palliative care encounter. Hospitalizations with high-risk PE versus non-high-risk PE showed a higher utilization for palliative care (7.6% vs. 2.7%, P < 0.001). The annual trends of palliative care penetration among hospitalizations with PE showed a rising pattern (0.6% in 2005 vs. 5.6% in 2015, Ptrend<0.001). A similar trend was observed among those with high-risk PE (0.8% in 2005 vs. 12.8% in 2015, Ptrend<0.001). The trends of palliative care utilization among cancer and non-cancer admissions increased over time (1.3%in 2005 to 15.5% in 2015 vs. 0.5% in 2005 to 3.9% in 2015, both P-trends<0.001). Some racial and regional disparities were identified among the predictors of palliative care utilization. Conclusions: Palliative care penetration among acute PE hospitalizations remains suboptimal even among high-risk PE, and cancer hospitalizations, but has been increasing in recent years. Future studies are needed to investigate the barriers for palliative care utilization and narrowing this gap among admissions with acute PE.


Comparison of shallow-water seston among biogenic habitats on tidal flats.
Aquatic structure-formers have the potential to establish mosaics of seston in shallow water if they modify the relative amounts of deposition (or filtration) and resuspension of particles. By sampling surface water adjacent to Lagrangian drifters traveling 0.1 to 2 m above the bottom, we tested the modification of seston in water masses flowing over two biogenic marine species (native eelgrass, Zostera marina; introduced oysters, Crassostrea gigas) in comparison to unstructured tidal flats. Water properties were examined at five intertidal sites in Washington State, USA, each with 27 drifts (three drifts at different stages of the tidal cycle in each of three patches of three habitat types; drift distance 116 m (109SD), duration 24 min (15SD)). At the initiation of each drift, habitat differences in water properties were already apparent: chlorophyll-a and total suspended solid (TSS) concentrations were greater in structured habitats than bare, and TSS was also inversely related to water depth. Water flowed more slowly across eelgrass than other habitat types. As water flowed across each habitat type, TSS generally increased, especially in shallow water, but without habitat differences; chlorophyll-a in these surface-water samples showed no consistent change during drifts. At higher TSS concentrations, quality in terms of organic content declined, and this relationship was not habitat-specific. However, quality in terms of chlorophyll-a concentration increased with TSS, as well as being greater in water over eelgrass than over other habitat types. These results support widespread mobilization of seston in shallow water ebbing or flooding across Washington State's tidal flats, especially as water passes into patches of biogenic species.


[Serum acid phosphatase activity in rats with hypoxia of different etiologies].
Experiments on male rats have shown that the acid phosphatase activity increases in all the types of hypoxia (circulatory-hemic, hemic and hypoxic), in blood serum. An increase in the activity of this enzyme distinctly correlates with hypoxia gravity. A supposition is advanced that the blood enzyme level of lysosomal hydrolases can reflect the functional state of the lysosomal apparatus in cells of the organism.


A comparative analysis of major clinical outcomes with drug-eluting stents versus bare metal stents in male versus female patients.
To conduct a risk-adjusted gender-based analysis of clinical outcomes following drug-eluting stent (DES) versus bare metal stent (BMS) implantation in patients with coronary artery disease. We compared risk-adjusted total mortality rate, myocardial infarction, and event-free survival (defined as freedom from death, myocardial infarction and/or repeat revascularisation) in a consecutive cohort of 7,662 patients undergoing percutaneous coronary intervention at our institution, including 1,835 (25.4%) women. Follow-up was six months to 6.2 years (mean: 3.5 years; median: 3.6 years). The women were older than men and more likely to suffer from diabetes, hypertension or congestive heart failure. Smokers were more often men, and men were more likely to have had prior coronary bypass surgery compared to women. A DES was used in 39.9% of males and 39.5% of females. Both genders derived a significant long-term clinical benefit from DES compared to BMS; advantages were observed for mortality (men: HR=0.78, 95% CI: 0.64-0.96, p=0.016; women: HR=0.62, 95% CI: 0.45-0.85, p=0.003) and major adverse cardiac events (men: HR=0.73, 95% CI: 0.63-0.84, p<0.001; women: HR=0.76, 95% CI: 0.52-0.84, p=0.001). Among BMS-treated patients, women had worse cumulative clinical outcomes than men. DES eliminated the gender differences in cardiac prognosis. Our analysis indicated a profound prognostic advantage for DES versus BMS among both genders, though female patients appeared to derive the greatest benefit.


A self-probing primer PCR method for detection of very short DNA fragments.
A novel self-probing primer method that based on the fluorescence resonance energy transfer principle is designed to detect DNA fragments of approximately 40 bp. Four self-probing primer reaction systems were developed to target a maize endogenous reference gene (HMG), a soybean endogenous reference gene (Lectin), a rapeseed endogenous reference gene (CruA) and an exogenous gene 5-enolpyruvylshikimate-3-phosphate synthase (ctp2-cp4epsps). These four primer systems were confirmed to have a high level of inter-species specificity and good intra-species stability. The limit of detection was estimated to be 10 copies of haploid genomes for all four assays. The validation results demonstrated that the self-probing primer methods are able to quantify the DNA amount in the different samples with good sensitivity and precision. When highly processed food products were assayed, the self-probing primer method produced better results than the TaqMan probe method. Overall, the self-probing primer method is suitable for qualitative and quantitative detection of very short DNA targets in samples of different sources.


Synthesis of Functionalized Pyrazin-2(1 H)-ones via Tele-Nucleophilic Substitution of Hydrogen Involving Grignard Reactants and Electrophiles.
The reaction of 6-chloro-1-methylpyrazin-2(1 H)-one with Grignard reactants followed by quenching with different electrophiles gave access to a variety of 3,6-difunctionalized 1-methylpyrazin-2(1 H)-ones. This regioselective three-component reaction represents the first example of a tele-nucleophilic substitution of hydrogen (SNH) in which the anionic σH adduct is quenched by electrophiles (other than a proton) before elimination takes place. Quenching the reaction with iodine (I2) or bromine (Br2) provides an alternative reaction pathway, yielding a 3-functionalized 6-chloro-1-methylpyrazin-2(1 H)-one or 5-bromo-6-chloro-1-methylpyrazin-2(1 H)-one, respectively. The halogens present offer opportunities for further selective transformations.


Pseudophosphatases as Regulators of MAPK Signaling.
Mitogen-activated protein kinase (MAPK) signaling pathways are highly conserved regulators of eukaryotic cell function. These enzymes regulate many biological processes, including the cell cycle, apoptosis, differentiation, protein biosynthesis, and oncogenesis; therefore, tight control of the activity of MAPK is critical. Kinases and phosphatases are well established as MAPK activators and inhibitors, respectively. Kinases phosphorylate MAPKs, initiating and controlling the amplitude of the activation. In contrast, MAPK phosphatases (MKPs) dephosphorylate MAPKs, downregulating and controlling the duration of the signal. In addition, within the past decade, pseudoenzymes of these two families, pseudokinases and pseudophosphatases, have emerged as bona fide signaling regulators. This review discusses the role of pseudophosphatases in MAPK signaling, highlighting the function of phosphoserine/threonine/tyrosine-interacting protein (STYX) and TAK1-binding protein (TAB 1) in regulating MAPKs. Finally, a new paradigm is considered for this well-studied cellular pathway, and signal transduction pathways in general.


[Prophylactic external decompression for massive cerebral infarction].
When cerebral infarct extends over a wide area and severe cerebral edema follows, there may be some cases where external decompression is necessarily indicated. Decompression is generally performed when signs of tentorial herniation appear and brainstem damage seems to be still reversible. We have been performing operations in such indication, but result of operations were poor. We were led to search for a accurate way to save acute massive cerebral infarction. A prophylactic external decompression being carried out just when a tentorial herniation is certainly imminent, could be an option. Analysis of serial CT scannings on infarction cases definitely revealed that before cerebral edema became manifest and tentorial herniation developed, there was a period when there were such findings as uniform: low density appears over the whole middle cerebral artery territory. this low density is homogeneous. lateral ventricle is slightly compressed and cortical sulci disappear suggesting slight cerebral edema. We have tried external decompression on three cases as soon as we found these CT findings, before there were signs of tentorial herniation and the outcome were satisfactory.


Folic acid supplementation in early pregnancy and asthma in children aged 6 years.
The objective of the study was to assess whether folic acid intake during the first trimester of pregnancy is related to asthma in the offspring by the age of 6 years. This was a prospective cohort study of 1499 women who were followed up from the first trimester of pregnancy. Their children were followed up until they were 6 years old. Fifty-one percent of the women used folic acid in the month before conception and 88% in the third month of pregnancy. The adjusted odds ratio for asthma per 100 μm increase in the average daily intake of folic acid was 0.98 (95% confidence interval, 0.93-1.04). For categories of daily folate intake, there was no evidence of associations with childhood asthma or evidence of any dose response relation for any time period (all P(trend) > .05). Our results do not support any association of folic acid supplementation in pregnancy and asthma risk in offspring by age 6 years.


Motor cortex maps articulatory features of speech sounds.
The processing of spoken language has been attributed to areas in the superior temporal lobe, where speech stimuli elicit the greatest activation. However, neurobiological and psycholinguistic models have long postulated that knowledge about the articulatory features of individual phonemes has an important role in their perception and in speech comprehension. To probe the possible involvement of specific motor circuits in the speech-perception process, we used event-related functional MRI and presented experimental subjects with spoken syllables, including [p] and [t] sounds, which are produced by movements of the lips or tongue, respectively. Physically similar nonlinguistic signal-correlated noise patterns were used as control stimuli. In localizer experiments, subjects had to silently articulate the same syllables and, in a second task, move their lips or tongue. Speech perception most strongly activated superior temporal cortex. Crucially, however, distinct motor regions in the precentral gyrus sparked by articulatory movements of the lips and tongue were also differentially activated in a somatotopic manner when subjects listened to the lip- or tongue-related phonemes. This sound-related somatotopic activation in precentral gyrus shows that, during speech perception, specific motor circuits are recruited that reflect phonetic distinctive features of the speech sounds encountered, thus providing direct neuroimaging support for specific links between the phonological mechanisms for speech perception and production.


A hairpin DNA aptamer coupled with groove binders as a smart switch for a field-effect transistor biosensor.
We report here that a hairpin-structured DNA that possesses an anti-ATP aptamer sequence successfully detected target ATP or adenosine in a temperature-dependent manner by nanoscale intramolecular displacement on the surface of a gold electrode as an extended gate of a field-effect transistor (FET). The structural switching of the hairpin aptamer from closed loop to open-loop conformations was accompanied by the release of the preloaded DNA binder (DAPI) from the stem part of the hairpin aptamer into the solution phase. The loss of intrinsic positive charges of DAPI (2+) from the diffusion layer at the gate/solution nano-interface as a result of target capturing was responsible for generating a specific signal by the field-effect. We emphasize a new aspect of the structured DNA aptamer in combination with FET: the DAPI-loaded hairpin aptamer successfully detected even uncharged adenosine, which remains a major challenge for FET-based biosensors. Given the simplicity in design of the primary and secondary structures of oligonucleotide aptamers, it is easy to apply this technology to a wide variety of bio-analytes, irrespective of their electric charges. In view of these advantages, our findings may offer a new trend in the design of stimuli-responsive "smart" biomolecular switches for semiconductor-based biosensors.


Cytotoxic and Inflammatory Potential of Air Samples from Occupational Settings with Exposure to Organic Dust.
Organic dust and related microbial exposures are the main inducers of several respiratory symptoms. Occupational exposure to organic dust is very common and has been reported in diverse settings. In vitro tests using relevant cell cultures can be very useful for characterizing the toxicity of complex mixtures present in the air of occupational environments such as organic dust. In this study, the cell viability and the inflammatory response, as measured by the production of pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-1 β (IL-1β), were determined in human macrophages derived from THP-1 monocytic cells. These cells were exposed to air samples from five occupational settings known to possess high levels of contamination of organic dust: poultry and swine feed industries, waste sorting, poultry production and slaughterhouses. Additionally, fungi and particle contamination of those settings was studied to better characterize the organic dust composition. All air samples collected from the assessed workplaces caused both cytotoxic and pro-inflammatory effects. The highest responses were observed in the feed industry, particularly in swine feed production. This study emphasizes the importance of measuring the organic dust/mixture effects in occupational settings and suggests that differences in the organic dust content may result in differences in health effects for exposed workers.


Optical coherence tomography imaging of surgical resolution of bilateral vitreomacular traction syndrome related to incomplete posterior vitreoschisis: a case report.
To report a case of surgical resolution of bilateral vitreomacular traction syndrome related to incomplete posterior vitreoschisis as documented by optical coherence tomography (Stratus OCT, Carl Zeiss Meditec, Dublin, CA). In both eyes of a 72-year-old man with bilateral blurred vision, OCT examination disclosed a relevant increase in mean foveal thickness (right eye = 714 microm; left eye = 757 microm) due to a vitreomacular traction syndrome. At the edges of the most highly elevated area of vitreo-macular traction, OCT scans showed a characteristic splitting of the hyperreflective signal in both eyes, usually identified as posterior vitreous cortex. Both eyes underwent vitrectomy with epiretinal membrane peeling. Postoperative OCT examination showed vitreomacular traction resolution in both eyes with an evident decrease in mean foveal thickness (right eye = 364 microm; left eye = 335 microm). Right visual acuity improved from 20/200 to 20/50; left visual acuity changed from 20/150 to 20/40. OCT was a useful tool in identifying an unusual case of bilateral vitreomacular traction syndrome linked to incomplete posterior vitreoschisis and following a favorable course after surgical management.


In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis.
Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.


Sudden death due to aortic dissection in early pregnancy - a case report.
Forensic pathologists come across many deaths due to natural causes which are sudden. Sudden natural deaths in females who are pregnant warrant thorough investigation and a medico-legal autopsy to rule out any foul play. Here, we report a case of 21-year-old primigravida in her first trimester who suddenly complained of severe chest pain and was brought dead to the hospital with no history suggestive of prior natural disease. At autopsy, the death was attributed to dissection of ascending aorta.


Treating gonorrhea.
The records of 1,381 patients with gonorrhea were examined by the Massachusetts Department of Public Health to determine the efficacy of their treatment schedules. Urethritis, cervicitis and pharyngitis were treated with 4.8 million u. of aqueous procaine penicillin G intramuscularly, without probenecid. Cure rates were 98 percent in urethritis, 97 percent in pharyngitis and 98 percent in cervicitis. Patients allergic to penicillin were treated with tetracycline orally or spectinomycin intramuscularly. In patients with proctitis, a 98 percent cure rate was achieved with one intramuscular injection of procaine penicillin G, followed by ampicillin orally for four days.


Neurosurgical management of cerebral astrocytomas in children.
A study of astrocytomas occurring in children (mean age 9.13 years) is reported. Two hundred sixty-one cases operated within 10 years (1986-1995) were reviewed. The subtentorial localization was preponderant and was seen in 145 cases (55.04%). The pathological results for supratentorial astrocytomas show an important number of high-grade, malignant astrocytomas--74 cases (64.3%). Surgery was the most important aspect of the treatment. The microscopic tumoral removal was total in 201 cases (77%), subtotal in 37 cases (14.2%); bioptic sampling was done in only 23 cases (8.8%). In grade III and IV astrocytomas, radiotherapy (high-voltage) and chemotherapy were routinely used. The patients were followed-up, both clinically and by CT, between 6 months and 10 years. Neurological evaluation (6 months post-operative) shows a preponderance of minimal sequelae (71%). Clinical signs of recurrences occurred in 56 cases (21.45%). In 37 cases (66.07%), a surgical indication was retained. Cumulative probability of survival of children with intracranial astrocytomas at 1 year was 0.714 and at 5 years was 0.655.


The Danish Melanoma Database.
The aim of the database is to monitor and improve the treatment and survival of melanoma patients. All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD). In 2014, 2,525 patients with invasive melanoma and 780 with in situ tumors were registered. The coverage is currently 93% compared with the Danish Pathology Register. The main variables include demographic, clinical, and pathological characteristics, including Breslow's tumor thickness, ± ulceration, mitoses, and tumor-node-metastasis stage. Information about the date of diagnosis, treatment, type of surgery, including safety margins, results of lymphoscintigraphy in patients for whom this was indicated (tumors > T1a), results of sentinel node biopsy, pathological evaluation hereof, and follow-up information, including recurrence, nature, and treatment hereof is registered. In case of death, the cause and date are included. Currently, all data are entered manually; however, data catchment from the existing registries is planned to be included shortly. The DMD is an old research database, but new as a clinical quality register. The coverage is high, and the performance in the five Danish regions is quite similar due to strong adherence to guidelines provided by the Danish Melanoma Group. The list of monitored indicators is constantly expanding, and annual quality reports are issued. Several important scientific studies are based on DMD data. DMD holds unique detailed information about tumor characteristics, the surgical treatment, and follow-up of Danish melanoma patients. Registration and monitoring is currently expanding to encompass even more clinical parameters to benefit both patient treatment and research.


The prevalent deep intronic c. 639+919 G>A GLA mutation causes pseudoexon activation and Fabry disease by abolishing the binding of hnRNPA1 and hnRNP A2/B1 to a splicing silencer.
Fabry disease is an X-linked recessive inborn disorder of the glycosphingolipid metabolism, caused by total or partial deficiency of the lysosomal α-galactosidase A enzyme due to mutations in the GLA gene. The prevalent c.639+919 G>A mutation in GLA leads to pathogenic insertion of a 57bp pseudoexon sequence from intron 4, which is responsible for the cardiac variant phenotype. In this study we investigate the splicing regulatory mechanism leading to GLA pseudoexon activation. Splicing analysis of GLA minigenes revealed that pseudoexon activation is influenced by cell-type. We demonstrate that the wild-type sequence harbors an hnRNP A1 and hnRNP A2/B1-binding exonic splicing silencer (ESS) overlapping the 5'splice site (5'ss) that prevents pseudoexon inclusion. The c.639+919 G>A mutation disrupts this ESS allowing U1 snRNP recognition of the 5'ss. We show that the wild-type GLA 5'ss motif with the ESS is also able to inhibit inclusion of an unrelated pseudoexon in the FGB gene, and that also in the FGB context inactivation of the ESS by the c.639+919 G>A mutation causes pseudoexon activation, underscoring the universal nature of the ESS. Finally, we demonstrate that splice switching oligonucleotide (SSO) mediated blocking of the pseudoexon 3'ss and 5'ss effectively restores normal GLA splicing. This indicates that SSO based splicing correction may be a therapeutic alternative in the treatment of Fabry disease.


Increase of Plasma TNF-α Is Associated with Decreased Levels of Blood Platelets in Clinical Dengue Infection.
Dengue virus (DENV) infection has become an increasingly common concern in tropical and subtropical regions. It has protean manifestations ranging from febrile phase to severe life-threatening illness. In this study, we estimated Th1 and Th2 cytokines and correlated the levels with dengue severity along with certain hematological and biochemical parameters. We also studied the seroprevalence of dengue between October and December 2017 at the Government Theni Medical College, India. Individuals with dengue fever (DF) were positive for either IgM or IgG, or both. The biochemical and hematological parameters along with plasma tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), granulocyte monocyte-colony stimulating factor (GM-CSF), interleukin (IL)-13, IL-12p70, IL-10, IL-5, IL-4, and IL-2 cytokines were estimated. The prevalence of DF was 42.9% during the study period. IL-2, TNF-α, IL-4, and IL-10 levels were significantly elevated (p < 0.005) in patients with secondary DENV infection, whereas the level of IL-13 remained unaltered during both primary and secondary infections. No statistically significant difference was noticed with IL-12p70, IL-5, IFN-γ, and GM-CSF between the healthy controls and the primary and secondary DENV-infected groups. Increase of 1 unit of TNF-α was associated with a decrease of 160 units of blood platelets. Together, the study suggests that TNF-α could play a key role in the pathogenesis of dengue, and despite the decrease in platelet levels, it remains to be seen whether any other inflammatory cells regulate the levels of TNF-α in DENV infection.