Metagenomic analysis reveals Culex mosquito virome diversity and Japanese encephalitis genotype V in the Republic of Korea.
Recent outbreaks of emerging and re-emerging viruses have shown that timely detection of novel arboviruses with epidemic potential is essential to mitigate human health risks. There are rising concerns that emergent JEV genotype V (GV) is circulating in Asia, against which current vaccines may not be efficacious. To ascertain if JEV GV and other arboviruses are circulating in East Asia, we conducted next-generation sequencing on 260 pools of Culex tritaeniorhynchus and Culex bitaeniorhynchus mosquitoes (6540 specimens) collected at Camp Humphreys, Republic of Korea (ROK) in 2018. Interrogation of our data revealed a highly abundant and diverse virosphere that contained sequences from 122 distinct virus species. Our statistical and hierarchical analysis uncovered correlates of potential health, virological, and ecological relevance. Furthermore, we obtained evidence that JEV GV was circulating in Pyeongtaek and, retrospectively, in Seoul in 2016 and placed these findings within the context of human and fowl reservoir activity. Sequence-based analysis of JEV GV showed a divergent genotype that is the most distant from the GIII-derived live attenuated SA14-14-2 vaccine strain and indicated regions probably responsible for reduced antibody affinity. These results emphasize recent concerns of shifting JEV genotype in East Asia and highlight the critical need for a vaccine proven efficacious against this re-emergent virus. Together, our one-health approach to Culex viral metagenomics uncovered novel insights into virus ecology and human health.


MR signal enhancement in cervical spondylotic myelopathy. Correlation with surgical results in 35 cases.
In a review of Magnetic Resonance (MR) imaging findings of 35 cervical spondylotic myelopathy patients, a localized increased signal intensity was observed within the most compressed segment of the cervical cord on T2 and proton density weighted images. Size and duration of cervical cord constriction seemed to be the predisposing factors in producing such an abnormality. All patients underwent surgery. Postoperatively the high MR signal intensity disappeared in 3 (8.6%) cases, decreased in other 20 (57.1%) cases, and did not change in the remaining 12 (34.3%) cases. Thus reversible (edema, transient ischemia) and/or irreversible (malacia, gliosis) histological changes seemed to be represented in MR signal enhancement.


Quantitative nucleic acid amplification methods for viral infections.
Over the past 2 decades there have been substantial improvements in the methods used to quantify viral nucleic acid in body fluids and in our understanding of how to use viral load measurements in the diagnosis and management of patients with a number of viral infections. These methods are now integrated into a wide range of diagnostic and treatment guidelines and commonly deployed in a variety of clinical settings. Quantitative nucleic acid amplification methods that are used to measure viral load are described along with key issues and important variables that affect their performance. Particular emphasis is placed on those methods used in clinical laboratories as US Food and Drug Administration-cleared or laboratory-developed tests. We discuss the clinical applications of these methods in patients with HIV-1, hepatitis C virus, hepatitis B virus, cytomegalovirus, Epstein-Barr virus, and BK polyomavirus infections. Finally, the current challenges and future directions of viral load testing are examined. Quantitative nucleic acid amplification tests provide important information that can be used to predict disease progression, distinguish symptomatic from asymptomatic infection, and assess the efficacy of antiviral therapy. Despite the advances in technology, large challenges remain for viral testing related to accuracy, precision, and standardization. Digital PCR, a direct method of quantification of nucleic acids that does not rely on rate-based measurements or calibration curves, may address many of the current challenges.


Controversies in the management of stage III non-small-cell lung cancer.
Lung cancer remains the leading cause of death in the USA and is the most common cancer both in incidence and in mortality globally (1.35 million deaths annually). Non-small-cell lung cancer accounts for >80% of all lung cancers [1] . About 35-45% of non-small-cell lung cancer patients present with locally advanced non-metastatic stage III disease. However, confirmed stage III disease represents a very heterogeneous group ranging from borderline surgical candidate with minimal mediastinal involvement to bulky mediastinal nodes or contralateral nodal involvement with significant controversy regarding optimal management in these various situations. This article specifically addresses the role of surgery, radiotherapy and chemotherapy in multimodal approach to treat stage III patients with N2/N3 involvement and controversies surrounding these recommendations.


Millimeter-wave-detected, millimeter-wave optical polarization spectroscopy.
We report a new form of microwave optical double-resonance spectroscopy called millimeter-wave-detected, millimeter-wave optical polarization spectroscopy (mmOPS). In contrast to other forms of polarization spectroscopy, in which the polarization rotation of optical beams is detected, the mmOPS technique is based on the polarization rotation of millimeter waves induced by the anisotropy from optical pumping out of the lower or upper levels of the millimeter wave transition. By monitoring ground-state rotational transitions with the millimeter waves, the mmOPS technique is capable of identifying weak or otherwise difficult-to-observe optical transitions in complex chemical environments, where multiple molecular species or vibrational states can lead to spectral congestion. Once a transition is identified, mmOPS can then be used to record pure rotational transitions in vibrationally and electronically excited states, with the resolution limited only by the radiative decay rate. Here, the sensitivity of this nearly-background-free technique is demonstrated by optically pumping the weak, nominally spin-forbidden CS e (3)Sigma(-)-X (1)Sigma(+) (2-0) and d (3)Delta-X (1)Sigma(+) (6-0) electronic transitions while probing the CS X (1)Sigma(+) (v(")=0,J(")=2-1) rotational transition with millimeter waves. The J(')=2,N(')=2<--J(')=1,N(')=1 pure rotational transition of the CS e (3)Sigma(-) (v(')=2) state is then recorded by optically preparing the J(')=1,N(')=1 level of the e (3)Sigma(-) (v(')=2) state via the J(')=1,N(')=1<--J(")=1 transition of the e (3)Sigma(-)-X (1)Sigma(+) (2-0) band.


Airborne gamma-ray mapping using fixed-wing vertical take-off and landing (VTOL) uncrewed aerial vehicles.
Low-cost uncrewed aerial vehicles (UAVs) are replacing manned aircraft for airborne radiation mapping applications such as nuclear accident response scenarios or surveying ore deposits and mine sites because of their cost-effectiveness and ability to conduct surveys at lower altitude compared to manned counterparts. Both multi-rotor UAVs and fixed-wing UAVs are well established technologies for aerial radiation mapping applications, however, both also have drawbacks: multi-rotor UAVs are very limited in flight time and range, and fixed-wing UAVs usually require facilities for take-off and landing. A compromise solution is introduced in this work, using a fixed-wing vertical take-off and landing (VTOL) UAV that combines the flexibility of a multi-rotor UAV with the range and flight time of a fixed-wing UAV. The first implementation of a VTOL with radiation mapping capabilities is presented, based on a commercial WingtraOne UAV augmented with CsI scintillator and CZT semiconductor gamma spectrometers. The radiation mapping capabilities of the prototype are demonstrated in a case study, mapping the distribution of radionuclides around the South Terras legacy uranium mine in the south of England, United Kingdom, and the results are compared with previous studies using multi-rotor and manned aircraft to survey the same area.


Functions of propeptide parts in cysteine proteases.
Regulation of proteolytic enzyme activity is an essential requirement for cells and tissues because proteolysis at the wrong time and location may be lethal. Two principal mechanisms to control the activity of proteases have been developed during evolution. The first is the co-evolution of endogenous inhibitors, typically occurring in cellular compartments separated from those containing active enzymes. The second is the fact that proteases are synthesized as inactive or less active precursor molecules. They are activated, in some cases, upon an appropriate signal like acidification, Ca(++) -binding or, in other cases, by limited intra- or intermolecular proteolysis cleaving off an inhibitory peptide. These regulatory proenzyme regions have attracted much attention during the last decade, since it became obvious that they harbour much more information than just triggering activation. In this review we summarize experimental data concerning three functions of propeptides of clan CA family C1 cysteine peptidases (papain family), namely the selectivity of their inhibitory potency, the participation in correct intracellular targeting and assistance in folding of the mature enzyme. Cysteine peptidases of the CA-C1 family include members from the plant kingdom like papain as well as from the animal kingdom like the lysosomal cathepsins L and B. As it will be shown, the functions are determined by certain structural motifs conserved over millions of years after the evolutionary trails have diverged. The function of propeptides of two other important classes of cysteine peptidases - the calpains, clan CA family C4, and the caspases, clan CD family C 14 - are not considered in this review.


Carotid artery wall thickness and risk of stroke subtypes: the atherosclerosis risk in communities study.
Understanding associations of carotid atherosclerosis with stroke subtypes may contribute to more effective prevention of stroke. Between 1987 and 1989, 13 560 men and women aged 45 to 64 years and free of clinical stroke took part in the first examination of the Atherosclerosis Risk in Communities (ARIC) study. Incident strokes were ascertained by hospital surveillance. During an average follow-up of 15.7 years, 82 incident hemorrhagic and 621 incident ischemic strokes (131 lacunar, 358 nonlacunar, and 132 cardioembolic strokes) occurred. The incidence rates of hemorrhagic and ischemic strokes were greater across higher carotid intima-media thickness levels. Although this positive association was observed for all stroke subtypes, the age-, gender-, and race-adjusted risk ratios were higher for cardioembolic and nonlacunar strokes than for hemorrhagic and lacunar strokes. Compared with participants in the lowest quintile (<0.61 mm), the adjusted risk ratios for those in the highest quintile (≥0.85 mm) of intima-media thickness were 2.55 (95% CI, 1.09-5.94) for hemorrhagic, 2.89 (95% CI, 1.50-5.54) for lacunar, 3.61 (95% CI, 2.33-5.99) for nonlacunar, and 6.12 (95% CI, 2.71-13.9) for cardioembolic stroke. The risk ratios were attenuated by additional adjustment for covariates but remained statistically significant for nonlacunar and cardioembolic strokes (P for trend <0.001, respectively). The association between carotid intima-media thickness and lacunar stroke was somewhat stronger in blacks than in whites (P for interaction=0.07). Carotid atherosclerosis was associated with increased risk of all stroke subtypes, but the association of carotid atherosclerosis with stroke may vary by subtypes.


Intravenous high-dose vitamin C monotherapy for sepsis and septic shock: A meta-analysis of randomized controlled trials.
Vitamin C has been used as an adjuvant in the treatment of sepsis and septic shock; however, its role remains controversial. This study aimed to assess the effectiveness of intravenous high-dose vitamin C in sepsis and septic shock patients by meta-analysis. The PubMed, Embase, and Cochrane Library electronic databases were searched to identify relevant studies. The primary outcome was defined as the short-term all-cause mortality rate. Secondary outcomes included duration of vasoactive drug use, intensive care unit length of stay, sequential organ failure assessment scores up to 96 hours after treatment and 90-day mortality. Review Manager version 5.4 was used to perform the meta-analysis. Relative risk and mean differences (MD) with 95% confidence intervals were determined using fixed- or random-effects models. Eight randomized controlled trials (RCTs) comprising 1394 patients were eligible for assessment. Overall, the pooled results showed that high-dose vitamin C decreased short-term all-cause mortality in patients with sepsis, but no significant differences were observed in patients with septic shock. Additionally, high-dose vitamin C was associated with decreased duration of vasoactive drug use in patients with sepsis, but not in patients with septic shock. However, it did not significantly affect the duration of intensive care unit stay in RCTs of patients with sepsis and septic shock. Additionally, it did not significantly affect sequential organ failure assessment scores 96 hours post-treatment or 90-day mortality. These results suggest that intravenous high-dose vitamin C may improve outcomes in patients with sepsis, but do not benefit patients with septic shock. Further RCTs and other studies should be conducted to determine whether vitamin C should be recommended as an adjunctive sepsis treatment.


[How to improve social and professional reinsertion of patients with neurodiabilities ? Practical indications for the general practitioner].
One part of the population of neurolesioned patients is the transition of young patients with neurodisabilities to adult life. To guarantee favourable social and professional reinsertion is a major challenge, requiring inter-professional care. For this reason, in 2006 the CHUV, Lausanne created a transition-consultation framework with neuro-paediatricians and adult neurologists specialised in neuro-rehabilitation linked to a Swiss pilot social and professional reinsertion project collaborating with the invalidity insurance. As a model of the follow up of neurolesioned patients, this article reports the results of the reinsertion project that aims to bring awareness to the general practitioner of an inter-disciplinary care method adaptable to individuals. The holistic service saves time and improves the rate of successful reinsertion of young adults into social and professional life.


Single Nucleotide and Copy-Number Variants in IL4 and IL13 Are Not Associated with Asthma Susceptibility or Inflammatory Markers: A Case-Control Study in a Mexican-Mestizo Population.
Asthma is a complex and chronic inflammatory airway disease. Asthma's etiology is unknown; however, genetic and environmental factors could affect disease susceptibility. We designed a case-control study aimed to evaluate the role of single-nucleotide polymorphisms (SNP), and copy-number variants (CNV) in the IL4 and IL13 genes in asthma susceptibility and their participation in plasma cytokine levels depending on genotypes Methods: We include 486 subjects, divided into asthma patients (AP, n = 141) and clinically healthy subjects (CHS, n = 345). We genotyped three SNP, two in the IL4 and two in the IL13 gene; also, two CNVs in IL4. The IL-4, IL-13 and IgE plasma levels were quantified. Biomass-burning smoke exposure was higher in the AP group compared to CHS (47.5% vs. 20.9%; p < 0.01, OR = 3.4). No statistical differences were found in the genetic association analysis. In both CNV, we only found the common allele. For the analysis of IL-4, IL-13, and IgE measures stratified by genotypes, no significant association or correlation was found. In the Mexican-mestizo population, SNPs neither CNVs in IL4 nor IL13 are associated with asthma susceptibility or involved serum cytokine levels. Biomass-burning smoke is a risk factor in asthma susceptibility.


The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in MAPK-dependent amyloid precursor protein processing.
Rasagiline [N-propargyl-(1R)-aminoindan] a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor exerts neuroprotective and antiapoptotic effects against a variety of insults in cell cultures and in vivo and has finished its phase III clinical trials for Parkinson's disease. In the present study, we show that rasagiline (1 and 10 microM) significantly protected rat PC12 cells against beta-amyloid (Abeta1-42) toxicity. In addition, rasagiline significantly increased (approximately threefold) the secretion of the nonamyloidogenic soluble form of the amyloid precursor protein (sAPPalpha) from SH-SY5Y neuroblastoma and PC12 cells. The increase of sAPPalpha was dose-dependent and was blocked by the hydroxamic acid-based metalloprotease inhibitor Ro31-9790 (100 microM), suggesting that the effect is mediated via alpha-secretase activity. Rasagiline-induced sAPPalpha release was significantly reduced by the inhibitors of protein kinase C (PKC), GF109203X, and ERK mitogen-activated protein kinase (MAPK) PD98059. Moreover, rasagiline dose dependently (0.1-10 microM) increased the phosphorylation of p44 and p42 MAPK, which was abolished by PD98059 (30 microM) and GF109203X (2.5 microM). By comparing the actions of rasagiline with those of its S-isomer TVP1022, which is not an MAO inhibitor, we have been able to demonstrate that MAO-B inhibition is not a prerequisite for either sAPPalpha-induced release or ERK phosphorylation. In addition, structure-activity relationship among rasagiline-related compounds suggests the crucial role of the propargyl moiety in these molecules, because propargylamine itself significantly induced the secretion of sAPPalpha and increased MAPK phosphorylation with similar potency to that of rasagiline and its derivatives.


[Epidermoid carcinoma larynx in stage IV].
To determine the survival, loco-regional control, distant metastases and second primary in stage IV laryngeal carcinoma treated by surgery and radiotherapy. Retrospective study of 147 patients treated with surgery and radiotherapy with a 5 year minimun follow-up. Overall and cause specific survival at 5 and 10 years was 42%, 35% and 49%, 45.8% respectively. Loco-regional control was 57.7 % and 54.7% at 5 and 10 years. Local recurrences presented in 25.7%, regional recurrences in 74.2%, and distant metastases 10.9%. Second primary tumors developed in 12% of the patients, 50% of the cases in the lungs. Factors related to survival are evaluated. In our experience, surgery with postoperative radiotherapy in N+, controls 45% of stage IV laryngeal carcinoma. Regional recurrencies are the main cause of failure, more frequent in N+ patientes, present in the first 36 months after treatment.


Continuous simultaneous detection in mass spectrometry.
In mass spectrometry, several advantages can be derived when multiple mass-to-charge values are detected simultaneously and continuously. One such advantage is an improved duty cycle, which leads to superior limits of detection, better precision, shorter analysis times, and reduced sample sizes. A second advantage is the ability to reduce correlated noise by taking the ratio of two or more simultaneously collected signals, enabling greatly enhanced isotope ratio data. A final advantage is the elimination of spectral skew, leading to more accurate transient signal analysis. Here, these advantages are demonstrated by means of a novel Faraday-strip array detector coupled to a Mattauch-Herzog mass spectrograph. The same system is used to monitor elemental fractionation phenomena in laser ablation inductively coupled plasma mass spectrometry.


Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918-20 pandemic: a quantitative analysis.
The threat of an avian influenza pandemic is causing widespread public concern and health policy response, especially in high-income countries. Our aim was to use high-quality vital registration data gathered during the 1918-20 pandemic to estimate global mortality should such a pandemic occur today. We identified all countries with high-quality vital registration data for the 1918-20 pandemic and used these data to calculate excess mortality. We developed ordinary least squares regression models that related excess mortality to per-head income and absolute latitude and used these models to estimate mortality had there been an influenza pandemic in 2004. Excess mortality data show that, even in 1918-20, population mortality varied over 30-fold across countries. Per-head income explained a large fraction of this variation in mortality. Extrapolation of 1918-20 mortality rates to the worldwide population of 2004 indicates that an estimated 62 million people (10th-90th percentile range 51 million-81 million) would be killed by a similar influenza pandemic; 96% (95% CI 95-98) of these deaths would occur in the developing world. If this mortality were concentrated in a single year, it would increase global mortality by 114%. This analysis of the empirical record of the 1918-20 pandemic provides a plausible upper bound on pandemic mortality. Most deaths will occur in poor countries--ie, in societies whose scarce health resources are already stretched by existing health priorities.


A multi-center study of hemodynamic characteristics exhibited by children with unexplained syncope.
Syncope is common in children and adolescents, with 15% estimated to have had at least one syncopal episode by age 18. In recent years, an increasing number of children, especially girls at their school age, have developed unexplained syncope. The mechanism of an unexplained syncope exhibited by children is incompletely studied; the association between different hemodynamic patterns and clinical features is also not clear. The aim of the study was to investigate the hemodynamic patterns of children with unexplained syncope and to examine the clinical relevance. Two hundred and eight children [87 boys, 121 girls, aged 3 - 19 years, mean (11.66 +/- 2.72) years] were selectively recruited from May 2000 to April 2006 when they presented syncope as their main complaint at the Multi-center Network for Childhood Syncope in Beijing, Hunan Province, Hubei Province, and Shanghai of China. All of the patients underwent head-up tilt tests; data were analyzed using SPSS version 10.0 for Windows. Continuous variables were expressed as the mean +/- standard deviation. Dichotomous variables were compared through a chi(2) test. A value of P < 0.05 (two sided) was regarded as statistically significant. The age distribution of children with syncope was approximately normal. Head-up tilt tests was positive in 155 children, and the incidence of positive response of the baseline head-up tilt test for diagnosing unexplained syncope was 50.48%. The sensitivity value and diagnostic value of sublingual nitroglycerin head-up tilt test were both 74.52%. The hemodynamic pattern was normal in 53 children. The 155 children, who were positive in head-up tilt tests, showed signs of postural orthostatic tachycardia syndrome (60, 28.8%), the vasoinhibitory pattern (72, 34.6%), the cardioinhibitory pattern (5, 2.4%), and the mixed pattern (18, 8.7%). The gender distribution between the two age groups (age < 12 years vs age > or = 12 years) was not different (P > 0.05). The distribution of hemodynamic patterns between the children of the two age groups (age < 12 years vs age > or = 12 years), and the children with different complaints (dizziness vs syncope) was significantly different (P < 0.05), while the distribution between the children of different sexes and different lasting time of syncope (< or = 5 minutes vs > 5 minutes) was not significantly different (P > 0.05). Different hemodynamic patterns were differentiated by differing syncope inducements, presymptoms, and complicated symptoms during and after syncope. The tested girls were more prone when compared with the boys to have unexplained syncope, and the peak age was around twelve years old. The incidence of positive response of head-up tilt tests was also relatively higher for the girls. The distribution of hemodynamic patterns for different ages was different. For children with unexplained syncope, we should use head-up tilttests to distinguish the hemodynamic patterns in order to adopt rational therapeutic measures.


Modification of conducting arylidene copolymers by formation of inclusion complexes: synthesis, characterization, and applications as highly corrosion inhibitors for mild steel.
Modifying the metal surface is one solution to the industry's growing corrosion problem. Thus, via threading approach and insertion of copolymers (CoP5-7) containing polyarylidenes through the internal cavity beta-cyclodextrin β-CD, novel pseudopolyrotaxanes copolymers (PC5-7) are developed, resulting in mild steel corrosion inhibition. Inhibitors of corrosion based on β-CD molecules adsorb strongly to metal surfaces because of their many polar groups, adsorption centers, many linkages of side chains, and benzene rings. The corrosion inhibition efficiencies IE % statistics have been revised via the Tafel polarization method and Spectroscopy based on the electrochemical impedance (EIS), with PC7 achieving the highest 99.93% in 1.0 M H2SO4; they are mixed-type inhibitors. The chemical composition of the resulting PCs is determined with Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM) is utilized to examine the morphological structure of the produced polymers, and X-ray diffraction is employed to identify crystallinity. Encapsulating CoP5-7 with β-CD changes the morphological structures and increases the generated PCs' crystallinity. The thermal stability of PCs is studied, indicating the presence of these CoPs within the β-CD cavities enhances their thermal stability. This research will be a stepping stone for developing high-efficiency anti-corrosion coatings and various industrial applications.


Bilateral maxillary sinus hypoplasia and aplasia: radiological and clinical findings.
Maxillary sinus hypoplasia (MSH) is classified into three types depending upon embryological development of the sinus and uncinate process. Type III MSH is characterized by a near-absence of the uncinate process and an almost absent cleft-like sinus. Bilateral maxillary sinus aplasia or severe hypoplasia with associated paranasal sinus abnormalities is extremely rare. Two cases with severe maxillary sinus hypoplasia/aplasia (one of them with other associated paranasal sinus abnormalities) are presented in this article. This extremely rare abnormality should be kept in mind to prevent misdiagnosis and possible complications during endoscopic sinus surgery.


A SNP of NPC1L1 affects cholesterol absorption in Japanese.
Ezetimibe is known to target Niemann-Pick Type C1 Like1 (NPC1L1), a key protein in intestinal cholesterol absorption, and thus to decrease serum LDL-cholesterol (LDL-C) levels. The response of serum LDL-C levels to ezetimibe was reported to differe among NPC1L1 haplotypes.We analyzed NPC1L1 genotypes in Japanese and investigated differences in markers of cholesterol synthesis/absorption among the genotypes. Blood samples were collected from 42 adult volunteers to measure markers of cholesterol synthesis (lathosterol) and absorption (sitosterol and campesterol) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Based on a study by Hegele RA et al. in Canada, we selected three SNPs (1735 C>G, 25342 A>C and 27677 T>C (numbers relative to the transcription start site)) and analyzed them using PCR-RFLP. The frequencies of genotypes were as follows: 1735 C/G (46%)>C/C (35%)>G/G (19%), 25342 A/A (97%)>A/C (3%)>C/C (0%) and 27677 T/T (97%)>T/C (3%)>C/C (0%). Serum campesterol levels were significantly higher in the 1735 G/G group than 1735 C/G+C/C group, but lathosterol levels showed no significant differences between the genotypes. Our results revealed differences in the frequency of the NPC1L1 polymorphism between Japanese and Canadians. In Japanese, the 1735 G/G group showed enhanced cholesterol absorption from the intestine, as compared to the 1735 C/G+C/C group.


Silicon nanowires coated with silver nanostructures as ultrasensitive interfaces for surface-enhanced Raman spectroscopy.
Silver nanoparticles (Ag NPs) were chemically deposited on silicon nanowires (SiNWs), prepared using the vapor-liquid-solid (VLS) growth mechanism, using an in situ electroless metal deposition technique. The resulting SiNWs/Ag NPs composite interfaces showed large Raman scattering enhancement for rhodamine 6G (R6G) with a detection limit of 10(-14) M and an enhancement factor of 2.3 x 10(8). This large enhancement factor was attributed to the presence of "hot" spots on the SiNWs/Ag NPs substrate.


Identification of Heschl's gyrus on phase difference enhanced imaging.
Background The white matter in the Heschl's gyrus (HG-WM) may appear differently to the other gyri on phase difference enhanced imaging (PADRE), which can enhance the myelin density. Purpose To evaluate the signal intensity (SI) of HG-WM using the PADRE technique and to compare the images with susceptibility-weighted imaging (SWI)-like images. Material and Methods The participants included 19 normal controls (38 HGs; mean age, 60.1 years; age range, 28-80 years). Coronal PADRE and SWI-like images were acquired using a 3T magnetic resonance (MR) system. The SI of the HG-WM was classified into three grades based on a comparison with the SI of the superior temporal gyrus: Grade 1, isointense; Grade 2, slightly hypointense, and Grade 3, markedly hypointense. Results In the assessment of the SI of the HG-WM, the HG-WM appeared hypointense in all 38 sites of the 19 participants; the hypointensity corresponded to Grade 2 in 13 (34%) images and Grade 3 in 25 (66%) images. On the other hand, the HG-WM was classified as Grade 1 (isointense) in all of the SWI-like images. Conclusion The HG-WM appears hypointense on PADRE, which probably reflects the higher myelin content. PADRE may be useful for identifying the HG through the assessment of the SI of the HG-WM.


Association of estrogen receptor-alpha gene polymorphisms with coronary artery disease in patients with familial hypercholesterolemia.
To investigate the association of estrogen receptor (ER)-alpha gene polymorphisms with coronary artery disease (CAD), we studied 197 men and 98 postmenopausal women with heterozygous familial hypercholesterolemia. We examined the known polymorphisms, including PvuII, XbaI, TA repeat, and CA repeat, and identified 6 novel polymorphisms in the ER-alpha gene. The distributions of -1989T/G (a novel polymorphism in promoter B) and XbaI in intron 1 were associated with CAD in postmenopausal women and in men, with a higher frequency of the G/G genotype (P=0.03) or X1/X1 genotype (P=0.02) in the CAD group. The frequency of alleles of TA repeats >17 was found to be significantly higher in postmenopausal women with CAD than in those without CAD (P=0.04), but not in men. Logistic regression analysis with all coronary risk factors as covariates showed that the G/G genotype was a higher risk for CAD (odds ratio 4.5, 95% CI 1.0 to 19.5;P=0.04) but that X1/X1 was not. We conclude that -1989T/G or its linked polymorphisms in the ER-alpha gene may confer risk for CAD and that the G/G genotype may be an independent predictor for CAD in patients with familial hypercholesterolemia.


The second acidic constant of salicylic acid.
The second dissociation constant of salicylic acid (H2L) has been determined, at 25 degrees C, in NaCl ionic media by UV spectrophotometric measurements. The investigated ionic strength values were 0.16, 0.25, 0.50, 1.0, 2.0 and 3.0 M. The protolysis constants calculated at the different ionic strengths yielded, with the Specific Interaction Theory, the infinite dilution constant, log beta1(0) = 13.62 +/- 0.03, for the equilibrium L2- + H+ <==> HL-. The interaction coefficient between Na+ and L2-, b(Na+, L2-) = 0.02 +/- 0.07, has been also calculated.


Development and Current Status of Home-Delivered Meals Programs in the United States: Who Is Served?
Federal home-delivered meals programs for the frail elderly began in the United States in the 1970s. During the 1980s the provision of meals to the homebound elderly was expanded through development of state-funded meals programs. The time has come to pose two questions relative to coverage and impact of these programs. These questions are whether the program serves those who are most needy, and whether the meals programs reduce the need for more costly care. Information available suggests that the elderly most often served are those with socioeconomic problems reducing their ability to obtain regular meals. Medical disability is less often used as a criterion for program eligibility or priority. The recent finding that provision of home-delivered meals reduces hospitalization rates should be reexamined to answer the question of whether the medically needy are actually kept out of the hospital by provision of home-delivered meals.


Interleukin-1 beta rather than lymphotoxin as the major bone resorbing activity in human multiple myeloma.
Human myeloma cells were purified from bone marrow aspirates from four patients having advanced myeloma, including one with common acute lymphoblastic leukemia antigen-positive myeloma. All of these myelomas had marked bone lytic lesions. From the culture supernatants of these purified myeloma cells, bone-resorbing activities were significantly revealed by 45Ca-release bone resorption assay, and IL-1 activities were also detected by IL-1 bioassay (mouse thymocyte comitogenic assay). Sandwich enzyme immunoassay for IL-1 alpha or IL-1 beta revealed that IL-1 beta was responsible for IL-1 activity of these culture supernatants. Furthermore, the bone resorbing activities of these culture supernatants were completely neutralized by pretreatment of anti-IL-1 beta, but not anti-IL-1 alpha antibody. By Northern blot analysis, IL-1 beta mRNA was identified from these myeloma cells. Therefore, it is concluded that myeloma cells produce IL-1 beta, which acts as bone-resorbing activity in multiple myeloma.


LINGO-1 negatively regulates TrkB phosphorylation after ocular hypertension.
The antagonism of LINGO-1, a CNS-specific negative regulator of neuronal survival, was shown to promote short-term survival of retinal ganglion cell (RGC) in an ocular hypertension model. LINGO-1 antagonists, combined with brain-derived neurotrophic factor (BDNF), can increase the length of neuron survival through an unclear molecular mechanism. To determine the relationship between LINGO-1 and BDNF/TrkB receptor in neuronal protection, we show here that LINGO-1 forms a receptor complex with TrkB and negatively regulates its activation in the retina after ocular hypertension injury. LINGO-1 antagonist antibody 1A7 or soluble LINGO-1 (LINGO-1-Fc) treatment upregulates phospho-TrkB phosphorylation and leads to RGC survival after high intraocular pressure injury. This neuronal protective effect was blocked by anti-BDNF antibody. LINGO-1 antagonism therefore promotes RGC survival by regulating the BDNF and TrkB signaling pathway after ocular hypertension.


Patterns of recurrence in FIGO stage IB1-IB2 cervical cancer: Comparison between minimally invasive and abdominal radical hysterectomy.
Aim of our study was to evaluate whether the different laparotomic (ARH) or minimally invasive (laparoscopic and robotic) approaches (MIS) in FIGO stage IB1-IB2 cervical cancer, present different patterns of recurrence of the disease. The secondary endpoint of the study was the evaluation of the variables most involved with the risk of relapse and therefore lower DFS and OS. The study enrolled patients with definitive histological diagnosis of squamous or adenocarcinoma stage IB1-IB2 cervical cancer who underwent minimally invasive or abdominal radical hysterectomy from 2001 to 2018. The study enrolled 360 patients and 59 patients (16.4 %) reported a disease relapse. The data showed that ARH group was not associated with different recurrence patterns than MIS group (p = 0.14). Moreover, there was no statistically significant difference regarding DFS (p = 0.52) and OS (p = 0.29) between the ARH group and the MIS group. MIS, in FIGO stage IB1-IB2 cervical cancer, is not associated with different relapse patterns compared to ARH, nor with a higher risk of distance metastasis and finally, without significant difference in term of DFS and OS. More studies are needed to determine the factors that modify the site of relapse.


Training the Workforce to Conduct Embedded Pragmatic Clinical Trials to Improve Care for People Living with Dementia and Their Caregivers.
The National Institute on Aging IMbedded Pragmatic Alzheimer's Disease and Alzheimer's Disease-Related Dementias Clinical Trials (IMPACT) Collaboratory serves as a national resource for the conduct of embedded pragmatic clinical trials to improve the care of people living with dementia (PLWD) in partnership with the healthcare systems that serve them. Inherent in this objective is the need to train and support a cadre of investigators prepared to conduct this work now and in the future. The Training Core of the IMPACT Collaboratory supports the training of investigators to become experts in this field through three objectives: (1) curricula development and dissemination; (2) network generation and navigation; and (3) a career development award program. The innovative approach of the Training Core will require developing content and providing training experiences that recognize the unique challenges of research at the intersection of health systems, pragmatic trials, and PLWD and their caregivers. Ultimately, we seek to build the nation's capacity to conduct research that bridges the gaps between efficacy studies to effectiveness research to implementation science. Although foundational resources in the methods of each of these areas are already available, few actually focus on pragmatic trials embedded within healthcare systems that focus on PLWD. To bring new interventions for PLWD from efficacy to widespread implementation, researchers must build diffusability, adaptability, heterogeneity, and scalability into the design of the intervention. In achieving these objectives, the Training Core will utilize the network of investigators, institutions, and stakeholders represented in the IMPACT Collaboratory. J Am Geriatr Soc 68:S21-S27, 2020.


A level set based framework for quantitative evaluation of breast tissue density from MRI data.
Breast density is a risk factor associated with the development of breast cancer. Usually, breast density is assessed on two dimensional (2D) mammograms using the American College of Radiology (ACR) classification. Magnetic resonance imaging (MRI) is a non-radiation based examination method, which offers a three dimensional (3D) alternative to classical 2D mammograms. We propose a new framework for automated breast density calculation on MRI data. Our framework consists of three steps. First, a recently developed method for simultaneous intensity inhomogeneity correction and breast tissue and parenchyma segmentation is applied. Second, the obtained breast component is extracted, and the breast-air and breast-body boundaries are refined. Finally, the fibroglandular/parenchymal tissue volume is extracted from the breast volume. The framework was tested on 37 randomly selected MR mammographies. All images were acquired on a 1.5T MR scanner using an axial, T1-weighted time-resolved angiography with stochastic trajectories sequence. The results were compared to manually obtained groundtruth. Dice's Similarity Coefficient (DSC) as well as Bland-Altman plots were used as the main tools for evaluation of similarity between automatic and manual segmentations. The average Dice's Similarity Coefficient values were 0.96±0.0172 and 0.83±0.0636 for breast and parenchymal volumes, respectively. Bland-Altman plots showed the mean bias (%) ± standard deviation equal 5.36±3.9 for breast volumes and -6.9±13.14 for parenchyma volumes. The automated framework produced sufficient results and has the potential to be applied for the analysis of breast volume and breast density of numerous data in clinical and research settings.


Purification of highly active cytochrome bc1 complexes from phylogenetically diverse species by a single chromatographic procedure.
A method has been developed for purification of highly active ubiquinol-cytochrome c oxidoreductase (cytochrome bc1) complexes from wild-type Rhodobacter sphaeroides, Rhodobacter capsulatus MT1131, bovine heart and yeast mitochondria. This is the first report of the isolation of cytochrome bc1 complex from a wild-type strain of Rb. sphaeroides and from any strain of Rb. capsulatus. The purification involves extraction of membranes with dodecyl maltoside and two successive DEAE column chromatography steps. All of the resulting bc1 complexes are free of succinate dehydrogenase and cytochrome c oxidase activities. The purified bc1 complexes from both photosynthetic bacteria contain four polypeptide subunits, although the molecular weights of some of their subunits differ. They are also free of reaction center and light-harvesting pigments and polypeptides. The turnover number of the Rb. sphaeroides complex is 128 s-1, and that of the Rb. capsulatus complex is 64 s-1. The bc1 complex from bovine heart contains eight polypeptides and has a turnover number of 1152 s-1, while the yeast complex contains nine polypeptides and has a turnover number of 219 s-1. The activities of these complexes are equal to or better than those commonly obtained by previously reported methods. This method of purification is relatively simple, reproducible, and yields cytochrome bc1 complexes which largely retain the turnover number of the starting material and are pure on the basis of optical spectra, enzymatic activities and polypeptide composition. The purification of cytochrome bc1 complexes from energy-transducing membranes which differ markedly in their lipid and protein composition makes it likely that with minor modifications this method could be applied to species other than those described here.


Quality assurance in undergraduate medical education at the Medical College of Ohio.
This paper reports a four-year experience in teaching evaluation of care at a three-year medical school, the Medical College of Ohio at Toledo. Informal patient care evaluation evolved to more structured medical care evaluation in seminars and by chart audits. The introduction of professional standards review organizations prompted the teaching and evaluation of the quality and cost of primary care, especially as it applies to learning clinical tasks.


Endothelial dysfunction and coronary artery disease: a state of the art review.
Atherosclerotic coronary artery disease (CAD) is a major cause of morbidity and mortality in the developed world. Endothelial dysfunction plays an important role in the development of atherosclerosis and predicts cardiovascular (CV) outcomes independent of conventional CV risk factors. In recent years, there have been tremendous improvements in the pharmacological prevention and management of CAD. In this review, the pathophysiology of endothelial dysfunction in relation to CAD is discussed and various techniques of invasive and noninvasive assessments of peripheral and coronary endothelial function described. In addition, evidence for the association of endothelial dysfunction and CV outcomes has been examined and finally the role of therapeutic interventions in endothelial dysfunction has been discussed.


Ultrafast and Nanoscale Energy Transduction Mechanisms and Coupled Thermal Transport across Interfaces.
The coupled interactions among the fundamental carriers of charge, heat, and electromagnetic fields at interfaces and boundaries give rise to energetic processes that enable a wide array of technologies. The energy transduction among these coupled carriers results in thermal dissipation at these surfaces, often quantified by the thermal boundary resistance, thus driving the functionalities of the modern nanotechnologies that are continuing to provide transformational benefits in computing, communication, health care, clean energy, power recycling, sensing, and manufacturing, to name a few. It is the purpose of this Review to summarize recent works that have been reported on ultrafast and nanoscale energy transduction and heat transfer mechanisms across interfaces when different thermal carriers couple near or across interfaces. We review coupled heat transfer mechanisms at interfaces of solids, liquids, gasses, and plasmas that drive the resulting interfacial heat transfer and temperature gradients due to energy and momentum coupling among various combinations of electrons, vibrons, photons, polaritons (plasmon polaritons and phonon polaritons), and molecules. These interfacial thermal transport processes with coupled energy carriers involve relatively recent research, and thus, several opportunities exist to further develop these nascent fields, which we comment on throughout the course of this Review.


Lessons from making the Structural Classification of Proteins (SCOP) and their implications for protein structure modelling.
The Structural Classification of Proteins (SCOP) database has facilitated the development of many tools and algorithms and it has been successfully used in protein structure prediction and large-scale genome annotations. During the development of SCOP, numerous exceptions were found to topological rules, along with complex evolutionary scenarios and peculiarities in proteins including the ability to fold into alternative structures. This article reviews cases of structural variations observed for individual proteins and among groups of homologues, knowledge of which is essential for protein structure modelling.


Skin test results and self-reported symptom severity in allergic rhinitis: The role of psychological factors.
In allergic conditions, the degree of skin test reactivity does not always correlate with the severity of clinical symptoms. Additional factors may contribute to the reported symptom severity. To investigate the association between the magnitude of the skin prick test (SPT) response and the reported symptom severity in patients with allergic rhinitis and the possible modifying role of psychological factors. One hundred four patients with allergic rhinitis and 23 with non-allergic rhinitis, classified according to their SPT response to 19 aeroallergens, were asked to rate the severity of five symptoms and to indicate whether their symptoms intensified on exposure to five common aeroallergens. They also completed a psychological questionnaire. Results Reported symptom severity of allergic rhinitis did not correlate with weal size for any of the aeroallergens tested or with the number of positive responses on SPT. It was not related to patient age, sex, or education. The reported symptoms severity correlated positively (0.29, P < 0.01) with reported symptom intensification on exposure to allergens. Moreover, both outcomes were positively associated with the psychological factors of hypochondriasis (0.20, P < 0.05 and 0.18, P < 0.05, respectively), and somatic awareness (0.24, P < 0.05 and 0.33, P < 0.01, respectively), but not with neuroticism. The severity of symptoms experienced by patients with allergic rhinitis is apparently not related to the magnitude of SPT response, but rather to psychological factors of hypochondriasis and somatic awareness. Physicians should be aware of the contribution of psychological factors to patient perceptions of the intensity of symptoms and of the intensification of symptoms on their exposure to allergens.


The first Korean case with Floating-Harbor syndrome with a novel SRCAP mutation diagnosed by targeted exome sequencing.
Floating-Harbor syndrome is a rare autosomal dominant genetic disorder associated with SRCAP mutation. To date, approximately 50 cases of Floating-Harbor syndrome have been reported, but none have been reported in Korea yet. Floating-Harbor syndrome is characterized by delayed bony maturation, unique facial features, and language impairment. Here, we present a 6-year-old boy with a triangular face, deep-set protruding eyes, low-set ears, wide nose with narrow nasal bridge, short philtrum, long thin lips, clinodactyly, and developmental delay that was transferred to our pediatric clinic for genetic evaluation. He showed progressive delay in the area of language and cognition-adaption as he grew. He had previously undergone chromosomal analysis at another hospital due to his language delay, but his karyotype was normal. We performed targeted exome sequencing, considering several syndromes with similar phenotypes. Library preparation was performed with the TruSight One sequencing panel, which enriches the sample for about 4,800 genes of clinical relevance. Massively parallel sequencing was conducted with NextSeq. An identified variant was confirmed by Sanger sequencing of the patient and his parents. Finally, the patient was confirmed as the first Korean case of Floating-Harbor syndrome with a novel SRCAP (Snf2 related CREBBP activator protein) mutation (c.7732dupT, p.Ser2578Phefs*6), resulting in early termination of the protein; it was not found in either of his healthy parents or a control population. To our knowledge, this is the first study to describe a boy with Floating-Harbor syndrome with a novel SRCAP mutation diagnosed by targeted exome sequencing in Korea.


Correction: Computational investigation of the increased virulence and pathogenesis of SARS-CoV-2 lineage B.1.1.7.
Correction for 'Computational investigation of the increased virulence and pathogenesis of SARS-CoV-2 lineage B.1.1.7' by N. Arul Murugan et al., Phys. Chem. Chem. Phys., 2022, 24, 20371-20380, https://doi.org/10.1039/D2CP00469K.


Natural language processing systems for capturing and standardizing unstructured clinical information: A systematic review.
We followed a systematic approach based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses to identify existing clinical natural language processing (NLP) systems that generate structured information from unstructured free text. Seven literature databases were searched with a query combining the concepts of natural language processing and structured data capture. Two reviewers screened all records for relevance during two screening phases, and information about clinical NLP systems was collected from the final set of papers. A total of 7149 records (after removing duplicates) were retrieved and screened, and 86 were determined to fit the review criteria. These papers contained information about 71 different clinical NLP systems, which were then analyzed. The NLP systems address a wide variety of important clinical and research tasks. Certain tasks are well addressed by the existing systems, while others remain as open challenges that only a small number of systems attempt, such as extraction of temporal information or normalization of concepts to standard terminologies. This review has identified many NLP systems capable of processing clinical free text and generating structured output, and the information collected and evaluated here will be important for prioritizing development of new approaches for clinical NLP.


Regulation of constitutive and induced NF-kappaB activation in malignant melanoma cells by capsaicin modulates interleukin-8 production and cell proliferation.
In the present study, we demonstrate that upregulation of interleukin-1beta(IL-1beta)-mediated and tumor necrosis factor-alpha (TNF-alpha)-mediated IL-8 expression in human malignant melanoma cells is modulated by the activation of nuclear factor-kappaB (NF-kappaB). Addition of capsaicin (8-methyl-N-vanillyl-6-nonenamide), a known inhibitor of NF-kappaB, resulted in the inhibition of constitutive as well as IL-1beta-induced and TNF-alpha-induced IL-8 expression in melanoma cells. The inhibition of IL-8 expression was dependent on the concentration of capsaicin and duration of treatment. Further, electrophoretic mobility shift assay (EMSA) of nuclear extracts from melanoma cells showed a constitutive activation of NF-kappaB and activated protein 1 (AP-1), which was upregulated following treatment with IL-1beta. Treatment of melanoma cells with capsaicin inhibited activation of constitutive and IL-1beta-induced NF-kappaB, but not AP-1, leading to inhibition of IL-8 expression. Further, downregulation of IL-8 expression in capsaicin-treated melanoma cells resulted in inhibition of in vitro cell proliferation. These results demonstrate that constitutive and induced NF-kappaB activation regulates IL-8 expression in melanoma cells. Downregulation of constitutive and induced NF-kappaB activation in malignant melanoma cells leads to inhibition of IL-8 production and in vitro cell proliferation.


Comparative genomic analysis of duplicated homoeologous regions involved in the resistance of Brassica napus to stem canker.
All crop species are current or ancient polyploids. Following whole genome duplication, structural and functional modifications result in differential gene content or regulation in the duplicated regions, which can play a fundamental role in the diversification of genes underlying complex traits. We have investigated this issue in Brassica napus, a species with a highly duplicated genome, with the aim of studying the structural and functional organization of duplicated regions involved in quantitative resistance to stem canker, a disease caused by the fungal pathogen Leptosphaeria maculans. Genome-wide association analysis on two oilseed rape panels confirmed that duplicated regions of ancestral blocks E, J, R, U, and W were involved in resistance to stem canker. The structural analysis of the duplicated genomic regions showed a higher gene density on the A genome than on the C genome and a better collinearity between homoeologous regions than paralogous regions, as overall in the whole B. napus genome. The three ancestral sub-genomes were involved in the resistance to stem canker and the fractionation profile of the duplicated regions corresponded to what was expected from results on the B. napus progenitors. About 60% of the genes identified in these duplicated regions were single-copy genes while less than 5% were retained in all the duplicated copies of a given ancestral block. Genes retained in several copies were mainly involved in response to stress, signaling, or transcription regulation. Genes with resistance-associated markers were mainly retained in more than two copies. These results suggested that some genes underlying quantitative resistance to stem canker might be duplicated genes. Genes with a hydrolase activity that were retained in one copy or R-like genes might also account for resistance in some regions. Further analyses need to be conducted to indicate to what extent duplicated genes contribute to the expression of the resistance phenotype.


Subcutaneous polypoid lipoma of the first intermetatarsal space mimicking rudimentary polydactyly.
A case of a subcutaneous polypoid lipoma, presenting as a rudimentary polydactyly, is reported. The lesion was located between the first and second digits and extended into the first intermetatarsal space in a polypoid fashion. Radiographically, there were no osseous structures associated with the mass, and preliminary biopsy results showed no evidence of malignancy. The patient was treated with marginal excision of the mass and reduction of the intermetatarsal space with a Mini TightRope (Arthrex, Inc., Naples, FL). The final pathological diagnosis was polypoid lipomas, and the patient experienced a full and uneventful recovery.


[Association between homozygous c.318A>GT mutation in exon 2 of the EIF2B5 gene and the infantile form of vanishing white matter leukoencephalopathy].
Vanishing white matter disease is one of the most frequent leukodystrophies in childhood with an autosomal recessive inheritance. A mutation in one of the genes encoding the five subunits of the eukaryotic initiation factor 2 (EIF2B5) is present in 90% of the cases. The diagnosis can be accomplished by the clinical and neuroradiological findings and molecular tests. We describe a thirteen-month-old male with previous normal neurodevelopment, who was hospitalized for vomiting, hyperthermia and irritability. On examination, cephalic perimeter and cranial pairs were normal. Hypotonia, increased muscle stretching reflexes, generalized white matter hypodensity on cranial tomography were found. Fifteen days after discharge, he suffered minor head trauma presenting drowsiness and focal seizures. Magnetic resonance showed generalized hypointensity of white matter. Vanishing white matter disease was suspected, and confirmed by sequencing of the EIF2B5 gene, revealing a homozygous c.318A> T mutation in exon 2. Subsequently, visual acuity was lost and cognitive and motor deterioration was evident. The patient died at six years of age due to severe pneumonia. This case contributes to the knowledge of the mutational spectrum present in Mexican patients and allows to extend the phenotype associated to this mutation.


Spontaneously Resolved Recurrent Cervical Epidural Hematoma in a 37-Week Primigravida.
Study Design Case report. Objective To describe a patient with a recurrent spontaneous spinal epidural hematoma (SSEH) during pregnancy that had spontaneous remission. Methods A 27-year-old primigravida at 37 weeks' gestation suddenly felt a strong left shoulder pain without any trauma. She had a history of fenestration for a spontaneous cervical hematoma when she was 18 years old. An emergency magnetic resonance imaging revealed a recurrence of the cervical epidural hematoma at the C4-T1 level, but she had no paralysis. Results The patient subsequently underwent a cesarean section and delivered a healthy male infant. Her spinal epidural hematoma disappeared. Multislice computed tomography showed no evidence for a vascular malformation or tumor. Three years after the initial cesarean section, she underwent a second one and delivered another male infant. Conclusions We report on a rare case of recurrent SSEH during pregnancy with no neurologic deficits that was treated nonoperatively with close observation and resulted in spontaneous resolution. In such patients with no neurologic deficits, nonoperative management with close observation may be a reasonable alternative.


Hypertension persisting after pre-eclampsia: a prospective cohort study at Mulago Hospital, Uganda.
Pre-eclampsia/eclampsia usually resolves after delivery but sometimes hypertension persists and cardiovascular disease develops later. Our objective was to determine the incidence and maternal socio-demographic and obstetric risk factors for persistence of hypertension in women with pre-eclampsia/eclampsia. This was a prospective cohort study conducted from July 2009 to June 2011 at Mulago Hospital labour ward and postnatal clinics. We followed up 188 women admitted with pre-eclampsia/eclampsia until 3 months after delivery. Data was collected using interviewer-administered questionnaires, examination of participants and review of medical records. Stata (version12) software was used for data analysis. Univariable analysis was used to compute the relative risk of persistent hypertension at the 95% confidence level. This was followed by multivariable logistic regression analysis to determine factors independently associated with persistence of hypertension. 64 (34%) out of the 188 women analysed had persistent hypertension three months after delivery. Maternal age, gestational age at delivery and parity were predictors of persistent hypertension. The proportion of women with pre-eclampsia/eclampsia at risk of persistent hypertension at three months after delivery was high, with nearly one of three mothers remaining hypertensive. Follow up of mothers who develop pre-eclampsia is important so that early diagnosis and management of chronic hypertension can be made to avoid long term morbidity and mortality.


The site of the stimulatory action of vasopressin on sodium transport in toad bladder.
Vasopressin increases the net transport of sodium across the isolated urinary bladder of the toad by increasing the mobility of sodium ion within the tissue. This change is reflected in a decreased DC resistance of the bladder; identification of the permeability barrier which is affected localizes the site of action of vasopressin on sodium transport. Cells of the epithelial layer were impaled from the mucosal side with glass micropipettes while current pulses were passed through the bladder. The resulting voltage deflections across the bladder and between the micropipette and mucosal reference solution were proportional to the resistance across the entire bladder and across the mucosal or apical permeability barrier, respectively. The position of the exploring micropipette was not changed and vasopressin was added to the serosal medium. In 10 successful impalements, the apical permeability barrier contributed 54% of the initial total transbladder resistance, but 98% of the total resistance change following vasopressin occurred at this site. This finding provides direct evidence that vasopressin acts to increase ionic mobility selectively across the apical permeability barrier of the transporting cells of the toad bladder.


Nascent RNA kinetics: Transient and steady state behavior of models of transcription.
Regulation of transcription is a vital process in cells, but mechanistic details of this regulation still remain elusive. The dominant approach to unravel the dynamics of transcriptional regulation is to first develop mathematical models of transcription and then experimentally test the predictions these models make for the distribution of mRNA and protein molecules at the individual cell level. However, these measurements are affected by a multitude of downstream processes which make it difficult to interpret the measurements. Recent experimental advancements allow for counting the nascent mRNA number of a gene as a function of time at the single-cell level. These measurements closely reflect the dynamics of transcription. In this paper, we consider a general mechanism of transcription with stochastic initiation and deterministic elongation and probe its impact on the temporal behavior of nascent RNA levels. Using techniques from queueing theory, we derive exact analytical expressions for the mean and variance of the nascent RNA distribution as functions of time. We apply these analytical results to obtain the mean and variance of nascent RNA distribution for specific models of transcription. These models of initiation exhibit qualitatively distinct transient behaviors for both the mean and variance which further allows us to discriminate between them. Stochastic simulations confirm these results. Overall the analytical results presented here provide the necessary tools to connect mechanisms of transcription initiation to single-cell measurements of nascent RNA.


Different truncation methods of AUC between Japan and the EU for bioequivalence assessment: influence on the regulatory judgment.
In regulatory guidelines for bioequivalence (BE) assessment, the definitions of AUC for primary assessment are different in ICH countries, i.e., AUC from zero to the last sampling point (AUCall) in Japan, AUC from zero to infinity (AUCinf) or AUC from zero to the last measurable point (AUClast) in the US, and AUClast in the EU. To assure sufficient accuracy of truncated AUC for BE assessment, the ratio of truncated AUC (AUCall or AUClast) to AUCinf should be more than 80% both in Japanese and EU guidelines. We investigated how the difference in the definition of truncated AUC affects BE assessment of sustained release (SR) formulation. Our simulation result demonstrated that AUCall/AUCinf could be ≥80% despite AUClast/AUCinf being <80% and AUCall failed to detect formulation difference. In Japanese package inserts of generic drugs in SR formulation, there were products for which AUCall/AUCinf was ≥80% though AUClast/AUCinf was <80%. In conclusion, it was confirmed that the difference in definition of truncated AUC affected the judgment of validity of truncated AUC for BE assessment, and AUCall could fail to detect the substantially different in vivo dissolution profile of generic drugs with SR formulation from the original drug.


A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study.
dl-Methylphenidate (MPH) has been widely used to treat attention-deficit/hyperactivity disorder (ADHD) for the last half century. It had been exclusively available in the racemic form, i.e., a 50:50 mixture of d- and l-isomers. However, a single enantiomer formulation, d-MPH (dexmethylphenidate), became available for general clinical use in 2002. For this reason, the intrinsic pharmacological differences in the effects of d- and l-MPH have recently come under intense investigation. The primary therapeutic effects of MPH are generally recognized to reside in the d-isomer. The present investigation provides quantitative values for a broad range of receptor-level interactions of the individual MPH isomers to better characterize the distinction between dl-MPH versus d-MPH versus l-MPH as it relates to binding affinity at sites associated with relevant central nervous system (CNS) pharmacology, as well as peripheral physiology. Overall, there were few differences in binding affinities between d-MPH and the racemate whereas there were more apparent differences between d-MPH and l-MPH. d-MPH exhibited prominent affinity at the norepinephrine transporter (NET) site, even exceeding such affinity at the dopamine transporter (DAT). These results further demonstrate that affinity for catecholaminergic sites largely resides in the d-MPH isomer. Although binding affinity was not demonstrable at the serotonin (5-HT) transporter site (SERT), novel findings of the study included affinity for the 5-HT1A and 5-HT2B receptor sites for both d- and l-MPH, with d-MPH exerting by far the most predominant effects at these sites. Thus, the emerging data of favorable therapeutic effects of ADHD treatment with d-MPH (and dl-MPH) may be underpinned by affinity and potential pharmacologic effects at NET and DAT sites, as well as sites relevant to serotonergic neurotransmission that may modulate mood, cognition, and motor behavior. However, the present exploratory studies reflect receptor binding affinities only. The specific pharmacological activities (i.e., agonism vs. antagonism) of these compounds await further exploration.


Expanding the use of arsenic trioxide: leukemias and beyond.
Arsenic has a long history of use in Chinese and Western medicine but fell out of use in the mid-20th century because of the unacceptable side effects that occurred at the doses that were thought to be necessary. The re-emergence of arsenic trioxide (ATO) in clinical use is due largely to purification of this compound from traditional mixtures, and the definition of effective, low-dose regimens for the treatment of acute promyelocytic leukemia (APL). ATO was first purified and used in controlled studies in patients with APL in China in the 1970s. Studies have subsequently also been performed in the United States. Complete response (CR) rates reported in patients with relapsed or refractory APL have varied from 52% to 92%, with similar rates reported in patients with newly diagnosed disease. The mechanism of action of ATO suggests it may be active against other malignancies, and ATO has shown some activity in patients with accelerated phase chronic myelogenous leukemia (CML) and multiple myeloma (MM). Clinical trials are ongoing and planned to define the optimal use of this compound in hematologic malignancies. Preliminary results from studies in patients with primary hepatocellular and gallbladder tumors indicate that ATO may also prove active against some solid tumors.


Gender differences in reward and punishment for monetary and social feedback in children: An ERP study.
Gender differences in feedback processing have been observed among adolescents and adults through event-related potentials. However, information on whether and how this feedback processing is affected by feedback valence, feedback type, and individual sensitivity in reward/punishment among children remains minimal. In this study, we used a guessing game task coupled with electroencephalography to investigate gender differences in feedback processing, in which feedback to reward and punishment was presented in the context of monetary and social conditions. Results showed that boys were less likely to switch their response after punishment, had generally less feedback-related negativity (FRN) amplitude, and longer FRN latency in monetary and punishment conditions than girls. Moreover, FRN for monetary punishment, which is related to individual difference in reward sensitivity, was observed only in girls. The study provides gender-specific evidence for the neural processing of feedback, which may offer educational guidance for appropriate feedback for girls and boys.


Effect of Intralipid infusion on peripheral blood T cells and plasma cytokines in women undergoing assisted reproduction treatment.
Intravenous infusion of Intralipid is an adjunct therapy in assisted reproduction treatment (ART) when immune-associated infertility is suspected. Here, we evaluated the effect of Intralipid infusion on regulatory T cells (Treg cells), effector T cells and plasma cytokines in peripheral blood of women undertaking IVF. This prospective, observational pilot study assessed Intralipid infusion in 14 women exhibiting recurrent implantation failure, a clinical sign of immune-associated infertility. Peripheral blood was collected immediately prior to and 7 days after intravenous administration of Intralipid. Plasma cytokines were measured by Luminex, and T-cell subsets were analysed by flow cytometry. A small increase in conventional CD8+ T cells occurred after Intralipid infusion, but no change was seen in CD4+ Treg cells, or naïve, memory or effector memory T cells. Proliferation marker Ki67, transcription factors Tbet and RORγt, and markers of suppressive capacity CTLA4 and HLA-DR were unchanged. Dimensionality-reduction analysis using the tSNE algorithm confirmed no phenotype shift within Treg cells or other T cells. Intralipid infusion increased plasma CCL2, CCL3, CXCL8, GM-CSF, G-CSF, IL-6, IL-21, TNF and VEGF. Intralipid infusion elicited elevated pro-inflammatory cytokines, and a minor increase in CD8+ T cells, but no change in pro-tolerogenic Treg cells. Notwithstanding the limitation of no placebo control, the results do not support Intralipid as a candidate intervention to attenuate the Treg cell response in women undergoing ART. Future placebo-controlled studies are needed to confirm the potential efficacy and clinical significance of Intralipid in attenuating cytokine induction and circulating CD8+ T cells.


Sigma(s)-dependent regulation of yehZYXW, which encodes a putative osmoprotectant ABC transporter of Escherichia coli.
The Escherichia coli yehZYXW operon encodes a putative osmoprotectant uptake system of the ABC transporter family. yehZ is identical to osmF, an osmotically inducible gene identified previously. Construction and analysis of a yehZ-lacZ transcriptional fusion demonstrated that yehZ is inducible not only by osmolarity, but also upon entry into stationary phase. The osmotic and growth-phase regulations operate at a unique promoter, yehZp, and are totally dependent on the stress specific sigma factor sigma(s). The yehZYXW encoded ABC transporter appears as an additional element of the global stress response controlled by sigma(s).


Comparison of second-trimester maternal serum free-beta-human chorionic gonadotropin and alpha-fetoprotein between normal singleton and twin pregnancies: a population-based study.
The second-trimester maternal serum screening in twin pregnancy is still controversial, as the serum marker levels in twins are not as clear as those in singletons. This study aimed to evaluate the relationship between the levels of the second-trimester maternal serum free beta-human chorionic gonadotropin (free beta-HCG) and alpha-fetoprotein (AFP) in normal twin and singleton pregnancies and to estimate feasible analysis methods for utilizing these markers in second trimester screening for twin pregnancy. On the basis of a prospective population-based study of second-trimester maternal serum screening, the concentrations of maternal serum AFP and free beta-HCG of 195 normal twin pregnancy and 26,512 singleton controls at gestational weeks 15 to 20 were measured by time-resolved fluoroimmunoassay in one laboratory. The levels of markers were compared between the twins and singletons using weight-correction and gestational age-specific model. According to the research protocol, 95 communities were randomly sampled, which covered the whole Jiangsu province, the east of China. A total of 26 803 pregnant women (98%), from the target population accepted prenatal screening for maternal serum AFP, beta-HCG detection, and all babies were followed up for at least six months. There were 197 (0.73%) twin pregnancies, of which one case had fetal trisomy 18, and one case with fetal anencephaly. The others were normal twin pregnancy. From a total enrollment of 26 803 women participants, 26 512 women with normal singleton pregnancies were selected as the model controls. The other 291 pregnancies, including trisomy 21, neural tube defect (NTD), trisomy 18, and other fetal abnormalities, were excluded. No significant differences were found in the medians of gestational age-specific maternal serum free beta-hCG and AFP in normal twin pregnancy comparing with twice those in model controls with the exception of the medians for free beta-hCG during the 16th gestational week (P = 0.012). The weight-correction and gestational age-specific levels of Chinese Han population maternal serum free beta-hCG and AFP in normal twins were twice the levels as those in the singleton controls during the 17-19 gestational weeks.


Melting of copper and nickel at high pressure: the role of d electrons.
Melting curves of Cu and Ni were measured in the laser-heated diamond cell to 97 GPa (3800 K) and 60 GPa (2970 K), respectively. The temperatures of Cu are in good agreement with recent theoretical calculations. The Cu melting slope (dT/dP) is about 2.5 times steeper than for Ni. The present results confirm the key role d-shell electrons play in determining the temperature dependence of high pressure melting curves in transition metals that have filled or partially filled d electron bands.


The effects of partial sleep restriction and altered sleep timing on olfactory performance.
Olfaction can increase the drive to eat and may partially explain the consistent increases in energy intake (EI) following sleep restriction. We investigated the effects of 50% sleep restriction with altered sleep timing on olfactory performance. We also evaluated whether changes (Δ) in olfactory performance were associated with Δ24 h EI. Twelve men and six women (age: 23±4 years; BMI: 23±3 kg/m2) completed three randomized cross-over conditions: habitual sleep duration, 50% sleep restriction with advanced wake-time, and 50% sleep restriction with delayed bedtime. Sleep was measured in-laboratory (polysomnography). Olfactory performance ('sniffin sticks') and 24 h EI (food menu) were evaluated the next day. A trend for a significant condition*sex interaction was noted for threshold-discrimination-identification (TDI) scores (P=0.09); TDI scores were lowest in women and highest in men, following sleep restriction with advanced wake-time. Δolfactory performance were not associated with Δ24 h EI. The impact of sleep restriction on olfactory performance may differ between sexes. Changes in olfactory performance were not associated with changes in 24 h EI. Studies investigating prolonged effects of sleep loss on the relationship between olfactory performance with EI are needed.


Postoperative adjuvant chemotherapy in non-small cell lung cancer: prognostic value of DNA ploidy and post-recurrent survival.
Eighty-six patients with non-small cell lung cancer who underwent curative operations were postoperatively randomized to control and adjuvant chemotherapy groups. In the adjuvant chemotherapy group, patients received cisplatin-based combination chemotherapy 3 or 4 weeks after operation and the average cycle of chemotherapy was 2.3 (from 1 to 6 cycles). In this trial, no evidence of improved survival or delayed recurrence was seen in the treated patients. In multivariate analysis of prognostic variables, the most important factor was the pathological stage of the disease and, second, DNA ploidy of the primary tumor. Although histology (squamous vs. non-squamous cell carcinoma) had a trend to influence the survival, it was not a significant factor. A total of 33 patients had recurrences: 17 and 16 patients were in control and adjuvant chemotherapy groups, respectively. Postrecurrent survival in the adjuvant chemotherapy group was significantly shorter than that in the control group, as determined by the generalized Wilcoxon and log rank tests. Median survival time after recurrence in the control and adjuvant therapy groups was 18.5 and 7.5 months, respectively. These results suggest that DNA ploidy of primary tumors should be considered as a prognostic factor in future trials of adjuvant therapy. Furthermore, analysis of postrecurrent survival in the adjuvant chemotherapy trial, as well as that of overall and disease-free survivals should be done.


Inadvertent hypothermia: a literature review.
While working on my first placement in the operating department recovery room, I was surprised by the frequency of patients coming into recovery with mild hypothermia, having taken their temperature on arrival. In many cases the patient did not arrive with a forced-air warming blanket, or any device other than a cotton blanket. It seemed to me that it would be more efficient, kinder and possibly more cost-effective to takesteps to prevent perioperative hypothermia rather than to treat the consequences.


Identifying cryptic population structure in multigenerational pedigrees in a Mexican American sample.
Cryptic population structure can increase both type I and type II errors. This is particularly problematic in case-control association studies of unrelated individuals. Some researchers believe that these problems are obviated in families. We argue here that this may not be the case, especially if families are drawn from a known admixed population such as Mexican Americans. We use a principal component approach to evaluate and visualize the results of three different approaches to searching for cryptic structure in the 20 multigenerational families of the Genetic Analysis Workshop 18 (GAW18). Approach 1 uses all family members in the sample to identify what might be considered "outlier" kindreds. Because families are likely to differ in size (in the GAW18 families, there is about a 4-fold difference in the number of typed individuals), approach 2 uses a weighting system that equalizes pedigree size. Approach 3 concentrates on the founders and the "marry-ins" because, in principle, the entire pedigree can be reconstructed with knowledge of the sequence of these unrelated individuals and genome-wide association study (GWAS) data on everyone else (to identify the position of recombinations). We demonstrate that these three approaches can yield very different insights about cryptic structure in a sample of families.


[Optimal immunosuppressive therapy based on pharmacokinetics and pharmacodynamics of antimetabolites in clinical practice].
An immunosuppressive antimetabolite, mycophenolate mofetil (MMF), has been widely used in combination with a calcineurin inhibitor for organ transplantation and autoimmune diseases. A fixed dosing of MMF often causes bone marrow toxicity or cytomegalovirus antigenemia under the optimal dosing of calcineurin inhibitors. Pharmacokinetic characteristics of MMF and its relation to the degree of immune suppression have not been fully clarified in clinical practice. This review summarizes our achievements on pharmacokinetic disposition of mycophenolic acid (MPA) and inosine 5'-monophosphate dehydrogenase (IMPDH) activity in patients with kidney transplantation and with lupus nephritis. Contribution of enterohepatic recirculation to plasma disposition of MPA in lupus nephritis patients was similar to that in tacrolimus-treated kidney transplant recipients. MPA pharmacokinetics in lupus nephritis was characterized by high MPA clearance most likely due to better renal function. In addition, concomitant metal cation decreased MPA concentration in patients receiving tacrolimus but not cyclosporine. This interaction may depend on amount of biliary-excreted MPA glucuronide. Renal clearance of MPA was higher in cyclosporine- than tacrolimus-treated patients. Its ratio to creatinine clearance was much higher than unbound fraction of MPA in each calcineurin inhibitor treatment. These kinetic data revealed the presence of renal tubular secretion in the urinary excretion process. In multivariate analysis, the plasma disposition of MPA and its glucuronides affected IMPDH activity in erythrocytes. The IMPDH activity might be a useful marker reflecting a long-term exposure by MPA. Our findings in this review would contribute to optimal dosing of MMF in immunosuppressive regimen including a calcineurin inhibitor.


New findings on thymic epithelial tumors: Something is changing.
Thymic epithelial tumors (TETs) are uncommon neoplasms with a wide range of anatomical, clinical, histological and molecular malignant entities. To date the management of TETs within clinical practice is based on a multimodal therapeutic strategy including surgery, chemotherapy and radiotherapy with a multidisciplinary approach and prognostic evaluation is mainly based on Masaoka staging and World Health Organization classification. Therefore novel strategies are needed, especially for refractory and/or recurrent TETs and for thymic carcinomas that present a poor prognosis. Personalized approaches are currely being developed and molecular targets are emerging from recent integrated genomic analyses. Targeted therapy will represent an important treatment option for TETs with an aggressive histology. To date, data indicate that vascular endothelial growth factor molecules, insulin-like growth factor 1 receptor, cyclin-dependent kinases and mammalian target of rapamycin may be potentially useful as targeted biological therapies.


Clinical indication for intraoperative 3D imaging during open reduction of fractures of the mandibular angle.
This retrospective study investigated 3-dimensional (3D) imaging with intraoperative Cone-Beam Computed Tomography (CBCT) in Mandibular Angle Fractures (MAF) treated by open reduction. The aim of this study was to demonstrate the image quality of intraoperative CBCT in this region and the benefit for the patients. 83 patients with 86 MAF were included in this study. 8 patients were female and 75 male. Patient age ranged from 11 to 68 years (average age 26.8 years). All patients were examined with the mobile CBCT scanner ARCADIS Orbic 3D (Siemens Medical Solutions, Erlangen, Germany) directly after surgical treatment of the MAF. As a direct result of intraoperative CBCT four patients (5%) underwent intraoperative revision. The intraoperative acquisition of the data sets was uncomplicated and in all cases it was possible to effectively visualise and assess the MAF in 3D quality. The results showed that intraoperative CBCT is a reliable imaging technique for real-time intraoperative assessment of treated MAF. Use of the mobile 3D CBCT scanner is easy to integrate into routine practice and offers the advantage that immediate revision surgery can be performed.


Rare presentation of the cutaneous metastasis of colon cancer imitating herpes zoster.
The cutaneous metastasis of colon cancer is rare, and most commonly manifests as nodules or masses. In the case of our patient, a rarely described vesiculomaculopapular rash resembling herpes zoster was observed and treated as such; however, biopsy later revealed metastatic colonic adenocarcinoma. Metastasis of colon cancer to the skin typically confers a poor prognosis, however, early identification may allow for quicker intervention and more aggressive treatments, that may extend survival. Given the immunocompromised state of cancer patients undergoing antineoplastic therapy, a herpes zoster eruption would not be unexpected, but an astute primary care provider should keep metastatic disease in their differential.


Value of mucosal biopsies in the monitoring of acute small bowel rejection.
The value of mucosal biopsies in evaluating small bowel rejection is controversial. In this study, the value of mucosal biopsies was estimated in unmodified porcine small bowel rejection. Ten animals received the distal half of the small bowel as a heterotopic loop (Thiry-Vella loop). The allografts were followed by proximally and distally harvested full-thickness and mucosal biopsies every other day, starting from the 3rd day and continuing until the grafts became necrotic. The histological parameters in both types of biopsies were semiquantitatively scored from 0 to 3 and compared with each other. The difference in mean values on the subsequent days was not remarkable, the results favoring slightly higher values in full-thickness than in mucosal biopsies. Our results suggest that multiple mucosal biopsies are adequate in monitoring morphological changes of small bowel grafts during rejection and that the proximal and distal ileum are similarly affected by acute rejection.


The addition of silica nanoparticles on the mechanical properties of dental stone.
The current application of nanotechnology in dentistry is limited to nanoparticles incorporated into adhesive systems and composite resins. Dental stone is a widely used material, and the incorporation of silica nanoparticles is still unexplored. The purpose of this in vitro study was to evaluate the mechanical properties of dental stone after the addition of silica nanoparticles in different concentrations. A total of 180 specimens were prepared, 90 for each dental stone (Durone and Fuji Rock). For the control group (CG), no silica particles were added, while test group TGnI had silica nanoparticles added to 1 wt%, and test group TGnV had silica nanoparticles added to 5 wt%. The roughness, diametral tensile strength (DTS), and compressive strength were measured 24 hours after the start of spatulation. The mean roughness values for Durone were 0.55, 0.36, and 0.28 μm for CG, TGnI, and TGnV; for Fuji Rock, the mean roughness values were 0.47 for CG, 0.31 for TGnI, and 0.35 μm for TGnV. The mean DTS values for Durone were 6.0, 5.1, and 5.0 MPa for CG, TGnI, and TGnV, respectively, and for Fuji Rock, the mean DTS values were 6.4, 5.2, and 4.5 MPa for CG, TGnI, and TGnV, respectively. The mean compressive strength values for Durone were 35.4, 32.7, and 32.4 MPa for CG, TGnI, and TGnV, respectively, and for Fuji Rock, the mean compressive strength values were 42.9, 31.2, and 29.8 MPa for CG, TGnI, and TGnV respectively. Surface roughness was statistically lower for the Durone and Fuji Rock stones (P<.001) when silica nanoparticles were added. The addition of silica nanoparticles did not significantly affect the DTS and compressive strength of Durone compared with CG (P>.05) but did affect the DTS of Fuji Rock when 5 wt% was added and the compressive strength in both concentrations (P<.05).


Carcinoma of the small bowel. A complication of regional enteritis.
The 35th and 36th cases of adenocarcinoma arising in small bowel affected with regional enteritis are presented. The pathology of all reported cases is reviewed. An association between regional enteritis and carcinoma of the small bowel is suggested.


Glycyrrhizic acid suppresses the development of precancerous lesions via regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats.
Colon carcinogenesis is a multistep process and it emanates from a series of molecular and histopathological alterations. Glycyrrhizic acid (GA) is a natural and major pentacyclic triterpenoid glycoside of licorice roots extracts. It has several pharmacological and biological properties such as anti-inflammatory, anti-viral, and anti-cancer. In the present study, we investigated the chemopreventive potential of GA against 1,2-dimethyhydrazine (DMH)-induced precancerous lesions i.e., aberrant crypt foci (ACF) and mucin depleted foci (MDF), and its role in regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats. Animals were divided into 5 groups. In group III, IV and V, GA was administered at the dose of 15 mg/kg b. wt. orally while in group II, III and IV, DMH was administered subcutaneously in the groin at the dose of 20 mg/kg b.wt once a week for first 5 weeks and animals were euthanized after 9 weeks. GA supplementation suppressed the development of precancerous lesions and it also reduced the infiltration of mast cells, suppressed the immunostaining of Ki-67, NF-kB-p65, COX-2, iNOS and VEGF while enhanced the immunostaining of p53, connexin-43, caspase-9 and cleaved caspase-3. GA treatment significantly attenuated the level of TNF-α and it also reduced the depletion of the mucous layer as well as attenuated the shifting of sialomucin to sulphomucin. Our findings suggest that GA has strong chemopreventive potential against DMH-induced colon carcinogenesis but further studies are warranted to elucidate the precise mechanism of action of GA.


An audit of intrathecal morphine analgesia for non-obstetric postsurgical patients in an adult tertiary hospital.
We conducted a retrospective audit of adult non-obstetric patients who had received a single dose of intrathecal morphine for postoperative analgesia. These patients were predominantly admitted to a regular postsurgical ward with strict hourly nursing observations, treatment protocols in place and supervision by an Acute Pain Service for the first 24 hours after intrathecal morphine administration. A total of 409 cases were examined for sedation score, incidence of respiratory depression and other side-effects, admission to the high dependency or intensive care unit and opioid-tolerance. Respiratory depression was defined as requiring treatment with naloxone (implying a sedation score of 3 irrespective of respiratory rate), or a sedation score of 2 with a respiratory rate less than six breaths per minute. The patients were predominantly elderly (57.2% were over the age of 70 years) and 84.8% had undergone vascular surgery. Of the total of 409 cases, only one case of respiratory depression was observed. A total of 77 patients were admitted to high dependency or intensive care unit for various reasons including management of postsurgical complications and patient co-morbidities. Our findings suggest that elderly patients who receive intrathecal morphine analgesia can be safely managed in a regular postsurgical ward.


Sex differences in the acute locomotor response to methamphetamine in BALB/c mice.
Women use methamphetamine more frequently than men and are more vulnerable to its negative psychological effects. Rodent models have been an essential tool for evaluating the sex-dependent effects of psychostimulants; however, evidence of sex differences in the behavioral responses to methamphetamine in mice is lacking. In the present study, we investigated acute methamphetamine-induced (1mg/kg and 4mg/kg) locomotor activation in female and male BALB/c mice. We also evaluated whether basal locomotor activity was associated with the methamphetamine-induced locomotor response. The results indicated that female BALB/c mice displayed enhanced methamphetamine-induced locomotor activity compared to males, while basal locomotor activity was positively correlated with methamphetamine-induced activity in males, but not females. This study is the first to show sex-dependent locomotor effects of methamphetamine in BALB/c mice. Our observations emphasize the importance of considering sex when assessing behavioral responses to methamphetamine.


Pregnancy, fetal, and neonatal outcomes after a first booster dose of covid-19 vaccine during pregnancy in Ontario, Canada: population based, retrospective cohort study.
To assess risk of adverse pregnancy, fetal, and neonatal outcomes after a third dose (first booster dose) of covid-19 vaccine during pregnancy among individuals who had completed both doses of primary covid-19 vaccine series before pregnancy. Population based, retrospective cohort study. Ontario, Canada, from 20 December 2021 to 31 August 2022. Individuals were included if they were pregnant with an expected date of delivery from 20 December 2021 (start date of third dose eligibility for everyone ≥18 years) to 31 August 2022, who had completed the two doses of primary covid-19 messenger RNA vaccine series before pregnancy, and became eligible for a third dose (≥six months since dose two) before the end of pregnancy. Pregnancy outcomes included hypertensive disorders of pregnancy, placental abruption, caesarean delivery, chorioamnionitis, and postpartum hemorrhage. Fetal and neonatal outcomes included stillbirth, preterm birth, admission to neonatal intensive care unit for >24 h, newborn 5 min Apgar score <7, and small-for-gestational age infant (<10th percentile). We estimated hazard ratios and 95% confidence intervals for study outcomes, treating dose three as a time varying exposure and adjusting for confounding using inverse probability weighting. Among 32 689 births, 18 491 (56.6%) were born to individuals who received a third covid-19 dose during pregnancy. Compared with eligible individuals who did not receive a third dose during pregnancy, no increased risks were associated with receiving a third covid-19 vaccine dose during pregnancy for placental abruption (adjusted hazard ratio 0.84 (95% confidence interval 0.70 to 1.02)), chorioamnionitis (0.67 (0.49 to 0.90)), postpartum haemorrhage (1.01 (0.89 to 1.16)), caesarean delivery (0.90 (0.87 to 0.94)), stillbirth (0.56 (0.39 to 0.81)), preterm birth (0.91 (0.84 to 0.99)), neonatal intensive care unit admission (0.96 (0.90 to 1.03)), 5 min Apgar score<7 (0.96 (0.82 to 1.14)), or small-for-gestational age infant (0.86 (0.79 to 0.93)). Receipt of a third covid-19 vaccine dose during pregnancy was not associated with an increased risk of adverse pregnancy, fetal, or neonatal outcomes. These findings can help to inform evidence based decision making about the risks and benefits of covid-19 booster doses during pregnancy.


Single-nucleotide variants in human RNA: RNA editing and beyond.
Through analysis of paired high-throughput DNA-Seq and RNA-Seq data, researchers quickly recognized that RNA-Seq can be used for more than just gene expression quantification. The alternative applications of RNA-Seq data are abundant, and we are particularly interested in its usefulness for detecting single-nucleotide variants, which arise from RNA editing, genomic variants and other RNA modifications. A stunning discovery made from RNA-Seq analyses is the unexpectedly high prevalence of RNA-editing events, many of which cannot be explained by known RNA-editing mechanisms. Over the past 6-7 years, substantial efforts have been made to maximize the potential of RNA-Seq data. In this review we describe the controversial history of mining RNA-editing events from RNA-Seq data and the corresponding development of methodologies to identify, predict, assess the quality of and catalog RNA-editing events as well as genomic variants.


Heparan Sulfate Mimetics: A New Way to Optimize Therapeutic Effects of Hydrogel-Embedded Mesenchymal Stromal Cells in Colonic Radiation-Induced Damage.
Clinical expression of gastrointestinal radiation toxicity on non-cancerous tissue could be very life threatening and clinicians must deal increasingly with the management of late side effects of radiotherapy. Cell therapy, in particular mesenchymal stromal cell (MSC) therapy, has shown promising results in numerous preclinical animal studies and thus has emerged as a new hope for patient refractory to current treatments. However, many stem cell clinical trials do not confer any beneficial effect suggesting a real need to accelerate research towards the successful clinical application of stem cell therapy. In this study, we propose a new concept to improve the procedure of MSC-based treatment for greater efficacy and clinical translatability. We demonstrated that heparan sulfate mimetic (HS-m) injections that restore the extracellular matrix network and enhance the biological activity of growth factors, associated with local injection of MSC protected in a hydrogel, that increase cell engraftment and cell survival, improve the therapeutic benefit of MSC treatment in two animal models relevant of the human pathology. For the first time, a decrease of the injury score in the ulcerated area was observed with this combined treatment. We also demonstrated that the combined treatment favored the epithelial regenerative process. In this study, we identified a new way, clinically applicable, to optimize stem-cell therapy and could be proposed to patients suffering from severe colonic defect after radiotherapy.