Chrysin Modulates Aberrant Epigenetic Variations and Hampers Migratory Behavior of Human Cervical (HeLa) Cells.
Purpose: Plant-derived phytochemicals have shown epigenetic modulatory effect in different types of cancer by reversing the pattern of DNA methylation and chromatin modulation, thereby restoring the function of silenced tumor-suppressor genes. In the present study, attempts have been made to explore chrysin-mediated epigenetic alterations in HeLa cells. Methods: Colony formation and migration assays followed by methylation-specific PCR for examining the methylation status of CpG promoters of various tumor-suppressor genes (TSGs) and the expression of these TSGs at the transcript and protein levels were performed. Furthermore, global DNA methylation; biochemical activities of DNA methyltransferases (DNMTs), histone methyl transferases (HMTs), histone deacetylases (HDACs), and histone acetyl transferases (HATs) along with the expression analysis of chromatin-modifying enzymes; and H3 and H4 histone modification marks analyses were performed after chrysin treatment. Results: The experimental analyses revealed that chrysin treatment encourages cytostatic behavior as well as inhibits the migration capacity of HeLa cells in a time- and dose-dependent manner. Chrysin reduces the methylation of various tumor-suppressor genes, leading to their reactivation at mRNA and protein levels. The expression levels of various chromatin-modifying enzymes viz DNMTs, HMTs, HDACs, and HATS were found to be decreased, and H3 and H4 histone modification marks were modulated too. Also, reduced global DNA methylation was observed following the treatment of chrysin. Conclusion: This study concludes that chrysin can be used as a potential epigenetic modifier for cancer treatment and warrants for further experimental validation.


Sensitivity of GABAergic Tonic Currents to Acute Ethanol in Cerebellar Granule Neurons is Not Age- or δ Subunit-Dependent in Developing Rats.
The age of first exposure to ethanol (EtOH), as well as reduced sensitivity to its motor-impairing effects, are associated with a future predisposition to abuse EtOH. In adolescence, acute EtOH potentiates GABA transmission, including tonic inhibition mediated by δ-containing extrasynaptic GABAA receptors (GABAA Rs) in cerebellar granule neurons (CGNs), an effect that likely contributes to EtOH-induced motor impairment. Prenatal EtOH exposure is strikingly prevalent and is associated with increased EtOH abuse later in life; however, the acute effects of EtOH on GABA transmission in developing CGNs are unknown. Using whole-cell patch-clamp electrophysiological techniques in acute brain slices, we examined the acute effects of EtOH on GABA transmission and functionally assessed the role of δ-containing GABAA Rs in CGNs of preweanling (postnatal day [P] 12 to 14) and postweanling (P28 to 30) male Sprague-Dawley rats. The magnitude of basal tonic currents were similar at both ages. However, 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride, an agonist with preferential affinity for δ-containing GABAA Rs, significantly potentiated tonic currents to a larger magnitude in CGNs from postweanlings compared to preweanlings. Conversely, acute application of EtOH (80 mM) significantly increased tonic currents and the frequency of spontaneous inhibitory postsynaptic currents to a similar extent in CGNs from pre- and postweanlings. These findings highlight the sensitivity of the developing cerebellum to EtOH. Furthermore, this study demonstrates age-dependent functional changes in a well-characterized circuitry that may contribute to the short- and long-term effects of prenatal exposure to EtOH.


Clinical Characteristics and Outcomes of Hyphema in Patients with Sickle Cell Trait: 10-Year Experience at the Wilmer Eye Institute.
To report the clinical characteristics, complications, and outcomes of hyphema in patients with sickle cell trait (SCT). Retrospective case series. Medical records of SCT patients (confirmed by hemoglobin electrophoresis) presenting with hyphema at the Wilmer Eye Institute over 10 years (January 2008 through December 2017) were reviewed in detail. Data were collected regarding etiology, demographics, clinical course and management. Main outcome measures included intraocular pressure (IOP) and visual acuity (VA). A total of 14 black patients (males: 57%; median age: 20 years) were included in the study with a median follow-up of 4 months (range: 1 week to 6 years). Ten patients had traumatic hyphema with a mean presenting VA of approximately 1.10 logMAR (Snellen equivalent=20/250) and a mean presenting IOP of 40 mmHg. Nine of them required medical intervention to lower IOP, and six of them ultimately required surgical intervention, primarily in the form of anterior chamber paracentesis and/or washout. The mean time to achieve IOP control was 3 days, and the mean final VA was approximately 0.10 logMAR (Snellen Equivalent=20/25). Four patients had non-traumatic hyphema with a mean presenting VA of approximately 1.8 logMAR (Snellen equivalent=20/1260) and a mean presenting IOP of 31 mmHg. Three of them required medical intervention to lower IOP, and two of them ultimately required surgical intervention. Overall, seven patients underwent anterior chamber washout, six needed an anterior chamber paracentesis to lower the IOP, two required tube shunt placement procedures and one patient underwent a trabeculectomy. The mean time to achieve IOP control was 5 days, and the mean final VA was approximately 0.80 logMAR (Snellen equivalent=20/125). Patients with SCT are likely to develop elevated IOP in the setting of hyphema, with a majority requiring one or more surgical interventions to achieve IOP control.


Adjunctive Rufinamide in Children with Lennox-Gastaut Syndrome: A Literature Review.
Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset, developmental epileptic encephalopathy, with different etiologies and co-morbidities. Seizure treatment in LGS represents a major challenge; new antiepileptic drugs (AEDs) are developed to especially address seizures resulting in high morbidity and mortality, such as drop seizures. Rufinamide (RFN) is one of the latest AEDs licensed for patients with LGS. Its mechanism of action involves sodium channels in a way that is unrelated to other AEDs. Here we discuss the use of adjunctive RFN in children and adolescents with LGS and its efficacy and safety profile, based on a systematic literature review. RFN shows a very favorable profile in terms of adverse events and drug-interactions in children. It is particularly effective on tonic-atonic seizures and spasms, impacting on the quality of life of the patients. Further studies are needed to clarify the interaction profile with the newest AEDs for LGS and to assess correlations between the etiology of LGS and drug response to individualize treatment and maximize efficacy.


Choice of Study Populations for Vaccines.
The natural history of cytomegalovirus (CMV) infection is complex. Individuals may experience primary infection, reactivation of latent infection, or reinfection with a new strain despite natural immunity. The ability of this virus to continue to replicate despite substantial immune responses is attributable to the many immune evasion genes encoded within its genome. Given this complex natural history and immunology, the design of clinical trials of CMV vaccines may require components not usually found in trials of vaccines designed to protect against viruses that cause only acute infections. In this article, we focus on specific aspects of clinical trial design that could be adopted to address the complexities of CMV infections. We consider women of childbearing age, toddlers, recipients of solid organ transplantation, and stem cell transplant patients, emphasizing the parallels between women and solid organ transplantation that could allow vaccines to be developed in parallel in both these patient groups. We emphasize the potential for studies of passive immunity to inform the selection of immunogens as candidates for active immunization and vice versa. We also illustrate how application of whole-genomic sequencing could document whether vaccines protect against reactivation or reinfection of CMV or both.


Nutritional aspects of malabsorption syndromes.
Therapy of the malabsorption syndrome centers on adequate diagnosis of the underlying pathology, with vigorous therapeutic efforts directed at correcting this and thereby preventing ongoing losses of nutrients. Dietary therapy includes a high-protein, high-calorie, low-fat diet often supplemented with MCTs in an effort to minimize steatorrhea. Water-soluble vitamin deficiency is rare, but supplementation with small daily doses is innocuous and probably should be prescribed. Significant fat-soluble vitamin deficiencies are seen more commonly and can be monitored by physical examination and the prothrombin time. Calcium, magnesium, and vitamin D deficiencies are more common than originally suspected. Adequate therapy requires monitoring of the serum calcium, magnesium, parathyroid hormone levels, and, optimally, 24-hour urinary collections for calcium. Supplementation of these mineral deficiencies requires ongoing close observation to prevent hypercalcemia. Iron deficiency can be easily diagnosed by available serum iron determination, and replacement with oral supplements is curative. Trace metal deficiencies occur, but our capabilities of detecting and treating them is still in its infancy. Figure 3 outlines our approach to the evaluation and treatment of the patients suspected of having the malabsorption syndrome.


The vitamin and mineral intake of a free-living young elderly Australian population in relation to total diet and supplementation practices.
Although there have been several studies of the nutritional intake and status of elderly sections of industrialized countries such as Britain, the United States and Australia, most of these studies relate to institutionalized elderly or those receiving social support such as meals-on-wheels. The study reported here presents the results of a dietary survey of a randomly selected group of free-living younger elderly residents of Adelaide, Australia. Mean intakes for most nutrients were equal to or above the recommended intakes. The proportion of subjects 'at risk' was not as high as reported for less able elderly groups but the nutrients 'at risk' were similar, namely: folate, calcium, vitamin B6, zinc, magnesium and copper. Comparisons with the results of two other random surveys of free-living elderly residents of Boston and Gothenburg showed some variation in total intakes especially amongst women but many similarities in the patterns of nutrient density and nutrients 'at risk'.


Examination of Genetic Susceptibility in Radiation-Associated Meningioma.
Previous epidemiological studies have demonstrated elevated susceptibility to ionizing radiation in some families, thus suggesting the presence of genetic components that conferred increased rate of radiation-associated meningioma (RAM). In this study, we exome-sequenced and investigated the segregation pattern of rare deleterious variants in 11 RAM pedigrees. In addition, we performed a rare-variant association analysis in 92 unrelated familial cases of RAM that were ancestry-matched with 88 meningioma-free controls. In the pedigree analysis, we found that each family carried mostly a unique set of rare deleterious variants. A follow-up pathway analysis of the union of the genes that segregated within each of the 11 pedigrees identified a single statistically significant (q value = 7.90E-04) "ECM receptor interaction" set. In the case-control association analysis, we observed no statistically significant variants or genes after multiple testing correction; however, examination of ontological categories of the genes that associated with RAM at nominal P values <0.01 identified biologically relevant pathways such as DNA repair, cell cycle and apoptosis. These results suggest that it is unlikely that a small number of highly penetrant genes are involved in the pathogenesis of RAM. Substantially larger studies are needed to identify genetic risk variants and genes in RAM.


Quantitative measurement of indomethacin crystallinity in indomethacin-silica gel binary system using differential scanning calorimetry and X-ray powder diffractometry.
Differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRPD) methods were developed for the quantitative analysis of the crystallinity of indomethacin (IMC) in IMC and silica gel (SG) binary system. The DSC calibration curve exhibited better linearity than that of XRPD. No phase transformation occurred in the IMC-SG mixtures during DSC measurement. The major sources of error in DSC measurements were inhomogeneous mixing and sampling. Analyzing the amount of IMC in the mixtures using high-performance liquid chromatography (HPLC) could reduce the sampling error. DSC demonstrated greater sensitivity and had less variation in measurement than XRPD in quantifying crystalline IMC in the IMC-SG binary system.


Indications, results, and complications of refractive corneal surgery with lasers.
Large numbers of patients are being treated for myopia, hyperopia, and astigmatism using the excimer laser. For many patients who are treated for myopia and hyperopia, the procedure is elective and these treatments remain investigational. The use of other lasers for refractive surgery is at an earlier stage, with human trials commencing for infrared lasers. Animal studies are being performed for pulsed picosecond and solid-state ultraviolet lasers. The indications for refractive treatment should be clearly defined, although the results of laser application remain the subject of investigation. Complications of laser application to the cornea occur in the immediate, short-term, and long-term posttreatment period. A continual improvement in refractive results along with a reduction in complications remains the goal of laser refractive research.


Antimicrobial susceptibility pattern of Vibrio cholerae O1 strains during two cholera outbreaks in Dar es Salaam, Tanzania.
To determine and compare the antimicrobial susceptibility patterns of Vibrio cholerae 01 strains, which were isolated in two cholera epidemics in 1997 and 1999 in Dar es Salaam. V. cholerae 01 strains isolated from patients with cholera in Dar es Salaam city during 1997 (94 isolates) and 1999 (87 isolates) were stored on nutrient agar slants at room temperature and antimicrobial susceptibility pattern was determined, using Kirby Bauer method. Department of Microbiology and Immunology, Muhimbili Medical Centre, Dar es Salaam, Tanzania. A total of 181 V. cholerae 01 strains were studied during two epidemic periods when tetracycline or erythromycin was used for treatment of patients with severe disease. Among the 94 V. cholerae 01 strains isolated in 1997; 98.6%, 93.6%, 83%, 81.9%, 36.2%, 35.5%, 3.2% were sensitive to ciprofloxacin, tetracycline, ampicillin, erythromycin, nalidixic acid, chloramphenicol and trimethoprim/sulphamethoxazole, respectively. Among the 87 V. cholerae 01 isolates collected in 1999, 100%, 58.6%, 46.0%, 46%, 47.1%, 19.5%, 3.4% were sensitive to ciprofloxacin, tetracycline, ampicillin, erythromycin, chloramphenicol, nalidixic acid and trimethoprim/sulphamethoxazole, respectively. Between 1997 and 1999, there was a significant increase in the proportion of V. cholerae 01 isolates resistant to tetracycline, ampicillin, nalidixic acid and to erythromycin but there was no change for susceptibility to ciprofloxacin and trimethoprim/sulphamethoxazole. Significant proportion of V. cholerae 01 strains in Dar es Salaam were resistant to commonly used antimicrobial agents during the two years of the study. Therefore, there is a great need to control the utilisation of antimicrobial agents in cholera control, in addition to continuing carrying out surveillance of antimicrobial resistance as a guide to choice of antimicrobial treatment. Rotational use of the available drugs with regular monitoring of susceptibility may contribute to continuing usefulness of such drugs.


Extension of the D3 dispersion coefficient model.
A new model, termed D4, for the efficient computation of molecular dipole-dipole dispersion coefficients is presented. As in the related, well established D3 scheme, these are obtained as a sum of atom-in-molecule dispersion coefficients over atom pairs. Both models make use of dynamic polarizabilities obtained from first-principles time-dependent density functional theory calculations for atoms in different chemical environments employing fractional atomic coordination numbers for interpolation. Different from the D3 model, the coefficients are obtained on-the-fly by numerical Casimir-Polder integration of the dynamic, atomic polarizabilities α(iω). Most importantly, electronic density information is now incorporated via atomic partial charges computed at a semi-empirical quantum mechanical tight-binding level, which is used to scale the polarizabilities. Extended statistical measures show that errors for dispersion coefficients with the proposed D4 method are significantly lower than with D3 and other, computationally more involved schemes. Alongside, accurate isotropic charge and hybridization dependent, atom-in-molecule static polarizabilities are obtained with an unprecedented efficiency. Damping function parameters are provided for three standard density functionals, i.e., TPSS, PBE0, and B3LYP, allowing evaluation of the new DFT-D4 model for common non-covalent interaction energy benchmark sets.


TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors.
(E)-5-(Pyrimidin-5-yl)-1,2,3,4,7,8-hexahydroazocine (TC299423) is a novel agonist for nicotinic acetylcholine receptors (nAChRs). We examined its efficacy, affinity, and potency for α6β2∗ (α6β2-containing), α4β2∗, and α3β4∗ nAChRs, using [125I]-epibatidine binding, whole-cell patch-clamp recordings, synaptosomal 86Rb+ efflux, [3H]-dopamine release, and [3H]-acetylcholine release. TC299423 displayed an EC50 of 30-60 nM for α6β2∗ nAChRs in patch-clamp recordings and [3H]-dopamine release assays. Its potency for α6β2∗ in these assays was 2.5-fold greater than that for α4β2∗, and much greater than that for α3β4∗-mediated [3H]-acetylcholine release. We observed no major off-target binding on 70 diverse molecular targets. TC299423 was bioavailable after intraperitoneal or oral administration. Locomotor assays, measured with gain-of-function, mutant α6 (α6L9'S) nAChR mice, show that TC299423 elicits α6β2∗ nAChR-mediated responses at low doses. Conditioned place preference assays show that low-dose TC299423 also produces significant reward in α6L9'S mice, and modest reward in WT mice, through a mechanism that probably involves α6(non-α4)β2∗ nAChRs. However, TC299423 did not suppress nicotine self-administration in rats, indicating that it did not block nicotine reinforcement in the dosage range that was tested. In a hot-plate test, TC299423 evoked antinociceptive responses in mice similar to those of nicotine. TC299423 and nicotine similarly inhibited mouse marble burying as a measure of anxiolytic effects. Taken together, our data suggest that TC299423 will be a useful small-molecule agonist for future in vitro and in vivo studies of nAChR function and physiology.


Challenges for ensuring availability and accessibility toin health care services under Brazil's Unified Health System (SUS).
Shortages and imbalances in the distribution of the health workforce, are social and political problems that, along with the socio-economic inequality, reduce the access of the population to the health services. This study aims to understand the challenges of SUS policy-makers and managers to ensure the availability and geographical accessibility to health service providers. The analysis was guided by a framework of the health labour market and health policy interventions. Two main problems have been identified: shortage of doctors and maldistribution of professionals between levels of health care and between geographical areas. This review focused on eight interventions in the last 30 years, whose mainly aim was to correct the maldistribution of physicians in the SUS such as Rondon Project, Interiorization of Health Work Program, Medical Specialists Training Program, PHC Program and More Doctors Program. The discussion focuses on the factors that influence the outcome of these interventions.


[William Osler (1849-1919): the man and his descriptions].
William Osler was generally regarded as the greatest and most respected physician of his time. This paper describes Osler's life, his philosophy and views. He was an outstanding clinician who emphasized bedside teaching and observation. He possessed an extraordinary charm that inspired many others. As Professor of Medicine at four institutions in three countries, he was a great influence on medical education. He was a prolific writer, and his textbook became the most popular and widely read treatise on medicine in the world. He also was a medical historian, a classical scholar, and an avid bibliophile. He emphasized the value of hard work and ongoing education. His compassion and concern for patients and colleagues reflected his personality. We summarize Osler's descriptions, and some of his aphorisms. His wisdom is as relevant now, as it was in his time. Osler blended the art and science of Medicine perhaps better than anyone else, and remains a valuable role model for students and physicians more than ninety two years after his death.


Implication of polymorphisms in DNA repair genes with an increased risk of hepatocellular carcinoma.
We explored the association between 4 XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) polymorphisms with the development and prognosis of hepatocellular carcinoma (HCC). A total of 218 cases with HCC and 277 healthy controls were included in the study. Genotyping of the XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) polymorphisms was performed in a 384-well plate format on the Sequenom MassARRAY platform. We found that individuals with the XRCC1 399AA genotype had a higher risk of HCC compared with the GG genotype (odds ratio, OR = 1.85, 95% confidence interval, CI = 1.03-3.23). Similarly, individuals carrying the XPD 751GG genotype showed a greatly increased risk of HCC (OR = 2.97, 95%CI = 126- 7.38). Cox regression analysis showed that individuals carrying XPD 751Gln/Gln genotypes had a 0.30-fold increased risk of death from HCC. These results suggest that polymorphisms in XRCC1 and XPD may have functional significance in HCC.


The 1.6 A crystal structure of the AraC sugar-binding and dimerization domain complexed with D-fucose.
The crystal structure of the sugar-binding and dimerization domain of the Escherichia coli gene regulatory protein, AraC, has been determined in complex with the competitive inhibitor D-fucose at pH 5.5 to a resolution of 1.6 A. An in-depth analysis shows that the structural basis for AraC carbohydrate specificity arises from the precise arrangement of hydrogen bond-forming protein side-chains around the bound sugar molecule. van der Waals interactions also contribute to the epimeric and anomeric selectivity of the protein. The methyl group of D-fucose is accommodated by small side-chain movements in the sugar-binding site that result in a slight distortion in the positioning of the amino-terminal arm. A comparison of this structure with the 1.5 A structure of AraC complexed with L-arabinose at neutral pH surprisingly revealed very small structural changes between the two complexes. Based on solution data, we suspect that the low pH used to crystallize the fucose complex affected the structure, and speculate about the nature of the changes between pH 5.5 and neutral pH and their implications for gene regulation by AraC. A comparison with the structurally unrelated E. coli periplasmic sugar-binding proteins reveals that conserved features of carbohydrate recognition are present, despite a complete lack of structural similarity between the two classes of proteins, suggesting convergent evolution of carbohydrate binding.


Glia-neuron interactions underlie state transitions to generalized seizures.
Brain activity and connectivity alter drastically during epileptic seizures. The brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state. It is, however, less clear which mechanisms underlie the state transitions. By studying neural and glial activity in zebrafish models of epileptic seizures, we observe striking differences between these networks. During the preictal period, neurons display a small increase in synchronous activity only locally, while the gap-junction-coupled glial network was highly active and strongly synchronized across large distances. The transition from a preictal state to a generalized seizure leads to an abrupt increase in neural activity and connectivity, which is accompanied by a strong alteration in glia-neuron interactions and a massive increase in extracellular glutamate. Optogenetic activation of glia excites nearby neurons through the action of glutamate and gap junctions, emphasizing a potential role for glia-glia and glia-neuron connections in the generation of epileptic seizures.


Addition of right-sided and posterior precordial leads during stress testing.
Exercise treadmill testing has limited sensitivity for the detection of coronary artery disease, frequently requiring the addition of imaging modalities to enhance the predictive value of the test. Recently, there has been interest in using nonstandard electrocardiographic (ECG) leads during exercise testing. We consecutively enrolled all patients undergoing exercise myocardial imaging with four additional leads recorded (V4R, V7, V8, and V9). The test characteristics of the 12-lead, the 15-lead (12-lead, V7, V8, V9), and the 16-lead (12-lead, V4R, V7, V8, V9) ECGs were compared with stress imaging in all patients. In the subset of patients who underwent angiography within 60 days of stress testing, these lead arrays were compared with the catheterization findings. There were 727 subjects who met entry criteria. The mean age was 58.5 +/- 12.3 years, and 366 (50.3%) were women. Pretest probability for disease was high in 241 (33.1%), intermediate in 347 (47.7%), and low in 139 (19.1%). A total of 166 subjects had an abnormal 12-lead ECG during exercise. The addition of 3 posterior leads to the standard 12-lead ECG resulted in 7 additional subjects having an abnormal electrocardiographic response to exercise. The addition of V4R resulted in only 1 additional patient having an abnormal ECG during exercise. The sensitivity of the ECG for detecting ischemia as determined by stress imaging was 36.6%, 39.2%, and 40.0% (P = NS) for the 12-lead, 15-lead, and 16-lead ECGs, respectively. In those with catheterization data (n = 123), the sensitivity for determining obstructive coronary artery disease was 43.5%, 45.2%, and 45.2% (P = NS) for the 12-lead, 15-lead, and 16-lead ECGs, respectively. The sensitivity of imaging modalities was 77.4% when compared with catheterization. In patients undergoing stress imaging studies, the addition of right-sided and posterior leads did not significantly increase the sensitivity of the ECG for the detection of myocardial ischemia. Additional leads should not be used to replace imaging modalities for the detection of coronary artery disease.


Investigating the Effects of Role Demands, Psychosocial Stress Symptoms and Safety Leadership on Mineworkers' Safety Performance.
This study aimed to investigate the effects of role demands on safety performance in mining companies under the mediating role of psychosocial stress symptoms. Three dimensions of safety leadership were also tested as moderators on the relationship between psychosocial stress symptoms and safety performance. To collect data to analyze the hypothesized relationships in the present study, a total of 850 questionnaires were distributed to mineworkers in Ghana. Hierarchical regression analysis was employed as the main statistical technique in analyzing the data using SPSS version 21 software. Results from hierarchical regression analysis showed that psychosocial stress symptoms fully mediated the relationship between role demands and safety compliance but showed no mediation on role demands and safety participation. Also, only safety coaching from safety leadership demonstrated to have a moderating effect on the relationship between psychosocial stress symptoms and safety compliance of safety performance. The study proposes that it is important to examine the effects of role demands on specific job performance. The importance of safety coaching as a key element of planning to improve safety performance should not be underestimated.


Mannitol-induced acute renal failure.
The osmotic diuretic mannitol may be used in diverse clinical settings, such as providing "renal protection" in patients at risk for acute renal failure, decreasing intracranial pressure in patients with intracranial trauma, and preventing the dialysis-disequilibrium syndrome. Mannitol is commonly used after cardiac catheterization, cardiovascular surgery, and exposure to intravenous contrast dyes. This study presents a case in which a long-term renal transplant recipient receiving cyclosporine therapy concomitantly developed acute renal failure after the administration of high-dose mannitol in an attempt to induce an osmotic diuresis. The diagnosis of "osmotic nephrosis" was confirmed by renal biopsy, and the condition was reversed by cessation of the agent. Studies in experimental animals indicate that cyclosporin A can potentiate the tubular toxicity of mannitol, but such an association has not been verified in humans. Numerous studies confirm the nephrotoxic potential of high-dose mannitol, especially in patients with renal insufficiency. The clinical utility of the osmolar gap in preventing mannitol nephrotoxicity is emphasized.


Degradation Mechanism of Conversion-Type Iron Trifluoride: Toward Improvement of Cycle Performance.
Conversion-type iron trifluoride (FeF3) has attracted considerable attention as a positive electrode material for lithium secondary batteries due to its high energy density and low cost. However, the conversion process through which FeF3 operates leads it to suffer from capacity degradation upon repeated cycling. To improve the cycle performance, in this study we investigated the degradation mechanism of conversion-type FeF3 electrode material. Bulk analyses of FeF3 upon cycling reveal incomplete oxidation to Fe3+ concomitant with the aggregation of LiF at the charged state. In addition, surface analyses of FeF3 reveal that a film covered the electrode surface after 10 cycles, which leads to a remarkable increase in resistance. We show that the choice of the electrolyte formulation is crucial in preventing the formation of the film on the electrode surface; thus, FeF3 shows better performance in an electrolyte comprising LiBF4 solute in cyclic carbonate solvents than in chain carbonate-containing LiPF6 as the electrolyte. This study underpins that a careful selection of solvent, rather than solute, is significantly essential to improve the cycle performance of the FeF3 electrode.


The role of a FADS1 polymorphism in the association of fatty acid blood levels, BMI and blood pressure in young children-Analyses based on path models.
The recent obesity epidemic in children also showed an increase in the prevalence of hypertension. As blood pressure (BP) is associated with (long-chain) polyunsaturated fatty acids (LC PUFA), genetic variation in desaturase enzymes being involved in the synthesis of LC PUFA may be associated with BP. This study aimed to investigate the direct effects (independent of mediating variables) and indirect effects (mediated through intermediate variables) of a common variant in the FADS1 gene, rs174546, known to affect delta-5 desaturase (D5D) activity on PUFA level, body mass index (BMI) and BP. A subsample of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) baseline survey including 520 children aged 2 to <10 years from six European countries was included. The association between rs174546 (T<C) and BP z-score as well as the mediating effects of selected key PUFA levels (dihomo-gamma-linolenic acid, DGLA; arachidonic acid, ARA; eicosapentaenoic acid, EPA) or estimated D5D activity (D5D index) and BMI z-score were investigated through path model analyses, adjusting for sex, age, educational level of parents, family history of hypertension, lifestyle factors and blood levels of saturated and monounsaturated fatty acids, triglycerides and low density lipoprotein cholesterol. Whole blood fatty acids were measured by a validated gas chromatographic method and recorded as percentage of weight of all fatty acids detected. Minor allele carriers of the SNP rs174546 had significantly higher DGLA and lower ARA and EPA levels as well as a lower D5D index. Via ARA and BMI z-score, the polymorphism had an indirect lowering effect on systolic BP z-score for each additional T allele (standardized effect estimate -0.057, p = 0.007). For DGLA, EPA and D5D index, the indirect effects of rs174546 on systolic BP were also negative but did not reach significance. DGLA and EPA had an increasing indirect effect on systolic BP via BMI. Results for diastolic BP were in general similar but effect estimates were lower compared to systolic BP. Genetic variation in FADS1 influences BP via ARA and BMI indicating a favorable effect of the minor allele in SNP rs174546. Thus, polymorphisms with an impact on the D5D activity may play a role for the BP level mediated through PUFA and BMI. Therefore, health effects of dietary n-6 and n-3 PUFA may vary depending on genetic FADS1 variants.


Expression of an inter-alpha-trypsin inhibitor heavy chain-like protein in the pig endometrium during the oestrous cycle and early pregnancy.
In pigs, changes in an unidentified endometrial glycoprotein, pGP30, are temporally associated with rapid trophoblast elongation and initial placental attachment on day 12 of gestation. Identification of endometrial pGP30 was undertaken through protein purification, NH2-terminal amino acid sequencing and cDNA sequencing of products generated through reverse transcription-polymerase chain reaction. Sequencing of 35 amino acids from the NH2-terminal end of pGP30 revealed that the 30 kDa glycoprotein is a cleavage product from the C-terminal region of inter-alpha-trypsin inhibitor heavy chain 4 (I alpha IH4), previously known as inter-alpha-trypsin inhibitor heavy chain-like protein. I alpha IH4 is unique compared with the three other inter-alpha-trypsin inhibitor heavy chains as it does not contain a binding site for bikunin that has serine protease inhibitory activity and is sensitive to cleavage by kallikrein. Endometrial gene expression of I alpha IH4 was detected during the oestrous cycle (days 0-18) and early pregnancy (days 10-18). Gene expression of I alpha IH4 appeared to be enhanced during the midluteal phase (days 12 and 15) of the oestrous cycle and the period of trophoblast attachment (days 12-18). Expression of I alpha IH4 was not detected in day 12 conceptus tissue mRNA. Endometrial expression of I alpha IH4 in pigs may function as an acute phase protein for protection of the uterus from the inflammatory response induced by conceptus attachment to the uterine epithelium.


Transcavum interforniceal endoscopic surgery of the third ventricle.
Intraventricular anatomy has been detailed as it pertains to endoscopic surgery within the third ventricle, particularly for performing endoscopic third ventriculostomy (ETV) and endoscopic colloid cyst resection. The expanding role of endoscopic surgery warrants a careful appraisal of these techniques as they relate to frequent anatomical variants. Given the common occurrence of cavum septum pellucidum (CSP) and cavum vergae (CV), the endoscopic surgeon should be familiar with that particular anatomy especially as it pertains to surgery within the third ventricle. From a prospective database of endoscopic surgical cases were selected those cases in which the defined pathology necessitated surgery within the third ventricle and there was coexistent CSP and CV. Pertinent radiographic studies, operative notes, and archived video files were reviewed to define the relevant anatomy. Features of the intracavitary anatomy were assessed regarding their importance in approaching the third ventricle. Four cases involving endoscopic surgery within the third ventricle (2 colloid cyst resections and 2 ETVs) were identified in which the surgical objective was accomplished through a septal cavum. In each case the width of the body of the lateral ventricle was reduced and the foramen of Monro was obscured. Because of the ventricular distortion, a stereotactic transcavum route was used for approaching the third ventricle. Entry into the third ventricle was accomplished through an interforniceal fenestration immediately behind the anterior commissure. The surgical goal was met in each case without any neurological change or postoperative morbidity. During the follow-up period, there has been no recurrence of a colloid cyst and no need of a secondary cerebrospinal fluid diversionary procedure. In the presence of a CSP and CV, endoscopic navigation into the third ventricle can be problematic via a transforaminal approach. Alternatively, a transcavum interforniceal route for endoscopic surgery in the third ventricle is suggested, with the rostral lamina and the anterior commissure as important anatomical landmarks. Endoscopic third ventriculostomy and endoscopic colloid cyst resection performed via a transcavum interforniceal route in patients with a coexistent septal cavum is a feasible and safe option.


A Metataxonomic Approach Could Be Considered for Cattle Clinical Mastitis Diagnostics.
Mastitis is one of the most costly diseases affecting the dairy industry, and identification of the causative microorganism(s) is essential. Here, we report the use of next-generation sequencing of bacterial 16S rRNA genes for clinical mastitis diagnosis. We used 65 paired milk samples, collected from the mastitic and a contralateral healthy quarter of mastitic dairy cattle to evaluate the technique as a potential alternative to bacterial culture or targeted PCR. One large commercial dairy farm was used, with one trained veterinarian collecting the milk samples. The 16S rRNA genes were individually amplified and sequenced using the MiSeq platform. The MiSeq Reporter was used in order to analyze the obtained sequences. Cattle were categorized according to whether or not 1 of the 10 most abundant bacterial genera in the mastitic quarter exhibited an increase in relative abundance between the healthy and mastitic quarters equal to, or exceeding, twofold. We suggest that this increase in relative abundance is indicative of the genus being a causative mastitis pathogen. Well-known mastitis-causing pathogens such as Streptococcus uberis and Staphylococcus spp. were identified in most cattle. We were able to diagnose 53 out of the 65 studied cases and identify potential new mastitis pathogens such as Sneathia sanguinegens and Listeria innocua, which are difficult to identify by bacterial culture because of their fastidious nature.


EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-β/Smad3 Signaling.
Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the cause. EphrinB2 (erythropoietin-producing hepatoma interactor B2), a pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified. We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process. EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the profibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 (signal transducer and activator of transcription 3) and TGF-β (transforming growth factor-β)/Smad3 (mothers against decapentaplegic homolog 3) signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3 and identified that the MAD homology 2 domain of Smad3 and the coil-coil domain and DNA-binding domain of Stat3 mediated the interaction. This study uncovered a previously unrecognized profibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-β/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.


Prenatal lead exposure and the pregnancy outcome. A case-control study in southern Poland.
In an attempt to test null hypothesis (Ho): that prenatal lead exposure does not increase the risk of prematurity and the delivery of SGA infants, a case-control study was performed in four hospitals of Southern Poland (Kraków, Rabka, Limanowa, Zakopane). Lead content was determined in maternal and cord blood as well as in head and pubic hair by the GF AAS (Perkin Elmer). A significant interregional variation of lead content in maternal blood was observed. Lead concentration in maternal and cord blood was significantly higher in the group of mothers of SGA newborns when compared to the controls. This was not the case with respect to the mothers of preterm infants. Also, the comparison of lead concentration in head and pubic hair revealed no statistically significant case-control differences. For a combined population of cases and controls, a significant gradient of lead concentration between maternal and cord blood was demonstrated. The correlation between lead content in different body compartments was observed. Conclusions. Different blood lead levels observed in mothers from four hospitals suggest different exposure. Higher lead concentration in maternal blood was associated with an increased risk of the delivery of SGA infant.


Statistical estimation of the number of breast cancer patients with disabilities resulting from surgery.
The prolongation of the post-operative life of cancer patients brings new medical demands. The purpose of this paper is to estimate the total number of women patients with breast cancer who will have disability resulting from surgical treatment from 2000 to 2020 in Japan. The estimation was carried out using four indices: the number of cases of women diagnosed with breast cancer, the proportion of surgical operations, the frequency of disability from surgical treatment, and the crude survival rate of the patient group. The crude survival rates of surgically-treated breast cancer patients were estimated by the Weibull model. The frequencies of iatrogenic disabilities were calculated from several reports of complaints of pain in the chest wall or axilla and lymphedema of the arm, and 95% confidence intervals were calculated by the Monte Carlo simulation. The number of women patients with disability from breast cancer treatment from 2000 to 2020 was estimated to be 42,016 (95% CI: 41,236, 42,796) people in 2000 and 72,514 (95% CI: 71,196, 73,832) people in 2020 for pain in the chest wall or axilla, and 22,486 (95% CI: 22,148, 22,823) people in 2000 and 38,692 (95% CI: 38,094, 39,290) people in 2020 for lymphedema of the arm. Treatment supports required for the disability are medication and social support. Cancer patients with disability after treatment need long-term support in their daily life.


Children and adolescents living with HIV and AIDS: a review.
Worldwide, more than one million children are infected with human immunodeficiency virus (HIV) and in the United States it has become the sixth leading cause of death among 15-24-year-olds. Despite the trend of increasing rates of infection, advances in therapies have led to survival past 5 years of age for more than 65% of infected children. This global health threat will therefore continue to have a significant impact on child and adolescent psychiatry and psychology. This paper reviews current studies and reports on the consequences of the acquired immunodeficiency syndrome (AIDS) epidemic in the psychiatric care and development of children and adolescents infected by HIV. From a search of all the English-language-based literature on pediatric AIDS, 140 studies are reviewed which address HIV infection and its psychological and social implications. Several topics of mental health significance are examined: (1) the epidemiology of HIV, (2) neurocognitive development among those infected, (3) psychological impact of infection, and (4) the family and social context of HIV. The transition of HIV from an acute, lethal disease to a subacute, chronic disease has enormous implications for the neurocognitive and psychosocial development of children and families. As children and adolescents infected with HIV continue to live longer, normal developmental milestones and educational needs will take on new significance. Many children will continue to be adversely impacted by non-HIV factors such as poverty, inadequate medical services, and a lack of social support. This review outlines recent developments that hold promise to effectively reduce the treatment burden on the infected, their families, and health care providers and to decrease the incidence of transmission to the uninfected.


[Effect of nebivolol on the level of constitutional, inducible, and total NO-synthase in serum of patients with type II diabetes mellitus].
Nebivolol (Nebilet) has been shown to promote increase in the content of inducible and total NO-synthase, which fact can have a positive effect on the functional condition of the endothelium and its antioxidant properties in patients with type II diabetes mellitus concurrent with arterial hypertension. It is recommended that nebivolol be taken in by the above patients to normalize arterial pressure.


Instrumental and metabolic evaluation of patients affected by peripheral arterial occlusive disease (PAOD) following surgical revascularization surgery.
Experiments were performed on eight subjects affected by peripheral arterial occlusive disease (PAOD) of the lower limbs. Each patient was submitted to Ecodoppler, angiography and the "Treadmill test". Two bioptic muscle of these patients. A sample was used for the spectrophotometric and spectrophotofluorimetric determinations of: glycogen, pyruvate, lactate, citrate, alpha-ketoglutarate, malate, aspartate, glutamate, AMP, ADP, ATP and creatine phosphate (CP). The other bioptic sample was used to determine the following enzyme activities: hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase, citrate synthase, succinate dehydrogenase, malate dehydrogenase, total NADH cytochrome c reductase, cytochrome oxidase, aspartate aminotransferase and alanine aminotransferase. Patients showed an increase in lactate dehydrogenase, total NADH cytochrome c reductase and succinate dehydrogenase activities, a decrease in glycogen, ATP and CP concentrations. Telethermographic data showed patient muscle thermic emission quantitatively different from control group. The telethermographic test can be used as an additional diagnostic tool to determine and monitor the efficiency of a muscle undergoing metabolic failure.


Measurement of "regional" lumbar sagittal mobility.
Lumbar sagittal mobility is generally recorded as the overall movement occurring throughout the lumbar spine, in flexion and extension. However, increased information concerning mechanical function will be afforded if the mobility is expressed as the range separately available in the upper and lower regions of the lumbar spine. A simple, noninvasive and reliable technique is described which measures sagittal mobility available from T12 to L4, and from L4 to S1. It uses a modified draftsmans flexicurve and is suitable for use in clinical and field environments. J Orthop Sports Phys Ther 1987;9(4):166-169.


The effect of trunk flexion on lower-limb kinetics of able-bodied gait.
Able-bodied individuals spontaneously adopt crouch gait when walking with induced anterior trunk flexion, but the effect of this adaptation on lower-limb kinetics is unknown. Sustained forward trunk displacement during walking can greatly alter body center-of-mass location and necessitate a motor control response to maintain upright balance. Understanding this response may provide insight into the biomechanical demands on the lower-limb joints of spinal pathology that alter trunk alignment (e.g., flatback). The purpose of this study was to determine the effect of sustained trunk flexion on lower-limb kinetics in able-bodied gait, facilitating understanding of the effects of spinal pathologies. Subjects walked with three postures: 0° (normal upright), 25±7°, and 50±7° trunk flexion. With increased trunk flexion, decreased peak ankle plantar flexor moments were observed with increased energy absorption during stance. Sustained knee flexion during mid- and terminal stance decreased knee flexor moments, but energy absorption/generation remained unchanged across postures. Increased trunk flexion placed significant demand on the hip extensors, thus increasing peak hip extensor moments and energy generation. The direct relationship between trunk flexion and energy absorption/generation at the ankle and hip, respectively, suggest increased muscular demand during gait. These findings on able-bodied subjects might shed light on muscular demands associated with individuals having pathology-induced positive sagittal spine balance.


Functional cereals' anti-diabetic property, phenolic composition, and role on glycemic indices in-vitro.
This study analyzed the effects of functional cereals processed and produced from yellow corn, soybean, acha, orange peels and moringa leaves' polyphenolic content, glycemic index, starch composition and their effects on α-amylase and α-glucosidase enzymes in vitro. Functional cereals were produced as ready-to-eat cereals at different proportion with variations in the amount of measured acha flour, soybean flour, and blends of orange peels and moringa leaves while maintaining a constant amount of yellow corn. The produced orange peels and moringa leaves blends inclusion to functional cereals had significantly increased phenolic constituents, showed inhibitory activity on α-amylase and α-glucosidase enzymes in-vitro and reduced glycemic index, starch content and starch to sugar ratios. Interestingly, amongst the produced functional cereals, the best two cereals were with their composition made up of corn, acha, soybean, orange peel, moringa leaves (30: 5:15: 0.5: 0.5) and corn, acha, soybean, moringa leaves (30: 5: 15: 1) which both had the high inhibitory effects on the activities of α-amylase and α-glucosidase while depleting starch content in-vitro when compared with commercially consumed cereals (golden morn). PRACTICAL APPLICATIONS: Ready-to-eat cereals are highly consumed by children and by adults inclusively. Commercial breakfast cereals are readily available and consumed irrespective of the fact it has high calorie constituent as more emphasis is placed on their nutrients value which includes vitamins A, vitamin C and calcium for boosting immune system and for proper body growth and functioning. However, these commercial breakfast cereals (golden morn) owing to the high maize and millet content present in them are unfavorable to certain consumers or individuals with health challenges such as diabetic patients. This study shows that functional cereals produced in-vitro extensively are not only nutritious but also medicinal in nature, offering benefits in the management of diabetes and related complications.


The 3' proximal translational enhancer of Turnip crinkle virus binds to 60S ribosomal subunits.
During cap-dependent translation of eukaryotic mRNAs, initiation factors interact with the 5' cap to attract ribosomes. When animal viruses translate in a cap-independent fashion, ribosomes assemble upstream of initiation codons at internal ribosome entry sites (IRES). In contrast, many plant viral genomes do not contain 5' ends with substantial IRES activity but instead have 3' translational enhancers that function by an unknown mechanism. A 393-nucleotide (nt) region that includes the entire 3' UTR of the Turnip crinkle virus (TCV) synergistically enhances translation of a reporter gene when associated with the TCV 5' UTR. The major enhancer activity was mapped to an internal region of approximately 140 nt that partially overlaps with a 100-nt structural domain previously predicted to adopt a form with some resemblance to a tRNA, according to a recent study by J.C. McCormack and colleagues. The T-shaped structure binds to 80S ribosomes and 60S ribosomal subunits, and binding is more efficient in the absence of surrounding sequences and in the presence of a pseudoknot that mimics the tRNA-acceptor stem. Untranslated TCV satellite RNA satC, which contains the TCV 3' end and 6-nt differences in the region corresponding to the T-shaped element, does not detectably bind to 80S ribosomes and is not predicted to form a comparable structure. Binding of the TCV T-shaped element by 80S ribosomes was unaffected by salt-washing, reduced in the presence of AcPhe-tRNA, which binds to the P-site, and enhanced binding of Phe-tRNA to the ribosome A site. Mutations that reduced translation in vivo had similar effects on ribosome binding in vitro. This strong correlation suggests that ribosome entry in the 3' UTR is a key function of the 3' translational enhancer of TCV and that the T-shaped element contains some tRNA-like properties.


Phase I study of cis-diamminedichloroplatinum(II) administered as a constant 5-day infusion.
Thirty patients with metastatic malignancy of various types were treated with cis-diamminedichloroplatinum(II) (DDP) administered by continuous infusion for 120 hours. The starting dose was 20 mg/m2/day (100 mg/m2/course) and was escalated by stages to 40 mg/m2/day (200 mg/m2/course). Dose-limiting toxicity was observed at 30 mg/m2/day (150 mg/m2/course), manifested as marrow suppression and particularly thrombocytopenia in 13 of 14 patients evaluated at doses greater than or equal to 30 mg/m2/day. The gastrointestinal toxicity characteristic of bolus treatment schedules was less intense but was cumulative and dose-related. Renal toxic effects developed in five of 30 patients in spite of adequate hydration and daily diuretic therapy. Peripheral neuropathy developed in the only two patients who received four courses of continuous-infusion DDP. Antitumor effects were observed in six patients (oral cancer, two; lymphoma, one; prostatic cancer, one; hepatoma, one; and bronchogenic carcinoma, one). The recommended starting dose for continuous venous infusion therapy with DDP is 30 mg/m2/day for 5 days.


Cellular promoters incorporated into the adenovirus genome: cell specificity of albumin and immunoglobulin expression.
Recombinant adenoviruses were constructed in which the viral E1A gene was deleted and the E1B promoter was replaced by the rat albumin, mouse beta-major globin, or mouse immunoglobulin heavy-chain promoter. After infection of human or rat hepatoma cells, E1B-containing mRNAs could be detected only from the virus containing the albumin promoter. Conversely, only the immunoglobulin promoter was active in virus-infected myeloma cells. However, in hepatoma cells transcription from the albumin promoter in the virus was much less than that of the endogenous cellular albumin gene or of other viral genes. In primary mouse hepatocytes endogenous albumin gene transcription was high immediately after plating but declined within 24 h. Expression of the albumin promoter in the virus paralleled that of the cellular albumin gene. From these results it appears that cell-specific expression of albumin depends on the presence of tissue-specific trans-acting factors, but the presence of such factors does not suffice for a maximal rate of transcription, a conclusion that requires direct comparison within a differentiated cell of a newly introduced and preexisting active cell gene.


A multilayered electrospun graft as vascular access for hemodialysis.
Despite medical achievements, the number of patients with end-stage kidney disease keeps steadily raising, thereby entailing a high number of surgical and interventional procedures to establish and maintain arteriovenous vascular access for hemodialysis. Due to vascular disease, aneurysms or infection, the preferred access-an autogenous arteriovenous fistula-is not always available and appropriate. Moreover, when replacing small diameter blood vessels, synthetic vascular grafts possess well-known disadvantages. A continuous multilayered gradient electrospinning was used to produce vascular grafts made of collagen type I nanofibers on luminal and adventitial graft side, and poly-ɛ-caprolactone as medial layer. Therefore, a custom-made electrospinner with robust environmental control was developed. The morphology of electrospun grafts was characterized by scanning electron microscopy and measurement of mechanical properties. Human microvascular endothelial cells were cultured in the graft under static culture conditions and compared to cultures obtained from dynamic continuous flow bioreactors. Immunofluorescent analysis showed that endothelial cells form a continuous luminal layer and functional characteristics were confirmed by uptake of acetylated low-density-lipoprotein. Incorporation of vancomycin and gentamicin to the medial graft layer allowed antimicrobial inhibition without exhibiting an adverse impact on cell viability. Most striking a physiological hemocompatibility was achieved for the multilayered grafts.


Fractionated irradiation can induce functionally relevant multidrug resistance gene and protein expression in human tumor cell lines.
The molecular basis of radiotherapy-related multidrug resistance (MDR) is still unclear. Here we report on a study investigating the effect of fractionated irradiation on expression of the MDR-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance-related protein (LRP), the respective mRNAs, and the functional consequences. Cells of six colon and five breast cancer cell lines were irradiated with a total dose of 27 Gy, five fractions of 1.8 Gy per week. The mRNA expression was measured by quantitative RT-PCR, protein levels and drug sensitivity to cisplatin, doxorubicin and bendamustine were assessed by flow cytometry. Breast cancer cell lines showed enhancement of the mRNAs encoding for P-gp, MRP1 and LRP in comparison to nonirradiated cells. No up-regulation of the three mRNA species was observed in the colon cancer cell lines. After irradiation, three breast cancer cell lines showed an up-regulation of LRP, one line an up-regulation of MRP1, and four lines a small up-regulation of P-gp. In the colon cancer cell lines, radiation induced significant enhancement of all three proteins. In comparison to controls, the irradiated cells lines showed a significant resistance to cisplatin, doxorubicin and bendamustine. This study confirms the prior reports of enhancement of P-gp and MRP1 after irradiation, which is accompanied by a multidrug resistance phenomenon, but in addition proposes a novel mechanism in the appearance of MDR after radiation-induced enhancement of LRP.


[Noninduced single-stranded breaks in DNA in murine F9 teratocarcinoma cells].
Our previous study demonstrated the high incidence of non-induced DNA single strand breaks (SSB) in preimplantation mouse embryo genom (Patkin et al., 1994). F9 mouse teratocarcinoma cell line is an in vitro model for early embryonal differentiation, since F9 cells remind in many respects the inner cell mass cells of mouse blastocyst and are capable of differentiation under retinoic acid (RA) and dibutyryl cAMP (db-cAMP) treatment. Using gap filling reaction of F9 metaphase chromosomes and single-cell DNA electrophoresis, we have observed multiple SSB in undifferentiated F9 cells as well as in F9 cells at the early steps of RA-induced differentiation (days of RA treatment), but not in terminally differentiated F9 cells and in mouse embryonal fibroblasts. Rad51 nuclear protein that binds specifically single stranded DNA is highly expressed in all cells of undifferentiated F9 population and is not expressed in terminally differentiated F9 population. Multiple SSB could lead to enhanced rate of sister chromatid exchanges (SCE) in F9 cells. In undifferentiated F9 population the level of SCE was 9.6 +/- 0.44 per metaphase, that was not higher than in NIH 3T3 cell line. However, RA treatment for 48 h led to rising the SCE level up to 16.68 +/- 0.72 followed by its decrease to the initial rate by 72 h of RA treatment. Since the enhanced level of SSB in undifferentiated F9 cells and in mouse blastocyst does not normally lead to chromosomal instability, we consider SSB to be a natural consequence of fast-going DNA replication in these cells.


Reassessing the BODE score as a criterion for listing COPD patients for lung transplantation.
The BODE score (incorporating body mass index, airflow obstruction, dyspnea and exercise capacity) is used for the timing of listing for lung transplantation (LTx) in COPD, based on survival data from the original BODE cohort. This has limitations, because the original BODE cohort differs from COPD patients who are candidates for LTx and the BODE does not include parameters that may influence survival. Our goal was to assess whether parameters such as age, smoking status and diffusion indices significantly influence survival in the absence of LTx, independently of the BODE. In the present cohort study, the BODE was prospectively assessed in COPD patients followed in a tertiary care hospital with an LTx program. The files of 469 consecutive patients were reviewed for parameters of interest (age, gender, smoking status and diffusing capacity of the lungs for carbon monoxide [DL,CO]) at the time of BODE assessment, as well as for survival status. Their influence on survival independent of the BODE score was assessed, as well as their ability to predict survival in patients aged less than 65 years. A Cox regression model showed that the BODE score, age and DL,CO were independently related to survival (P-values <0.001), as opposed to smoking status. Survival was better in patients aged less than 65 in the first (P=0.004), third (P=0.002) and fourth BODE quartiles (P=0.008). The difference did not reach significance in the second quartile (P=0.13). Median survival for patients aged less than 65 in the fourth BODE quartile was 55 months. According to a receiver operating characteristic curve analysis, the BODE score as well as FEV1 and DL,CO fared similarly in predicting survival status at 5 years in patients aged less than 65 years. Age and DL,CO add to the BODE score to predict survival in COPD. Assessing survival using tools tested in cohorts of patients younger than 65 years is warranted for improving the listing of patients for LTx.


[Plastic closure of "difficult" duodenal stump with tamponade of ulcerous crater].
The method of plastic repair of the duodenal stump with an invaginated cone formed from the antral part of resected stomach was developed experimentally on 10 cadavers. Experimental surgeries on 16 mongrel dogs demonstrated primary healing and fast epithelisation of this duodenal stump. The method was used in 2 patients with giant penetrating ulcers of the posterior wall of the duodenum, promising results were seen.


COMPARISON OF HEPATIC PROFILE IN PRE AND POSTOPERATIVE OF BARIATRIC SURGERY: PRIVATE VS PUBLIC NETWORK.
Obesity is associated to several comorbidities, including nonalcoholic fatty liver disease, which implicates in isolated steatosis to steatohepatitis. The latter may progress to severe manifestations such as liver fibrosis, cirrhosis and hepatocellular carcinoma. To compare the presence of advanced liver fibrosis before and after bariatric surgery in patients of private and public health system. Patients from public and privative networks were studied before and after bariatric surgery. The presence or absence of advanced hepatic fibrosis was evaluated by NAFLD Fibrosis Score, a non-invasive method that uses age, BMI, AST/ALT ratio, albumin, platelet count and the presence or absence of hyperglycemia or diabetes. The characteristics of the two groups were compared. The established statistical significance criterion was p<0.05. Were analyzed 40 patients with a mean age of 34.6±9.5 years for private network and 40.6± 10.2 years for public. The study sample, 35% were treated at private health system and 65% in the public ones, 38% male and 62% female. Preoperatively in the private network one (7.1%) patient had advanced liver fibrosis and developed to the absence of liver fibrosis after surgery. In the public eight (30.8%) patients had advanced liver fibrosis preoperatively, and at one year after the proportion fell to six (23%). The non-alcoholic fatty liver disease in its advanced form is more prevalent in obese patients treated in the public network than in the treated at the private network and bariatric surgery may be important therapeutic option in both populations.


[Formula for calculating the IOL focal power].
A formula for calculating the focal IOL power based on SRK-II is suggested and clinically tested. Quadratic non-linear allowances in small (below 23 mm) and big values of the anterior-posterior eye axis are introduced into it, instead of linear allowances, to enhance the calculation accuracy.


Brominated phenols, anisoles, and dioxins present in blue mussels from the Swedish coastline.
Naturally occurring hydroxylated polybrominated diphenyl ethers (OH-PBDEs), their methoxylated counterparts (MeO-PBDEs), and polybrominated dibenzo-p-dioxins (PBDDs), together with their potential precursors polybrominated phenols (PBPs) and polybrominated anisoles (PBAs), were analyzed in blue mussels (Mytilus edulis) gathered along the east coast (bordering the Baltic Sea) and west coast of Sweden (bordering the North Sea). Brown algae (Dictyosiphon foenicolaceus) and cyanobacteria (Nodularia spumigena) from the Baltic Sea, considered to be among the primary producers of these compounds, were also analyzed for comparison. The samples were liquid-liquid extracted, separated into a phenolic and a neutral fraction, and subsequently analyzed by gas chromatography-mass spectrometry (GS-MS). The levels of OH-PBDEs, MeO-PBDEs and PBDDs were significantly higher in Baltic Sea mussels than in those from the west coast, whereas the levels of PBPs and PBAs displayed the opposite pattern. The blue mussels from the Baltic Sea contained high levels of all analyzed substances, much higher than the levels of, e.g., polybrominated diphenyl ethers. In addition, the GC-MS chromatogram of the phenolic fraction of the west coast samples was dominated by four unknown peak clusters, three of which were tentatively identified as dihydroxy-PBDEs and the other as a hydroxylated-methyl-tetraBDE. Clearly, all of the compounds analyzed are natural products, both in the Baltic and the North Sea. However, the geographical differences in composition may indicate different origin, e.g., due to differences in the occurrence and/or abundance of various algae species along these two coasts or possibly a more extensive dilution on the west coast.


Superficial Angiomyxoma of the Vulva in a Postmenopausal Woman: A Case Report and Review of Literature.
Superficial angiomyxomas (SAMs) are rare benign cutaneous tumors that involve the subcutaneous layer. They are commonly located in the trunk, lower limbs and head or neck of women of reproductive age. SAMs in the vulva of postmenopausal women are especially rare case. Herein, we report a vulvar SAM in a postmenopausal 60-year-old woman. The patient presented with a palpable cutaneous mass in the right labium majora that had appeared 3 months earlier. The mass was slow growing and approximately 5 cm in size and resembled a soft tissue malignancy. It appeared as a well-defined multilocular cystic mass in magnetic resonance images. The preoperative diagnosis was a benign cystic lesion such as an epidermoid cyst. Grossly, the completely excised mass was 6 × 5 cm in size and well circumscribed with a multilocular outer surface, a yellowish-gray gelatinous cut surface, and a smooth rubbery inner surface. Histologic review revealed that the mass contained small to moderate amount of cellular angiomyxoid nodules and bland-looking spindle-shaped to ovoid cells without atypia. Neutrophil infiltration, which is a diagnostic feature of SAMs, was observed. Immunohistochemistry showed expression of CD34, but not of estrogen receptors, progesterone receptors, or desmin in the SAM. The patient has been followed up for 12 months without recurrence.


The value of life in English law: revered but not sacred?
Terms such as sanctity and inviolability have failed to provide a legally coherent or ethically sound principle upon which to determine the scope of the intrinsic value of life against extrinsic, quality-of-life considerations in a medical context. In their recent work, Margaret Brazier and Suzanne Ost introduce a new term, reverence for life, which they suggest may be more appropriate when attempting to navigate the murky waters of the meaning of life and the value that should be attached to it. They suggest that reverence should be utilised as an alternative that better reflects the nuances and the realities of the dilemma. This paper explores the existing difficulties before considering how the principle of reverence might provide a principled compromise over when the presumption in favour of preserving life should be rebutted.


Development and Reach of the Stanford Tobacco Prevention Toolkit: Implementation of a Community-Based Participatory Approach.
We developed the Tobacco Prevention Toolkit (Toolkit) to enhance the impact of school-based tobacco education. This study describes the process of developing the Toolkit, its contents, and reach. Qualitative community-based participatory research (CBPR), including focus group discussions (N = 152) and working groups with parents, educators, researchers, and youth (N = 87) were used to develop the Toolkit and design its implementation. Toolkit reach was assessed through number of trained educators using the Toolkit, estimated number of youth recipients of the Toolkit resources, and using Google Analytics for online engagement. The Toolkit is a free, online resource aimed at preventing tobacco use by middle and high school students. Toolkit content addresses varied forms of tobacco including electronic cigarettes, hookah, smokeless tobacco, and cigarettes; addiction; and positive youth development; and is available in multiple interactive formats such as real-time quizzes, factsheets, activities, and presentations. The Toolkit is mainly delivered by trained educators, who adapt its content and duration to tailor their drug prevention teaching to student needs. As of April 2020, when data for this paper were collected, 4,750 educators have reached an estimated 1.3 million youth. The Toolkit website has 186,116 users and 802,602 page views, growing steadily since 2016. As of August 2021, additional students have been reached, for now a total of 1.85 million students reached. The Toolkit resources are evidence-based, comprehensive, responsive, interactive, easily accessible, and flexible. Applying CBPR was instrumental in developing the Toolkit and expanding its reach.


Achieving high convective volumes in on-line hemodiafiltration.
On-line hemodiafiltration (OL-HDF) has established itself as a highly efficient and safe form of renal replacement therapy, providing clinical benefits for several conditions that afflict end-stage chronic kidney disease patients. Additionally, evidence now ascribes a survival benefit to OL-HDF. The first indication that mortality rates decline with high-efficiency OL-HDF was provided by the European results from the DOPPS. Since then, the RISCAVID, CONTRAST and the Turkish HDF trials have all substantiated the original findings that higher convection volumes are favorable in terms of improved survival. With the emerging concept of convection volume impacting patient survival, we examine the factors and practical approaches by which maximal convection volumes can actually be achieved and individualized for each patient treated with OL-HDF. We believe that with these factors in mind, all attempts should be made to maximize convective volume, and hence the convective dose, to enable the patient to derive the full benefits of OL-HDF over extended periods.


Differential expression of GAS5 in rapamycin-induced reversion of glucocorticoid resistance.
This study evaluates the association between the long noncoding RNA GAS5 levels and the anti-proliferative effect of the glucocorticoid (GC) methylprednisolone (MP) alone and in combination with rapamycin in peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. The effect of MP, rapamycin, and MP plus rapamycin was determined in 17 healthy donors by labelling metabolically active cells with [methyl-3H] thymidine and the expression levels of GAS5 gene were evaluated by real-time RT-PCR TaqMan analysis. We confirmed a role for GAS5 in modulating GC response: poor responders presented higher levels of GAS5 in comparison with good responders. Interestingly, when PBMCs were treated with the combination of rapamycin plus MP, the high levels of GAS5 observed for each drug in the MP poor responders group decreased in comparison with rapamycin (P value = 0.0134) or MP alone (P value = 0.0193). GAS5 is involved in GC resistance and co-treatment of rapamycin with GCs restores GC effectiveness in poor responders through the downregulation of the long noncoding RNA. GAS5 could be considered a biomarker to personalize therapy and a novel therapeutic target useful for the development of new pharmacological approaches to restore GC sensitivity.


Treatment of nodules associated with port wine stains with CO2 laser: case series and review of the literature.
Port wine stains (PWS) are congenital malformations of capillaries, where with progression, blood vessels become ectatic and result in disfiguring nodules. To search the MEDLINE database and review literature on the treatment of PWS and present 2 cases of adults with PWS, complicated by hypertrophic and nodular lesions, treated successfully with CO2 laser. Two patients with PWS, with nodular and hypertrophic areas, were treated with CO2 laser. With the first patient, improvement of 90% or greater was noted in the 14 discrete nodules present within the PWS in a V2 distribution. At baseline, ectropion of the lower eyelid was noted which resolved completely after CO2 laser. With the second patient, improvement was noted as 90% or greater in the 40 of 51 discrete nodules present within the PWS extending across the right V1-V2 distribution. Carbon dioxide ablative laser resurfacing is safe and highly effective in the treatment of the nodular and hypertrophic components of PWS. Future treatment of PWS will likely involve a hybrid approach of utilizing nonablative lasers of varying wavelengths and pulse durations and treatment with novel laser devices, with the goal of early treatment to prevent progression of PWS to disfiguring lesions.


Leaf structural responses to pre-industrial, current and elevated atmospheric [CO2] and temperature affect leaf function in Eucalyptus sideroxylon.
Leaf structure and chemistry both play critical roles in regulating photosynthesis. Yet, a key unresolved issue in climate change research is the role of changes in leaf structure in photosynthetic responses to temperature and atmospheric CO2 concentration ([CO2]), ranging from pre-industrial to future levels. We examined the interactive effects of [CO2] (290, 400 and 650μLL-1) and temperature (ambient, ambient +4°C) on leaf structural and chemical traits that regulate photosynthesis in Eucalyptus sideroxylon A.Cunn. ex Woolls. Rising [CO2] from pre-industrial to elevated levels increased light-saturated net photosynthetic rates (Asat), but reduced photosynthetic capacity (Amax). Changes in leaf N per unit area (Narea) and the number of palisade layers accounted for 56 and 14% of the variation in Amax, respectively, associated with changes in leaf mass per area. Elevated temperature increased stomatal frequency, but did not affect Amax. Further, rising [CO2] and temperature generally did not interactively affect leaf structure or function. These results suggest that leaf Narea and the number of palisade layers are the key chemical and structural factors regulating photosynthetic capacity of E. sideroxylon under rising [CO2], whereas the lack of photosynthetic responses to elevated temperature may reflect the limited effect of temperature on leaf structure and chemistry.


Enriched biodiversity data as a resource and service.
Recent years have seen a surge in projects that produce large volumes of structured, machine-readable biodiversity data. To make these data amenable to processing by generic, open source "data enrichment" workflows, they are increasingly being represented in a variety of standards-compliant interchange formats. Here, we report on an initiative in which software developers and taxonomists came together to address the challenges and highlight the opportunities in the enrichment of such biodiversity data by engaging in intensive, collaborative software development: The Biodiversity Data Enrichment Hackathon. The hackathon brought together 37 participants (including developers and taxonomists, i.e. scientific professionals that gather, identify, name and classify species) from 10 countries: Belgium, Bulgaria, Canada, Finland, Germany, Italy, the Netherlands, New Zealand, the UK, and the US. The participants brought expertise in processing structured data, text mining, development of ontologies, digital identification keys, geographic information systems, niche modeling, natural language processing, provenance annotation, semantic integration, taxonomic name resolution, web service interfaces, workflow tools and visualisation. Most use cases and exemplar data were provided by taxonomists. One goal of the meeting was to facilitate re-use and enhancement of biodiversity knowledge by a broad range of stakeholders, such as taxonomists, systematists, ecologists, niche modelers, informaticians and ontologists. The suggested use cases resulted in nine breakout groups addressing three main themes: i) mobilising heritage biodiversity knowledge; ii) formalising and linking concepts; and iii) addressing interoperability between service platforms. Another goal was to further foster a community of experts in biodiversity informatics and to build human links between research projects and institutions, in response to recent calls to further such integration in this research domain. Beyond deriving prototype solutions for each use case, areas of inadequacy were discussed and are being pursued further. It was striking how many possible applications for biodiversity data there were and how quickly solutions could be put together when the normal constraints to collaboration were broken down for a week. Conversely, mobilising biodiversity knowledge from their silos in heritage literature and natural history collections will continue to require formalisation of the concepts (and the links between them) that define the research domain, as well as increased interoperability between the software platforms that operate on these concepts.


Transhiatal versus transthoracic esophagectomy for esophageal cancer.
Esophageal cancer continues to represent a formidable challenge for both patients and clinicians. Relative 5-year survival rates for patients have improved over the past three decades, probably linked to a combination of improved surgical outcomes, progress in systemic chemotherapy and radiotherapy, and the increasing acceptance of multimodality treatment. Surgical treatment remains a fundamental component of the treatment of localized esophageal adenocarcinoma. Multiple approaches have been described for esophagectomy, which can be thematically grouped under two major categories: either transthoracic or transhiatal. The main controversy rests on whether a more extended resection through thoracotomy provides superior oncological outcomes as opposed to resection with relatively limited morbidity and mortality through a transhiatal approach. After numerous trials have addressed these issues, neither approach has consistently proven to be superior to the other one, and both can provide excellent short-term results in the hands of experienced surgeons. Moreover, the available literature suggests that experience of the surgeon and hospital in the surgical management of esophageal cancer is an important factor for operative morbidity and mortality rates, which could supersede the type of approach selected. Oncological outcomes appear to be similar after both procedures.


Detection of mutation(s) or polymorphic loci in the genome of experimental animal and human cancer tissues by RAPD/AP-PCR depend on DNA polymerase.
Examination of mutations by random amplified polymorphic DNA (RAPD) (also called arbitrarily primed PCR = AP-PCR) in the breast and Wilm's human cancer tissues as well as in estrogen-induced hamster kidney cancer tissues revealed a gain or loss of amplified fragments sizes in breast and Wilm's tumors compared to their respective controls. We also observed changes in the intensity of amplified fragments in tumor DNA compared to control DNA. Most importantly, we found that detection of mutation in the genome of cancer tissue compared to normal tissue by RAPD/AP-PCR depends upon the type of DNA polymerases used. This is the first report showing that polymerase ability to extend a particular locus of the gene is influenced by mutation in the primer binding sites in the competitive environment where several genomic sequences flanked to a random primer are co-amplified by RAPD/AP-PCR. Findings of this study suggest that: i) instead of directly adopting published RAPD protocol it is essential to optimize RAPD reaction conditions by varying magnesium chloride and polymerase concentration with different amounts of DNA templates in order to observe reproducible fingerprints of randomly amplified polymorphic DNA fragments, ii) alterations in the genome as a loss, gain, or decrease and increase in amplification intensity of loci were observed in human tumors as well as in an experimental animal tumor, and iii) before concluding that a mutation is not present when using RAPD/AP-PCR, different polymerases should be used to amplify the genome of the same control or tumor tissues.


Evaluation of surgical skills in microgravity using force sensing.
Force measurements can be used to characterize surgical maneuvers in microgravity. : A series of surgical tasks was performed by a group of 20 participants (n=20) both in 1g on the ground and in 0 g aboard NASA's KC-135 aircraft in parabolic flight. The group included astronauts, a flight surgeon, surgeons, physicians, Ph.D.-scientists, and technical personnel. The interaction forces between the surgical instruments and the mock tissue were measured for a clip-applying, suturing, grasping, and cutting. Seven evaluations in 1g and a single evaluation in 0 g were performed by each of the participants. The data from a single participant are examined in detail. Statistical results for the group of 20 participants do not show significant differences in the average or peak forces during clip-applying or in the average forces applied during suturing in 0 g versus in 1g. However, the results do show statistically greater (43% higher) peak forces during suturing in microgravity. These data show the usefulness of analyzing force information to assess surgical task performance in microgravity. Although peak suturing forces were statistically higher in microgravity, their clinical relevance is unknown, but likely would not result in a change in clinical outcome. Overall, the data suggest that forces exerted during surgical tasks will not pose a significant barrier to effective surgery in microgravity.


Induction of stress genes by low doses of gamma rays.
Using cells of a human myeloid tumor cell line (ML-1), we have detected induction of several stress-responsive genes by doses of gamma rays below 50 cGy. We found a linear dose-response relationship for induction of CDKN1A (formerly known as CIP1/WAF1) and GADD45 mRNA levels over the range of 2-50 cGy, with no evidence of a threshold for induction. Although exposures to 2 and 5 cGy did not result in any detectable reduction in cloning efficiency or increased apoptosis in ML-1 cells, these exposures did produce a transient delay of cells in the phases of the cell cycle in addition to the observed up-regulation of CDKN1A and GADD45. The relative induction of genes such as CDKN1A by radiation doses that produce little toxicity indicates that surviving cells do contribute significantly to the observed stress responses. These studies should provide insight into the molecular responses to physiologically relevant doses that cannot necessarily be extrapolated from high-dose studies.


Circulating concentrations of interleukin-18, interleukin-18 binding protein, and gamma interferon in patients with alcoholic hepatitis.
Alcoholic hepatitis (AH) is associated with dysregulated inflammatory and immune responses. interleukin-18 (IL-18), described as gamma interferon (gammaIFN)-inducible factor, and its natural antagonist, IL-18 binding protein (IL-18 BP), has not been fully studied in patients with AH. Thus, our aim was: (i) to determine plasma values of IL-18, IL-18 BP, gammaIFN, and tumor necrosis factor alpha (TNF)-alpha in patients hospitalized for biopsy-proven AH; (ii) to correlate these cytokines with the severity of AH, as assessed by Maddrey's discriminant function (DF), the degree of liver failure using the Child-Pugh score and blood neutrophils; (iii) to compare cytokines values in survivors and non-survivors. Cytokines were measured using specific immunoassays within 7 days of admission. The diagnosis of AH was based on histology in all cases. We studied 43 cirrhotic patients with a Maddrey's DF>/=32 (severe AH), 29 patients with a score <32 (non-severe AH), 12 patients with abstinent alcoholic cirrhosis, and 10 healthy subjects. IL-18 and TNFalpha were increased in severe AH as compared with healthy subjects. Plasma IL-18 BP was elevated in patients with severe and non-severe AH as compared with healthy subjects. gammaIFN did not differ between groups. In patients with severe and non-severe AH, IL-18, IL-18 BP, TNFalpha, but not gammaIFN, were positively correlated to DF and Child-Pugh score. Neither IL-18 nor IL-18 BP correlated to TNFalpha. Patients who died (n=10) during the hospitalization had higher IL-18 BP and TNFalpha at admission as compared with survivors (322 [172-504] vs 222 [109-441] ng/ml; 7.5 [2.2-17.3] vs 3 [0.6-20] pg/ml, P<0.01, respectively). In cirrhotic patients with AH, IL-18, IL-18 BP, and TNFalpha correlate to the hepatitis severity and to the degree of liver failure. High IL-18 BP and TNFalpha at hospital admission in non-survivors suggest it may be of prognostic value.


Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: Definition, incidence and outcomes.
Acute traumatic coagulopathy (ATC) has been reported in the setting of isolated traumatic brain injury (iTBI) and associated with poor outcomes. Among patients with iTBI, we aimed to select an appropriate definition of ATC, outline the incidence of ATC and examine clinical variables associated with ATC. A retrospective review of The Alfred Trauma Registry was conducted and patients with iTBI (head AIS [Abbreviated Injury Score] ≥ 3 and all other body regions AIS < 3) were selected for analysis. The association of the international normalised ratio (INR) on arrival at hospital with the mortality on hospital discharge was explored, to select an appropriate clinical horizon to define ATC. The incidence of ATC was calculated using this definition. Injury and clinical variables measurable pre-hospital and immediately on arrival at the hospital were analysed to determine independent associations with ATC. There were 1718 patients with iTBI included in the study. The overall mortality was 12%, but significantly greater when initial INR was measured at ≥ 1.3 (45.1%; p < 0.01). The proportion of patients with ATC, using this definition, was 7.7% (95% CI: 6.5-9.0). The pre-hospital variables independently associated with ATC in the setting of iTBI were age (OR 1.02, 95% CI 1.01-1.03), shock index (SI) of ≥ 1 (OR 1.68, 95% CI 1.01-2.79) and abnormal pupils (OR 8.33, 95% CI 4.50-15.89). The presence of at least two factors, of age > 50 yrs, SI ≥ 1, or abnormal pupils, was 97.54% (95% CI: 96.6-98.2) specific for ATC. An abnormal initial INR in the setting of iTBI was associated with poor outcomes, regardless of magnitude. The incidence of ATC appears too low to recommend empiric pro-coagulant management for all patients with iTBI. The subgroup of patients older than 50 yrs., with shock or abnormal size of pupils, may be considered for interventional trials of early treatment against ATC.


Intubation difficulty scale contributors and time delay in clinical practice.
The intubation difficulty scale (IDS) includes 7 contributors that provide a comprehensive assessment of difficult intubation. However, the effect of each contributor is unclear, and the scale has not been revalidated recently and has not been validated in orient. This study determined the duration of successful intubation (DSI) for each of these 7 contributors.The patients were intubated by attending anesthesiologists. The duration and other data were recorded by 2 research assistants. Anaesthesiologists reported the IDS and their perceptions. A linear mixed-effects model with a DSI was constructed using IDS factors.In total, 1095 patients were enrolled. The average DSI was 23.9 ± 21.8 seconds (37.1% IDS = 0). All 7 factors were independently associated with duration, with the exception of vocal cord adduction. The best model was as follows: DSI (in seconds) = 15.2 + 31.1 (number of additional attempts) + 26.2 (number of additional operators) + 11.4 (number of alternative techniques) + 7.9 (increased lift force) + 4.9 (external laryngeal pressure) + 3.5 (Cormack grade 1). The mixed models were similar except for the regression coefficient for the number of alternative techniques that decreased from 11.4 to 6.9 seconds.We confirmed that each IDS contributor affects the DSI and validated a prediction model with 6 IDS contributors. This prediction model may facilitate the development of strategic plans for critical airway management. Furthermore, it could improve simulations and monitor learning progress and help provide valuable feedback.


Endoscopic, "Scarless" Composite Flap Face and Neck Lift.
Deep-plane or composite flap facelift techniques allow deep structural rejuvenation of the face by release of retaining ligaments in the subsuperficial musculoaponeurotic system (sub-SMAS) plane with elevation and fixation of the SMAS/platysma/skin flap as a single, "en bloc" unit. This means that in the cases with mild to moderate skin laxity, the preauricular incision serves the purpose of access only. The author therefore developed an endoscopic-assisted, en bloc composite flap face and neck lift without a preauricular incision. The technique uses the prezygomatic and premasseteric (facial) and subplatysmal (neck) spaces as ideal optical cavities for endoscopic dissection and ligament release. Verticalization of fixation vectors and modified concho-mastoid traction sutures are used to minimize preauricular skin redundancy. The surgical procedure is described in detail. Clinical experience in 41 consecutive cases and comparison to other techniques with respect to relevant anatomy are also presented. This endoscopic en bloc composite flap facelift technique consistently and safely produced results comparable to conventional, "open" composite flap facelifts done by the same surgeon on similar candidates during a prior period.


Salmonella serovars from foodborne and waterborne diseases in Korea, 1998-2007: total isolates decreasing versus rare serovars emerging.
Salmonella enterica has been one of the most widespread foodborne pathogens in Korea. Between 1998 and 2007, a total of 9,472 Salmonella isolates were identified from foodborne and waterborne illness patients. During that time, Korea was transitioning into a developed country in industry as well as in its hygiene system. Although the isolation number of total Salmonella including serovar Typhi has decreased since 1999, the isolation of rare Salmonella serovars has emerged. Three most prevalent serovars during 1998-2007 were S. enterica Typhi, S. enterica Enteritidis, and S. enterica Typhimurium. There were remarkable outbreaks caused by rare serovars such as S. enterica Othmarschen, S. enterica London and S. enterica Paratyphi A, and overseas traveler-associated infections caused by S. enterica Weltevreden and S. enterica Anatum. Salmonella serovars from overseas travelers made a diverse Salmonella serovar pool in Korea. This study is the first review of the status of the human Salmonella infection trend in a developing country during 1998-2007. Newly emerging rare Salmonella serovars should be traced and investigated to control new type pathogens in the developed world.


Rural barriers to early lung cancer detection: Exploring access to lung cancer screening programs in New Hampshire and Vermont.
Rural populations face many health disadvantages compared to urban areas. There is a critical need to better understand the current lung cancer screening landscape in these communities to identify targeted areas to improve the impact of this proven tool. Data from the County Health Rankings of New Hampshire and Vermont was reviewed for population density, distribution of adult smokers, and level of education compared to the distribution of Lung Cancer Screening Facilities throughout these two states. Screening programs in southern counties of Vermont with lower levels of education have decreased access. In New Hampshire, there are no programs within 30 miles of the areas with the largest distribution of smokers, and decreased access in some areas with the lowest levels of education. Improving equitable access to high-quality screening services in rural regions and the creation of targeted interventions to address decreased access in areas of high tobacco use and low education is vital to decreasing the incidence of latestage presentations of lung cancer within these populations.


Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling.
Aim. The aim of this study was to investigate the influence of age, gender, obesity and scaling on glomerular filtration rate (GFR) and extracellular fluid volume (ECV) in healthy subjects. This is a retrospective multi-centre study of 1878 healthy prospective kidney transplant donors (819 men) from 15 centres. Age and body mass index (BMI) were not significantly different between men and women. Slope-intercept GFR was measured (using Cr-51-EDTA in 14 centres; Tc-99m-DTPA in one) and scaled to body surface area (BSA) and lean body mass (LBM), both estimated from height and weight. GFR was also expressed as the slope rate constant, with one-compartment correction (GFR/ECV). ECV was measured as the ratio, GFR to GFR/ECV. ECV was age independent but GFR declined with age, at a significantly faster rate in women than men. GFR/BSA was higher in men but GFR/ECV and GFR/LBM were higher in women. Young women (<30 years) had higher GFR than young men but the reverse was recorded in the elderly (>65 years). There was no difference in GFR between obese (BMI>30 kg/m2) and non-obese men. Obese women, however, had lower GFR than non-obese women and negative correlations were observed between GFR and both BMI and %fat. The decline in GFR with age was no faster in obese versus non-obese subjects. ECV/BSA was higher in men but ECV/LBM was higher in women. ECV/weight was almost gender independent, suggesting that fat-free mass in women contains more extracellular water. BSA is therefore a misleading scaling variable. There are several significant differences in GFR and ECV between healthy men and women.


[Cu(II) complexes with biomacromolecules. The use of Cu(II) ions as a structural spin label].
Complexes of Cu(II) ions with globular proteins (human serum albumin, bovine serum albumin, egg albumin, lisozim and DNA) have been studied using the ESR method. It was shown that Cu(II) ions may be use as structural "spin-label" to study conformational dynamics of macromolecules, including structural transition in biopolymers.


Lead Discovery of Dual G-Quadruplex Stabilizers and Poly(ADP-ribose) Polymerases (PARPs) Inhibitors: A New Avenue in Anticancer Treatment.
G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells, and has an antiproliferative effect in BRCA2 deficient tumor cells.