Transition of an estuarine benthic meiofauna assemblage 1.7 and 2.8 years after a mining disaster.
Estuaries are transitional coastal ecosystems that are threatened by multiple sources of human pollution. In 2015, mining tailings from an upstream dam failure caused massive metal contamination that impacted benthic assemblages on the Brazilian Rio Doce estuary. In this study, we investigate and compare meiofaunal assemblages with eDNA metabarcoding 1.7 years (2017) and 2.8 years (2018) after the initial contamination by mine tailings in order to evaluate the continued impact of sediment mine tailing contaminants on the structure of benthic assemblages after the disaster. The community was dominated by Arthropoda and Nematoda 1.7 yr after the impacts (42 and 29% of meiofaunal sequence reads, respectively) but after 2.8 years Arthropoda (64.8% of meiofaunal sequence reads) and Rotifera (11.8%) were the most common taxa. This continued impact on meiofaunal assemblage revealed a lower phylogenetic diversity (7.8-fold) in 2018, despite overall decrease in metal concentration (Al, Ba, Cr, As, Fe, Zn, Mn, Pb, Cd, Co) in sediments. Our data suggests that differences in benthic assemblages and loss of diversity may be influenced by contaminants in sediments of this estuary, and indicate that broad eDNA assessments are greatly useful to understand the full range of biodiversity changes in dynamic estuarine ecosystems.


Synthesis, structure, spectra and reactivity of iron(III) complexes of facially coordinating and sterically hindering 3N ligands as models for catechol dioxygenases.
A series of 1 : 1 iron(III) complexes of sterically hindered and systematically modified tridentate 3N donor ligands have been isolated and studied as functional models for extradiol-cleaving catechol dioxygenases. All of them are of the type [Fe(L)Cl(3)], where L is N-methyl-N'-(pyrid-2-ylmethyl)ethylenediamine (L1), N-ethyl-N'-(pyrid-2-ylmethyl)ethylenediamine (L2), N-benzyl-N'-(pyrid-2-ylmethyl)ethylenediamine (L3), N,N-dimethyl-N'-(pyrid-2-ylmethyl)ethylenediamine (L4), N'-methyl-N'-(pyrid-2-ylmethyl)-N,N-dimethylethylenediamine (L5), N'-ethyl-N'-(pyrid-2-ylmethyl)-N,N-dimethylethylenediamine (L6) and N'-benzyl-N'-(pyrid-2-ylmethyl)-N,N-dimethylethylenediamine (L7). They have been characterized by elemental analysis and spectral and electrochemical methods. The X-ray crystal structures of the complexes [Fe(L2)Cl(3)] 2, [Fe(L3)Cl(3)] 3 and [Fe(L7)Cl(3)] 7 have been successfully determined. All the three complexes possess a distorted octahedral coordination geometry in which the ligand is facially coordinated to iron(III) and the chloride ions occupy the remaining coordination sites. Upon replacing the N-ethyl group on the terminal nitrogen donor in 2 by the bulky N-benzyl group as in 3, the terminal Fe-N bond distance increases slightly from 2.229(5) A to 2.244(5) A. Upon incorporating the sterically demanding N-benzyl group on the central nitrogen donor in 4 to obtain 7, the central Fe-N(amine) bond distance increases from 2.181(5) A to 2.299(2) A. The catecholate adducts [Fe(L)(DBC)(Cl)] and [Fe(L)(DBC)(Sol)](+), where H(2)DBC is 3,5-di-tert-butylcatechol and Sol = solvent (H(2)O/DMF), have been generated in situ and their spectral and redox properties and dioxygenase activities have been studied in N,N-dimethylformamide and dichloromethane solutions. The adducts [Fe(L)(DBC)(Sol)](+) undergo cleavage of DBC(2-) in the presence of molecular oxygen to afford both intra- and extradiol cleavage products. The extradiol products are higher in dichloromethane than in DMF solution and the extradiol to intradiol product selectivity (E/I, 7.2 : 1-18.5 : 1) observed decreases upon increasing the steric bulk of N-alkyl substituent on the terminal nitrogen atom and upon incorporating an N-alkyl substituent on the central nitrogen atom. The plot of log(k(O(2))) vs. energy of the low energy catecholate-iron(III) LMCT band is linear, which is consistent with the proposal that the LMCT band energy corresponds to the energy needed for a spin-inversion process at the iron center upon dioxygen attack. Also, the rate of oxygenation is dictated by the solvent as well as the Lewis acidity of the iron(III) center, as shown by the linear plot of log(k(O(2))) vs.E(1/2) of the Fe(III)/Fe(II) redox potentials of the [Fe(L)(Sol)(3)](3+) complexes.


Toll-like receptor 2 and NLRP3 cooperate to recognize a functional bacterial amyloid, curli.
Amyloids are proteins with cross-β-sheet structure that contribute to pathology and inflammation in complex human diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes, and secondary amyloidosis. Bacteria also produce amyloids as a component of their extracellular matrix during biofilm formation. Recently, several human amyloids were shown to activate the NLRP3 inflammasome, leading to the activation of caspase 1 and production of interleukin 1β (IL-1β). In this study, we investigated the activation of the NLRP3 inflammasome by bacterial amyloids using curli fibers, produced by Salmonella enterica serovar Typhimurium and Escherichia coli. Here, we show that curli fibers activate the NLRP3 inflammasome, leading to the production of IL-1β via caspase 1 activation. Investigation of the underlying mechanism revealed that activation of Toll-like receptor 2 (TLR2) by curli fibers is critical in the generation of IL-1β. Interestingly, activation of the NLRP3 inflammasome by curli fibers or by amyloid β of Alzheimer's disease does not cause cell death in macrophages. Overall, these data identify a cross talk between TLR2 and NLRP3 in response to the bacterial amyloid curli and generation of IL-1β as a product of this interaction.


Peripheral joint involvement in psoriatic arthritis patients.
Peripheral joint involvement is a common, potentially debilitating feature of psoriatic arthritis (PsA). Joint involvement is commonly symmetrical and polyarticular similar to rheumatoid arthritis (RA) but it can also be oligoarticular, asymmetrical or occasionally monoarticular. Involvement of the distal interphalangeal joints is a feature which distinguishes PsA from RA. Articular involvement in PsA can be severe with a mutilating arthropathy found in about 5%. These patients are characterised clinically by digital shortening and on radiographs by erosion on both sides of the joint and/or osteolysis. Treatments targeting joint disease frequently reduces symptoms and signs resulting in prevention of damage progression.


Effect of persistent pulmonary hypertension on brain oxygenation in asphyxiated term newborns treated with hypothermia.
To better understand the impact of persistent pulmonary hypertension (PPHN) on brain oxygenation in term asphyxiated newborns treated with hypothermia. The regional cerebral oxygenation saturation (rSO2) measured by near-infrared spectroscopy was compared to pre/post-ductal oxygen saturation and mean arterial blood pressure in three term asphyxiated newborns with documented PPHN during their first 4 days of life while they were being treated with hypothermia. The cerebral oxygen saturation remained relatively stable when oxygen saturation was more than 92% and when there was no difference between pre- and post-ductal oxygen saturations. Episodes of desaturations with a difference between pre- and post-ductal saturations, as well as episodes of hypotension, caused a significant decrease in rSO2 in these newborns. This case series demonstrates that PPHN has a profound impact on brain oxygenation in term asphyxiated newborns treated with hypothermia during the first days of life after birth. PPHN may represent an additional risk factor for brain injury in these newborns during the first days of life.


Coronary artery disease in aircrew fatalities: morphology, risk factors, and possible predictors.
Coronary artery disease (CAD) is a common diagnosis at autopsies of military and civil aircrews. Identifying aviators with a high risk of an acute coronary syndrome is of aeromedical interest as it allows flight surgeons to employ prevention and intervention strategies to avoid death or a lifelong duties not including flying (DNIF) status of aircrew members. The aim of this study was to identify possible predictors of high-risk CAD. In this aeropathological and aeromedical study the coronary artery systems of 21 German aircrew members killed in aircraft accidents was comprehensively examined. Then laboratory findings and bicycle ergometry results from their medical records were correlated to evaluate their predictive potential for CAD in our cohort. Of those killed, 1/3 had no CAD whatsoever; the rest had mild, moderate, or severe CAD, depending on the classification system used. There were 48% who had findings considered disqualifying according to JAR FCL-3. Three cases (14%) showed thin cap fibroatheromas (TCFA). There were 15 ergometry tests recorded prior to the accident that could be reviewed. Minor findings were more frequent in the groups of more severe CAD, but not statistically significant. Laboratory findings did not correlate with CAD severity. Only serum cholesterol levels in the "disqualifying" group of the JAR-FCL classification were slightly higher compared to the remaining cases. Our results suggest that ergometry findings may help to identify individuals with asymptomatic CAD. Further verification, e.g., by noninvasive coronary imaging, would then be the basis for strict cardiovascular risk management. For future aeropathological studies on the prevalence of CAD, we suggest that a classification system be established regarding higher degree luminal narrowing as well as plaque morphology, and especially the occurrence of TCFA.


[Sepsis and multiple organ failure - update of current therapeutic concepts].
Severe sepsis with multiple organ dysfunctions is still the leading cause of death in non-cardiac intensive care units. The incidence is expected to rise in the future due to the growing number of older and immuno-compromized patients, the use of invasive procedures, and an increase in the percentage of aggressive or resistant microorganisms. Despite the enormous investment in critical care resources, mortality of severe sepsis remaines on a high level and ranges from 28 - 50 %. Based on the disappointing experiences with anti-inflammatory strategies, we now realize that sepsis is more than just inflammation. The new therapeutic approaches take account of this more sophisticated view of pathophysiologic changes, resulting in the modulation of the coagulation in combination with an improvement of the ICU-management of organ dysfunctions. This review discusses the therapeutic concepts, reported es exciting new interventions in the ICU setting to decrease the inacceptable high mortality in patients with severe sepsis.


Arynes in the Monoarylation of Unprotected Carbohydrate Amines.
A CsF-mediated method has been developed for the N-arylation of amino sugars that affords good to excellent yields of arylated products under mild conditions involving the in situ generation of arynes. The reaction conditions tolerate a variety of common carbohydrate protecting groups and also performs exceptionally well on unprotected amino sugar derivatives. The reactions are scalable in moderate to good yields with broad scope.


Detection of nodules in liver cirrhosis: spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients.
Detection and characterization of all focal lesions in the liver are critical for screening patients with chronic liver disease. The aim of this prospective study was to investigate the accuracy of magnetic resonance imaging (MRI) and spiral computed tomography for the diagnosis of hepatic nodules in cirrhotic patients when compared with pathological findings of the explanted liver. From February 1997 to July 1999, 34 cirrhotic patients waiting for orthotopic liver transplantation (OLT) (mean age, 53.5 +/- 9.3 years; 24 males) were included. All patients had MRI and spiral computed tomography examinations, and findings were matched with the histological findings. Data analyses were made using the McNemar chi-square test. Mean time between radiological examination (MRI or spiral computed tomography) and OLT was 43.8 +/- 39 days. A total of 88 nodules were found in the 34 patients: 54 hepatocellular carcinoma (HCC) (mean size, 18 +/- 10 mm) in 21 patients, 22 dysplastic nodules (mean size, 10.7 +/- 4.3 mm) in 11 patients, and 12 macroregenerative nodules in 13 patients. Lesion-by-lesion analyses showed that sensitivity of MRI and spiral computed tomography for nodule, HCC or dysplastic nodule diagnosis was 44.3 and 31.8% (P = 0.02), 61.1 and 51.9% (P = 0.2), and 27.3 and 0% (P = 0.04), respectively. Patient-by-patient analyses showed no statistical difference between spiral computed tomography and MRI for nodule diagnosis. In conclusion, in patients with liver cirrhosis, MRI is more accurate than spiral computed tomography for the detection of liver nodules and dysplastic nodules. However, tumour size is always a restricting factor for these two techniques, which are unable to detect small HCC in more than 60% of cases.


Shigella IpgB1 promotes bacterial entry through the ELMO-Dock180 machinery.
Shigella use a special mechanism to invade epithelial cells called 'the trigger mechanism of entry', which allows epithelial cells to trap several bacteria simultaneously. On contact, Shigella deliver effectors into epithelial cells through the type III secretion system. Here, we show that one of the effectors, IpgB1, has a pivotal role in producing membrane ruffles by exploiting the RhoG-ELMO-Dock180 pathway to stimulate Rac1 activity. Using pulldown assays, we identified engulfment and cell motility (ELMO) protein as the IpgB1 binding partner. IpgB1 colocalized with ELMO and Dock180 in membrane ruffles induced by Shigella. Shigella invasiveness and IpgB1-induced ruffles were less in ELMO- and Dock180-knockdown cells compared with wild-type cells. Membrane association of ELMO-Dock180 with ruffles were promoted when cells expressed an IpgB1-ELMO chimera, establishing that IpgB1 mimics the role of RhoG in producing membrane ruffles. Taken together, our findings show that IpgB1 mimicry is the key to invasion by Shigella.


Chronic polyradiculoneuropathy of infancy. A report of three cases with familial incidence.
Two siblings and a third child exhibited a syndrome of progressive muscular weakness and wasting, closely resembling Werdnig-Hoffmann's disease. Autopsy of one of the siblings and the third child showed nearly total absence of myelin sheaths in the cranial and spinal nerve roots, relative preservation of axons, and normal neurons in the motor cranial nerve nuclei and anterior spinal gray matter. The mother of the siblings had bilateral pes cavus, and the father of the third child had a sensory-motor polyneuropathy dating to childhood, associated with pes cavus and scoliosis. The disorder in these children and in a few similar cases in the literature shares some features of Charcot-Marie-Tooth disease and the hypertrophic neuropathy of Dejerine-Sottas, but it is difficult to classify as either of these familial neuropathies as presently defined. Elevation of cerebrospinal fluid protein is a useful finding in distinguishing such children from patients with Werdnig-Hoffmann's disease.


Cell- and protein-based therapy approaches for epidermolysis bullosa.
Dystrophic epidermolysis bullosa (DEB) is a clinically heterogeneous heritable skin fragility disorder characterized by mechanically induced mucocutaneous blistering. On the molecular level DEB is caused by mutations leading to deficiency in collagen VII (CVII), a large extracellular protein building anchoring fibrils that attach the epidermis to the dermis. Severely affected patients suffer from wounds, which heal with excessive scarring causing mutilating deformities of hands and feet. The patients are also predisposed to development of aggressive squamous cell carcinomas at sites of chronic wounds. Currently no available therapies exist for this extremely disabling and stigmatizing disorder. We are developing and evaluating cell- and protein-based therapies for the management of DEB. Dermal fibroblasts are easy to propagate in vitro, they produce CVII, and they have immunomodulating capacities, which makes it possible to use allogeneic fibroblasts for therapy without risking major adverse effects from the host's immune system. Hence, fibroblasts, and fibroblast-like cells such as mesenchymal stromal cells, are prime candidates for cell-based DEB therapies. An alternative for management of disorders caused by defects in proteins with relatively low turnover rate is to introduce the protein de novo to the tissue by direct application of the protein. CVII is long-lived and expressed in moderate amounts in the skin; this makes injection of collagen VII protein a realistic approach for the treatment of DEB. Here we present methods and protocols that we are using for fibroblast- and recombinant CVII-based therapies of DEB in our model of this disease, the CVII hypomorphic mouse. These protocols are directed towards management of DEB but they can be easily adapted for the treatment of other skin fragility disorders.


Salmonella pullorum in the common pheasant (Phasianus colchicus).
In 1996, pullorum disease due to Salmonella enterica serovar Gallinarum biovar pullorum (Salmonella pullorum) was diagnosed in pheasants on a gamebird rearing enterprise in south-west Scotland. The gross pathology and bacteriological findings are described, as are the results of screening for S pullorum on the site in 1997. The causal organism was readily isolated from the lung, liver, yolk sac and heart blood on direct culture, but less readily from the digestive tract or by the use of selective media. The bacteria recovered from the pheasants were identified as S pullorum phage type 7, a phage type previously associated with pheasants rather than domestic fowl, and the organisms were most probably introduced to the site by the movement of carrier pheasants.


Conduction System Pacing Upgrade in Chronic Heart Failure with Severe Left Ventricular Dysfunction and Chronic Atrial Fibrillation.
Cardiac resynchronization therapy (CRT) is a standard treatment for patients with severe congestive heart failure. However, one-third of patients receiving CRT are non-responders. Conduction system pacing (CSP), including His-bundle pacing (HBP) and left bundle branch area pacing (LBBAP), has become an alternative to CRT therapy. Furthermore, CRT therapy with CSP has shown to be more effective than CRT alone. When an implantable cardiac defibrillator or CRT-defibrillator is implanted with CSP, the problem of which port the HBP lead and LBBAP lead should be connected to arises. We report 2 cases of upgrading to CRT with CSP by utilizing the atrial ports for HBP and LBBAP leads. The procedure is a simple, reasonable, and effective therapy for end-stage heart failure.


Circulating microRNAs as Promising Biomarkers in Colorectal Cancer.
Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related deaths worldwide. Despite numerous advances in therapeutic approaches, this cancer has a poor prognosis when it is diagnosed at late stages. Therefore, the scientific effort is nowadays directed towards the development of new non-invasive and dynamic biomarkers to improve the survival expectancy of CRC patients. In this sense, deregulated expression of many miRNAs has been shown to play an important role for CRC carcinogenesis and dissemination. Noticeably, an increasing number of studies highlight that circulating miRNAs, including those traveling inside exosomes or those released by tumor cells into circulation, constitute a promising tool for early detection, prognosis and therapy selection of CRC. Therefore, in this review we focus on the clinical potential of blood circulating miRNAs as emerging biomarkers with high value to improve the clinical management of CRC patients, providing a deep and complete perspective of the realities and challenges to translate these biomarkers to the clinical context.


Low incidence of miscarriage induced by the scent of male littermates of original mates: male kinship reduces the bruce effect in female mice, Mus musculus.
The scent of a novel male can elicit pregnancy block in recently mated female mice (Mus musculus), a phenomenon known as the Bruce effect. Despite abundant literature on the Bruce effect in rodents, it remains unclear whether males related to a female's original mate can induce the Bruce effect in out-bred, communally living mice. We investigated this question using Kunming (KM) male mice of varying genetic relatedness. Recently mated females were subjected to three treatments: exposure to the urine of the mate, urine of the mate's male littermate, and urine of a male unrelated to the mate. It was found that the urine of male littermates of the females' mates did not elicit more pregnancy block than that of the females' mates. However, the urine of novel males caused a higher rate of female miscarriage than that of the females' mates. By using a habituation-dishabituation paradigm, we found that unmated females could discriminate the urine scents of two male littermates from those of a novel male unrelated to the littermates. To understand how females use urinary cues to discriminate between males with different genetic relationships, we used gas chromatography coupled with mass spectrometry (GC-MS) to examine the volatile composition of urine from males with varying relatedness. It was found that KM male littermates shared similar volatile compositions in their urine. Our results suggest that male kinship reduces the Bruce effect in female KM mice, and provide additional evidence for mate choice being partly mediated by the Bruce effect in KM mice.


"The Pain Left, I Was Off and Running": A Qualitative Analysis of Group Acupuncture and Yoga Therapy for Chronic Pain in a Low-Income and Ethnically Diverse Population.
Introduction: Chronic pain and the current opioid epidemic are pressing public health concerns, especially in low-income and ethnically diverse communities. Nonpharmacologic therapies that are safe, effective, and acceptable for the treatment of chronic pain conditions may provide a solution for addressing this issue. This qualitative analysis explores the experience of study participants who received combined acupuncture and yoga therapy (YT) to treat chronic pain delivered in a primary care setting. Methods: The group acupuncture with yoga therapy for chronic neck, low back, and osteoarthritic pain trial (GAPYOGA) assessed the feasibility and effectiveness of group acupuncture (GA) combined with YT in a low-income, racial, and ethnically diverse population. Individual in-depth interviews were conducted with a subset of patients in the trial. Nineteen participants were interviewed for qualitative analysis of their experience. Using the immersion and crystallization method, transcribed interviews were analyzed for themes meaningfully representing participant experience. Results: The combined GA and YT resulted in significant pain relief and transformative healing experiences. Three themes emerged from participant narratives: (1) transformative engagement with self in the healing process through pain relief, psychological well-being, and self-efficacy; (2) therapeutic relationship with acupuncture and yoga providers; and (3) fostering relationships with fellow participants in the group. Discussion: In this study of a low-income and ethnically diverse population, the combination of acupuncture and YT was found to alleviate pain, improve function, promote psychological well-being, and engage participants in self-care practices in a transformative healing process-resulting in physical and psychological benefits.


The prognostic significance of angiogenesis and the effect of vascular endothelial growth factor on angiogenic process in Wilms' tumour.
There is a subgroup of patients with Wilms' tumour (WT) having favourable clinicopathological features but adverse outcome. We aimed to investigate the prognostic significance of angiogenesis and whether it can be used for predicting which patients will fall into this category, and the possible role of vascular endothelial growth factor (VEGF) on angiogenesis in WT. Tumours in nephrectomy specimens from 63 WT patients were investigated for neovascularisation and VEGF expression by immunohistochemistry. The endothelial cells were highlighted by anti-CD34 and anti-CD31, and the microvessels in the hot-spots were counted. Correlations between the microvessel density (MVD), VEGF expression, clinicopathological features and prognosis were studied. Among 21 patients with follow-up data, favourable histology was detected in 17, seven of which died of disease. Patients with highly vascular tumours showed significantly poorer prognosis than those with low vascular tumours. There was no significant relationship between angiogenesis and VEGF expression. VEGF immunostaining revealed various patterns in different components of WT. We suggest that high MVD can be used as an indicator of poor prognosis with WT patients displaying favourable histology and there might be some additional growth factors other than VEGF which may also be responsible for angiogenesis in WTs.


Surface antigenic determinants of mammalian "hepadnaviruses" defined by group- and class-specific monoclonal antibodies.
The hepatitis B-like viruses (human hepatitis B virus, woodchuck hepatitis virus, ground squirrel hepatitis virus, and duck hepatitis B virus) are hepatotropic DNA viruses which have been referred to collectively as "hepadnaviruses." Using a murine monoclonal antibody (101-2) to the surface antigen of woodchuck hepatitis virus, we have shown that the surface antigens of mammalian hepadnaviruses (HBsAg, WHsAg, and GSHsAg) are antigenically related via a common determinant (HV/101). Furthermore, analysis with other monoclonal antibodies to WHsAg revealed that WHsAg and GHsAg are antigenically distinct, although the antigens had more determinants in common with each other than with HBsAg. The hepadnavirus group-specific antibody (101-2) reacted with HBsAg subtypic variants in a group-specific rather than subtype-specific manner. In conjunction with observations with an HBsAg-specific, group-reactive monoclonal antibody (BX259), the present data suggest that there are at least two group-reactive epitopes of HBsAg: one which is virus specific (HBV/259) and one which is common to two other mammalian hepadnaviruses (HV/101).


Effect of disinfectants containing glutaraldehyde on bonding of a tri-n-butylborane initiated resin to dentine.
The purpose of this study was to evaluate the effects of disinfectants on the bond strength of resin to dentine. The surface of bovine dentine was exposed to formaldehyde (FA) aqueous solutions, glutaraldehyde (GA) aqueous solutions, 2-hydroxyethyl methacrylate aqueous solutions (HEMA), a commercially available dentine primer (Gluma CPS desensitizer, GLUMA), isotonic sodium chloride solution (IS), and distilled water (DW), and placed in a humidor (HU) at 37 degrees C, or non-stored (baseline). All dentine surfaces were conditioned with a 10% citric acid and 3% ferric chloride solution (10-3 liquid), and then bonded to an acrylic rod with a self-curing adhesive resin (Super-Bond C&B). The mean tensile bond strengths determined 24 h after bonding were compared by analysis of variance (ANOVA) and Fisher's protected LSD test (n=5, P < or = 0.05). The exposure of dentine to IS, DW and HU for both 48 and 168 h resulted in a decrease in bond strength when compared with the baseline. The highest bond strengths after 168 h of exposure were obtained with 5% GA, 10% HEMA, and GLUMA, the values of which were equivalent to baseline and were significantly higher than that of FA. It is concluded that disinfectant pre-treatment with 5% GA or GLUMA stabilizes the bonding of tri-n-butylborane (TBB) initiated luting agent to bovine dentine conditioned with 10-3 liquid.


Second International Consensus Study of Antipsychotic Dosing (ICSAD-2).
Expert consensus-based clinically equivalent dose estimates and dosing recommendations can provide valuable support for the use of drugs for psychosis in clinical practice and research. This second International Consensus Study of Antipsychotic Dosing provides dosing equivalencies and recommendations for newer drugs for psychosis and previously reported drugs with low consensus. We used a two-step Delphi survey process to establish and update consensus with a broad, international sample of clinical and research experts regarding 26 drug formulations to obtain dosing recommendations (start, target range, and maximum) and estimates of clinically equivalent doses for the treatment of schizophrenia. Reference agents for equivalent dose estimates were oral olanzapine 20 mg/day for 15 oral and 7 long-acting injectable (LAI) agents and intramuscular haloperidol 5 mg for 4 short-acting injectable (SAI) agents. We also provide a contemporary list of equivalency estimates and dosing recommendations for a total of 44 oral, 16 LAI, and 14 SAI drugs for psychosis. Survey participants (N = 72) from 24 countries provided equivalency estimates and dosing recommendations for oral, LAI, and SAI formulations. Consensus improved from survey stages I to II. The final consensus was highest for LAI formulations, intermediate for oral agents, and lowest for SAI formulations of drugs for psychosis. As randomized, controlled, fixed, multiple-dose trials to optimize the dosing of drugs for psychosis remain rare, expert consensus remains a useful alternative for estimating clinical dosing equivalents. The present findings can support clinical practice, guideline development, and research design and interpretation involving drugs for psychosis.


A genome-wide association analysis of loss of ambulation in dystrophinopathy patients suggests multiple candidate modifiers of disease severity.
The major determinant of disease severity in Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether the dystrophin gene (DMD) mutation truncates the mRNA reading frame or allows expression of a partially functional protein. However, even in the complete absence of dystrophin, variability in disease severity is observed, and candidate gene studies have implicated several genes as modifiers. Here we present the largest genome-wide search to date for loci influencing severity in N = 419 DMD patients. Availability of subjects for such studies is quite limited, leading to modest sample sizes, which present a challenge for GWAS design. We have therefore taken special steps to minimize heterogeneity within our dataset at the DMD locus itself, taking a novel approach to mutation classification to effectively exclude the possibility of residual dystrophin expression, and utilized statistical methods that are well adapted to smaller sample sizes, including the use of a novel linear regression-like residual for time to ambulatory loss and the application of evidential statistics for the GWAS approach. Finally, we applied an unbiased in silico pipeline, utilizing functional genomic datasets to explore the potential impact of the best supported SNPs. In all, we obtained eight SNPs (out of 1,385,356 total) with posterior probability of trait-marker association (PPLD) ≥ 0.4, representing six distinct loci. Our analysis prioritized likely non-coding SNP regulatory effects on six genes (ETAA1, PARD6G, GALNTL6, MAN1A1, ADAMTS19, and NCALD), each with plausibility as a DMD modifier. These results support both recurrent and potentially new pathways for intervention in the dystrophinopathies.


Ectopic thoracic kidney.
A case of congenital thoracic kidney recently encountered at the University College Hospital, Ibadan, Nigeria is presented. Ectopic intrathoracic kidney, although very rare, should be considered in any patient with a mass at the base of the lung on a chest radiograph. Intravenous urography is diagnostic and may obviate the need for extensive investigation and operation for an asymptomatic kidney that functions normally and requires no treatment.


Older Americans and AIDS: some guidelines for prevention.
Social workers provide senior citizens with varied services in diverse settings and are in a position to assume leadership in slowing the spread of AIDS among this age group. Unfortunately older people often do not receive the knowledge needed to protect themselves against infection. Historically, older Americans have been largely ignored by HIV/AIDS prevention programs. The major risk behaviors among senior citizens include sexual activity without using condoms, alcohol and drug use, blood transfusions received before 1985, and misdiagnosed opportunistic illness such as Alzheimer's, Parkinson's, respiratory disease, and sexually transmitted diseases. The article discusses guidelines that can help social workers provide prevention education to older Americans. Social work's primary prevention AIDS education efforts can help older adults safely live out the rest of their lives secure in the understanding that they possess the knowledge to protect themselves from HIV/AIDS infection.


Insulin-like growth factors and their binding proteins: review of functions and clinical applications.
Insulin-like Growth Factors I & II (IGFs I & II) circulate in a concentration 1000 times that of insulin. The effect of these growth factors appears to be regulated by their binding proteins. The clinical usefulness of the IGFs resides currently in the growth hormone disease states and their treatment, as well as tumour related hypoglycemia. The growth hormone dependent binding protein (mol. wt 53kD) appears to possess a role in growth disorders, whereas the growth hormone independent binding protein (mol. wt 28kD) has recently been found to exert a role in glucose homeostasis.


Construction and Immunogenicity of Recombinant Vaccinia Virus Vaccine Against Japanese Encephalitis and Chikungunya Viruses Infection in Mice.
Japanese encephalitis virus (JEV) is recognized as a public health risk by the World Health Organization. In Asia, each year, ∼70,000 people become infected with JEV, which results in ∼10,000 deaths. Chikungunya virus (CHIKV) is an RNA virus, whose infection mainly causes fever, myalgia, and skin rash. Although the mortality rate is low, it seriously affects daily life. JEV and CHIKV infect humans through mosquitoes; therefore, a recombinant vaccinia virus coexpressing JEV E and CHIKV E1 proteins was constructed to prevent their concurrent infection. In this study, after mice first immunization, booster immunization was performed at 21 days postimmunization (dpi). At 35 dpi, mice were challenged with JEV and CHIKV. Specific antibodies significantly increased in the rVTT-CE1-JE-EGFP group, which were significantly (p < 0.01) higher than those of the control groups at 35 dpi. The plaque reduction neutralization tests (JEV) of rVTT-CE1-JE-EGFP group was 1:320 at 35 dpi. Furthermore, cytokine levels and the percentage of CD3+CD4+ and CD3+CD8+ T-lymphocytes in the rVTT-CE1-JE-EGFP group were significantly (p < 0.01) higher than those in the control groups at 35 dpi. After challenge, mice body weights in rVTT-CE1-JE-EGFP group were not significantly altered, and the survival rate was 100%. These results showed the rVTT-CE1-JE-EGFP group elicited significant humoral and cellular immune responses, thus indicating that the recombinant vaccine may serve as a candidate for effective prevention of CHIKV and JEV infection.


[Signal transduction abnormalities in systemic lupus erythematosus].
Engagement of T cell receptors by antigen-presenting cells or stimulation by cytokines determine whether the cell will become activated, anergic or die via apoptosis or necrosis. Ca2+ is a key second messenger that delivers signal from the cell surface, reactive oxygen intermediates and nitric oxide are recently recognized as important mediators of T cell activation. Nitric oxide is a multifunctional intracellular and intercellular messenger induces mitochondrial biogenesis in many cell types, such as lymphocytes. Mitochondria produce reactive oxygen intermediates and store and release Ca2+ in response to activation and death signals. Rapid Ca2+ fluxing is increased while sustained Ca2+ signaling is decreased in lupus T cells. Lupus T cells contain increased numbers and mass of mitochondria. Serum nitric oxide levels and production of nitric oxide by monocytes is increased in patients with systemic lupus erythematosus. Lupus T cells exhibit mitochondrial hyperpolarization and increased mitochondrial mass, which confer predisposition to necrosis rather than apoptosis in response to repetitive activation and death signals. Exposure of normal T cells to nitric oxide dose-dependently increase the mitochondrial mass and mimic rapid and sustained Ca2+ signal abnormalities observed in lupus T cells. Thus increased mitochondrial biogenesis may account for altered Ca2+ handling and represents novel targets for pharmacological intervention in SLE.


Biological similitude: statistical and functional relationships in comparative physiology.
A concept of biological similitude based on the distinction between extensive and intensive properties of animals is discussed. This concept provides a theoretical basis for using the power function as a mathematical-physical model whose numerical and dimensional constraints give some insight into the nature of the relationship between body mass and energy metabolism. In particular a theoretically mass-independent expression for energy metabolism is derived that can be used for qualitative intra- and interspecific comparisons of energy metabolism.


Establishing a pharmacy clinic in a city-county health department.
During a one-year rotation at an urban-county health department, a pharmacy resident implemented a pharmacy clinic to serve three major purposes: (1) to provide health care to patients with selected chronic illnesses, (2) to expand the revenue base of the health department pharmacy, and (3) to make possible the clinical instruction of Doctor of Pharmacy students and pharmacy residents. The resident's activities in the clinic included conducting interviews, performing physical examinations, initiating and adjusting therapy, and counseling patients. During the first four months of operation, 36 patients were seen in the clinic a total of 98 times. Seven chronic illnesses, along with a number of minor acute disorders, were evaluated and treated by the pharmacist. The pharmacist billed $1740.00 for patient care activities. The success of this initial program indicates that similar pharmacy clinics would be of benefit to other colleges of pharmacy as well as other institutional ambulatory health care providers.


Multivariate spatial meta kriging.
This work extends earlier work on spatial meta kriging for the analysis of large multivariate spatial datasets as commonly encountered in environmental and climate sciences. Spatial meta-kriging partitions the data into subsets, analyzes each subset using a Bayesian spatial process model and then obtains approximate posterior inference for the entire dataset by optimally combining the individual posterior distributions from each subset. Importantly, as is often desired in spatial analysis, spatial meta kriging offers posterior predictive inference at arbitrary locations for the outcome as well as the residual spatial surface after accounting for spatially oriented predictors. Our current work explores spatial meta kriging idea to enhance scalability of multivariate spatial Gaussian process model that uses linear model co-regionalization (LMC) to account for the correlation between multiple components. The approach is simple, intuitive and scales multivariate spatial process models to big data effortlessly. A simulation study reveals inferential and predictive accuracy offered by spatial meta kriging on multivariate observations.


Clinical utility of the chronic obstructive pulmonary disease knowledge questionnaire.
Although typically symptomatic, chronic obstructive pulmonary disease (COPD) is undertreated as compared to many asymptomatic conditions such as hypertension. Unfortunately, many patients lack basic information about their major disease states, including COPD. The purpose of this study was to assess the clinical utility of the valid and reliable COPD Questionnaire (COPD-Q) in a sample of underserved patients carrying a diagnosis of COPD. This prospective, descriptive study enrolled COPD patients at a family medicine residency teaching clinic. Patients were administered a telephone survey assessing COPD knowledge, demographic data, and health literacy. Data regarding COPD clinical outcomes were gathered through the electronic medical record. Average total COPD-Q score was 7.6 plus or minus 2.1 (total possible score=13). Total COPD-Q scores were significantly related to health literacy and educational attainment. The COPD-Q is a valid, reliable tool used to assess COPD knowledge in a setting that includes patients with limited health literacy. It is useful in identifying key knowledge deficits that will allow the clinician to offer focused, individualized patient education and counseling.


The effect of six-week aerobic training program on cardiovascular fitness, body composition and mental health among female students.
The purpose of the present study was to evaluate the effects of six-week aerobic training program including running and rope skipping on cardiovascular fitness, body mass index (BMI), and mental health among female students at the University of Isfahan, Iran. In this interventional study we included 30 female students in academic year 2011-12. The participants were randomly assigned in experimental group (n=15, mean±SD for age=26.06±1.18, weight (kg)=57.43±5.67, height (cm)=160.06±4.16) and control group (n=15, mean±SD for age=26.33±1.30, weight=57.66±5.08, height=161.86±3.29). Pre-test and post-test measurements include VO2 max with Queen Step test; BMI and General Health Questionnaire-28 as a measure of mental health were done. Analysis of covariance (ANCOVA) was used to test the effects of aerobic training as intervention (P<0.05). There was statistically significance difference between experimental and control groups after adjustment for their own baseline values concerning cardiovascular fitness (P=0.004), BMI (P<0.001) and mental health indices (P<0.001). A six-week aerobic practice improves cardiovascular strength, mental health and BMI considerably and could be more encouraged at universities.


Pandemic Footprints of Nursing Professionals: Processing Early Experiences.
Purpose: This study interpreted journaled experiences of registered nurses (RNs) who were working at the bedside early in the pandemic as they were simultaneously enrolled in a baccalaureate (RN-BSN) completion program. Design: This qualitative interpretive descriptive study used purposive sampling. Methods: Eighteen students participated in the journal assignment. Fifteen students consented to participate in journal analyses. Journals were de-identified and a code book was used to document the entirety of journal reflections to identify meaningful text, and, ultimately, assert thematic codes. Thorne's interpretive description guided analysis. Researchers coded four journals together to obtain trustworthiness and rigor. Each doctorally prepared researcher independently coded a subset of the remaining journals. Emerging significant statements and subthemes were discussed and verified as a team. Results: Researchers identified the essence of pandemic footprints as the following themes emerged: Physical Threats to Safety, Emotional Threats to Safety, Workplace Culture, Healing Energies, and Professional Identity. Conclusions: Compared to previously published research conducted at later points of the pandemic this study is unique. Study data captured nurses' expressed voices through journaling at the brink (March 2020) of what became a global reality. Results illuminated dichotomies that existed then, particularly in response to their own and others' safety and security, leaving profound imprints on their identities extending beyond care environments.


Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces.
Severe duodeno-gastro-oesophageal reflux (DGOR) is a risk factor for oesophagitis and Barrett's oesophagus. Patients with non-erosive reflux disease (NERD) have a slight increase in DGOR. Patients with gastro-oesophageal reflux disease (GORD), who are taking proton pump inhibitors (PPIs), still have reflux but of weakly acidic pH and persistence of bile. In these two groups of patients, heartburn might be due to increased oesophageal mucosal permeability and dilated intercellular spaces (DIS). We aimed to assess whether experimental short exposure of the oesophageal mucosa to bile acids, in low concentrations (at acidic, weakly acidic and neutral conditions) can increase mucosal permeability and provoke DIS. Rabbit oesophageal mucosa was studied in diffusion and Ussing chambers. We assessed the effects of different solutions containing bile acids, applied to the mucosal side, on transepithelial electrical resistance (R(T)) and permeability to fluorescein. The diameter of intercellular spaces was assessed by using transmission electron microscopy. Incubation of oesophageal mucosa with acidic solutions (pH 2.0) containing a range of bile acids (0.5-5 mmol/l) markedly decreased R(T) and increased mucosal permeability. Weakly acidic solutions (pH 5.0), and to some extent neutral solutions (pH 7.4), containing some bile acids also decreased R(T) and increased permeability, although the effects were much less marked and in some combinations no effect was seen. Exposure to bile acids provoked DIS in acid and weakly acidic conditions but not in neutral (pH 7.4) solutions. Experimental short exposure of the oesophageal mucosa to solutions with a bile acid concentration and acidity similar to that observed in the gastric contents of patients with NERD or ERD, and who are taking PPIs, may impair oesophageal mucosal integrity and even induce dilated intercellular spaces. Such a situation could, theoretically, underlie the occurrence and/or persistence of symptoms in these patients.


Tracking changing environments using stable carbon isotopes in fossil tooth enamel: an example from the South African hominin sites.
The environmental contexts of the karstic hominin sites in South Africa have been established largely by means of faunal associations; taken together these data suggest a trend from relatively closed and more mesic to open, drier environments from about 3 to 1.5 Ma. Vrba argued for a major shift within this trend ca. 2.4-2.6 Ma, an influential proposal that posited links between bovid (and hominin) radiation in Africa and the intensification of Northern Hemisphere Glaciation. Yet faunal approaches often rely on habitat and feeding preferences of modern taxa that may differ from those of their extinct predecessors. Here we explore ways of extending (13)C/(12)C data from fossil mammals beyond denoting "presence" or "absence" of C(4) grasses using the evolution of open environments in South Africa as a case study. To do so we calculated the relative proportions of C(3)-, mixed-, and C(4)-feeding herbivores for all the hominin sites for which we have sufficient data based on (13)C/(12)C analyses of fossil tooth enamel. The results confirm a general trend towards more open environments since 3 Ma, but they also emphasize a marked change to open grassy habitats in the latest Pliocene/early Pleistocene. Mean (13)C/(12)C for large felids also mirrored this trend.


Docetaxel-loaded polylactic acid-co-glycolic acid nanoparticles: formulation, physicochemical characterization and cytotoxicity studies.
In the present study, we developed novel docetaxel (DTX)-loaded polylactic acid-co-glycolic acid (PLGA) nanoparticles (NPs) using the combination of sodium lauryl sulfate (SLS) and poloxamer 407, the anionic and non-ionic surfactants respectively for stabilization. The NPs were prepared by emulsification/solvent evaporation method. The combination of these surfactants at weight ratio of 1:0.5 was able to produce uniformly distributed small sized NPs and demonstrated the better stability of NP dispersion with high encapsulation efficiency (85.9 +/- 0.6%). The drug/polymer ratio and phase ratio were 2:10 and 1:10, respectively. The optimized formulation of DTX-loaded PLGA NPs had a particle size and polydispersity index of 104.2 +/- 1.5 nm and 0.152 +/- 0.006, respectively, which was further supported by TEM image. In vitro release study was carried out with dialysis membrane and showed 32% drug release in 192 h. When in vitro release data were fitted to Korsmeyer-Peppas model, the n value was 0.481, which suggested the drug was released by anomalous or non-Fickian diffusion. In addition, DTX-loaded PLGA NPs in 72 h, displayed approximately 75% cell viability reduction at 10 microg/ml DTX concentration, in MCF-7 cell lines, indicating sustained release from NPs. Therefore, our results demonstrated that incorporation of DTX into PLGA NPs could provide a novel effective nanocarrier for the treatment of cancer.


Estimated cancer incidence and mortality in Hebei province, 2012.
This study estimates the numbers of new cancer cases and cancer deaths in Hebei province using incidence and mortality data from 9 population-based cancer registries in 2012. The data of new diagnosed cancer cases and cancer deaths in 2012 were collected from 9 population-based cancer registries of Hebei province in 2015. All the data met the National Central Cancer Registry of China (NCCR) criteria of data quality. The pooled data analysis was stratified by areas (urban/rural), gender, age group (0, 1.4, 5.9, 10.14, …, 85+) and cancer type. New cancer cases and deaths in Hebei province were estimated using age-specific rates and corresponding provincial population in 2012. The 10 most common cancers in different groups and the cumulative rates were calculated. Chinese population census in 2000 and Segi's population were used for age-standardized incidence/mortality rates. All cancer registries covered 4,986,847 populations, 6.84% of Hebei provincial population (2,098,547 in urban and 2,888,300 in rural areas). The percentage of cases morphologically verified (MV%) and death certificate-only cases (DCO%) were 76.40% and 4.72%, respectively. The mortality to incidence rate ratio (M/I) was 0.64. In 2012, it is estimated that there were about 187,900 new diagnosed cancer cases and 119,800 cancer deaths in Hebei province. The incidence rate of cancer was 258.12/100,000 (275.75/100,000 in males, 239.78/100,000 in females), and the age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 210.65/100,000 and 208.50/100,000, with the cumulative incidence rates (0.74 years old) of 24.46%. The cancer incidence and ASIRC were 256.99/100,000 and 211.32/100,000 in urban areas and 258.94/100,000 and 209.99/100,000 in rural areas, respectively. The cancer mortality rate was 164.63/100,000 (201.85/100,000 in males, 125.92/100,000 in females). Agestandardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 137.30/100,000 and 137.39/100,000 with the cumulative mortality rate (0.74 years old) of 14.58%, respectively. The cancer mortality rate in rural areas (167.16/100,000) was higher than that in urban areas (161.16/100,000). The most common cancers were lung cancer, stomach cancer, breast cancer, esophageal cancer, liver cancer and colorectal cancer, which accounted for 72.31% of all cancer cases. Lung cancer, stomach cancer, liver cancer, esophageal cancer and colorectal cancer were the major causes of cancer death in Hebei province, which accounted for 75.24% of all cancer deaths. The cancer spectrum differs between urban and rural, males and females in both incidence and mortality rates. The most common cancers were lung cancer, stomach cancer, esophageal cancer, breast cancer, liver cancer and colorectal cancer in Hebei province.


Characterization of gene expression changes over healthy term pregnancies.
During pregnancy, women experience numerous physiological changes but, to date, there is limited published data that characterize accompanying changes in gene expression over pregnancy. This study sought to characterize the complexity of the transcriptome over the course of pregnancy among women with healthy pregnancies. Subjects provided a venous blood sample during early (6-15 weeks) and late (22-33 weeks) pregnancy, which was used to isolate peripheral blood mononuclear cells prior to RNA extraction. Gene expression was examined for 63 women with uncomplicated, term deliveries. We evaluated the association between weeks gestation at sample collection and expression of each transcript. Of the 16,311 transcripts evaluated, 439 changed over pregnancy after a Bonferroni correction to account for multiple comparisons. Genes whose expression increased over pregnancy were associated with oxygen transport, the immune system, and host response to bacteria. Characterization of changes in the transcriptome over the course of healthy term pregnancies may enable the identification of genes whose expression predicts complications or adverse outcomes of pregnancy.


Hypertension prevalence and influence of basal metabolic rate on blood pressure among adult students in Bangladesh.
Hypertension is a global health issue and is currently increasing at rapid pace in South Asian countries including Bangladesh. Although, some studies on hypertension have been conducted in Bangladesh, there is a lack of scientific evidence in the adult student population that was missing from the previous and recent national cross-sectional studies. Moreover, the specific risk factors of hypertension in the Bangladeshi adults still need to be investigated. This study was conducted to estimate hypertension prevalence among adult students in Bangladesh and to test the hypothesis of Luke et al. (Hypertension 43:555-560, 2004) that basal metabolic rate (BMR) and blood pressure are positively associated independent of body size. The data was collected on 184 adult university students (118 female and 66 male) in Dhaka, Bangladesh. Anthropometric, BMR details and an average of at least two blood pressure measurements were obtained. Hypertension was defined by a systolic blood pressure (SBP) ≥ 140 mmHg and/or, diastolic blood pressure (DBP) ≥ 90 mmHg. Overall, 6.5% of participants had hypertension with significantly (p < 0.001) higher prevalence in male (12.1%) than in the female (3.4%) students. Age and BMI showed positive and significant correlation with hypertension among the students. When adjusted for body mass index (BMI), as well as other potentially confounding variables such as age, sex, smoking status and degree of urbanization, BMR was positively correlated with SBP and DBP (p < 0.001). Thus, higher BMR is associated with SBP and DBP; this is opposite the well documented inverse relationship between physical activity and blood pressure. If the influence of BMR on blood pressure is confirmed, the systematically elevated BMR might be an important predictor that can explain relatively high blood pressure and hypertension in humans. This study reports the prevalence and associated risk factors of hypertension in the Bangladeshi adult students. The study also showed a positive association between BMR and blood pressure among the participants. A large scale longitudinal study across the country is needed to find out the underlying causes of hypertension in the Bangladeshi adults. In addition, comprehensive and integrated intervention programs focusing on modifiable risk factors are recommended to make awareness and prevent hypertension.


Helicobacter pylori infection, glandular atrophy, intestinal metaplasia and topography of chronic active gastritis in the Nepalese and Japanese population: the age, gender and endoscopic diagnosis matched study.
The incidence and mortality from gastric cancer is high in Japanese but extremely low in Thailand. It is different among Asian countries. The aim of this study is to investigate the difference of peptic ulcer disease, glandular atrophy, intestinal metaplasia and topography of chronic active gastritis between the Nepalese and Japanese population. Nepalese patients were paired with Japanese patients by age, gender and endoscopic diagnosis in order to compare the prevalence of H. pylori infection (N=309) and the difference of H. pylori related peptic ulcer disease (N=48). Glandular atrophy and intestinal metaplasia scores were also compared between the Nepalese and Japanese population in H. pylori positive cases (N=152) and negative cases (N=145) using paired cases by age, gender and endoscopic diagnosis. Paired H. pylori-positive Nepalese and Japanese population were also used to compare the ratio of corpus gastritis to antrum gastritis (C/A ratio) (N=152). Among peptic ulcer diseases, gastric ulcer was frequent in Japanese and duodenal ulcer was frequent in Nepalese. The prevalence of H. pylori infection in the Nepalese and Japanese population were similar. Glandular atrophy and intestinal metaplasia scores in the H. pylori positive Japanese were significantly higher than those of Nepalese in all positions according to triple site biopsy. Furthermore, there were significant differences in glandular atrophy and intestinal metaplasia scores between in the H. pylori-negative Nepalese and Japanese population except intestinal metaplasia score in the greater curvature of the upper corpus. Japanese C/A ratio was significantly higher than that of Nepalese. Corpus predominant gastritis (C/A ratio>1.00) was characteristic in the elderly Japanese. Nepalese was antrum predominant (C/A ratio<1.00) in every age group. Gastric ulcer was a common disease in Japanese, in contrast duodenal ulcer was common in Nepalese. H. pylori infected Japanese patients showed severe atrophic and metaplastic gastritis in comparison with Nepalese. These results may be associated with the high incidence of gastric cancer in Japanese. Corpus predominant gastritis was found in the elderly Japanese and antrum predominant gastritis was found in every age Nepalese.


[Impasses of cutaneous cicatrization].
The neurovascular aspects of healing failure have a common pathogenetic factor, the diminished delivery of oxygen to peripheral tissues. Recent hypotheses on the pathogenesis of ulcers via venous insufficiency underline the presence of pericapillary fibrinous sleeves which justify the use of prolonged venous compression. Encouraging preliminary results have been reported concerning the use of topic vasodilators (prostaglandin E2, ketanserin) in the treatment of leg ulcers. Diabetic neurotrophic ulcers are of multifactorial origin, with disorders of the sympathetic nervous system having a determinant role. Whatever the cause of healing failure, diagnosis and treatment should also take into account general factors, whether extrinsic, or intrinsic.


[Soil microelements under different vegetation restoration patterns in yellow soil slope region of mid-subtropics].
With the Nüerzhai watershed in Wuling Mountain as a case, this paper studied the contents and availabilities of soil microelements and their relationships with soil organic matter and pH value in yellow soil slope region of mid-subtropics under seven typical vegetation restoration patterns, i. e., Pinus massoniana natural forest (I), Cunninghamia lanceolata plantation (II), Eucommia ulmoides plantation (III), Vernicia fordii plantation (IV), Machilus pingii secondary forest (V), Phyllostachys edulis - C. lanceolata mixed forest (VI), and wasteland-shrub community (VII). It was found that in 0-20 cm soil layer, the contents of B and Mn, Mo and Cu, Zn, and Fe reached the peaks under VII, IV, III and VI; while in 20-40 cm soil layer, III, IV, Vand VII had the highest contents of Cu, Zn, B, and Fe and Mn, Mo, respectively. In both two soil layers under VI, the contents of B, Mo, Cu and Mn were the lowest. Mn had the biggest single element available index, while Cu had the smallest one. The biggest and smallest total available index of soil microelements was 12.28 for VII and 2.95 for VI, respectively. There existed the regularities of Mn > Zn > Fe > Mo > B > Cu for single microelement available index and VII > V > III > IV > I > II > VI for comprehensive microelement available index under different vegetation patterns. A good linear relationship was observed between soil organic matter and B and Zn availabilities, and the relationship of soil organic matter with available Mn could be described by a quadratic equation. Soil pH was highly positively correlated with soil Cu and Zn contents, correlated with soil Mo and Mn contents, slightly correlated with soil B content, and slightly negatively correlated with soil Fe content.


Atmospheric pressure ion/molecule reactions for the selective detection of nitroaromatic explosives using acetonitrile and air as reagents.
Acetonitrile vapor and air are useful reagents for the selective detection of nitroaromatic compounds using atmospheric pressure ion/molecule reactions. Reagent ions CH2CN- and CN- generated from acetonitrile, and O-*, OH- and OOH- produced from the oxygen in air, react with vapor-phase and condensed-phase nitroaromatics in the course of atmospheric pressure chemical ionization (APCI) and desorption atmospheric pressure chemical ionization (DAPCI), respectively. The homogeneous and the heterogeneous phase reactions both lead to the formation of the same anionic adducts. These adducts have characteristic fragmentation patterns upon collisional activation, which makes these two reagents valuable for the selective detection of particular nitroaromatics, including explosives present as components of complex mixtures. Complementary information is available from the two reagents because their different chemistry facilitates analyte identification. DAPCI is demonstrated to be a useful ambient detection method for nitroaromatic explosives absorbed on surfaces.


Simultaneous spectrofluorimetric determination of selenium (IV) and (VI) by flow injection analysis.
A simple, sensitive, highly selective, automatic spectrofluorimetric method for the simultaneous determination of selenium (IV) and (VI) as selenite-selenate by flow injection analysis (FIA) has been developed. The method is based on the selective oxidation of the non-fluorescent reagent 2-(alpha-pyridyl)thioquinaldinamide (PTQA) in acidic solution (1.5-3.0 M H2SO4) by SeIV to give an intensely fluorescent oxidation product (lambda ex =350 nm; lambda em = 500nm). Selenium (VI) is reduced on-line to SeIV, in a reduction coil installed in a photo-reactor, which is then treated with PTQA and the fluorescene due to the sum of SeIV and SeVI is measured; SeVi is determined from the difference in fluorescence values. Various analytical parameters, such as effect of acidity, flow rate, sample size, dispersion coefficient, temperature, reagent concentration and interfering species were studied. The photo-reduction conditions were optimized, with an FIA procedure, for SeVI on the basis of its reduction efficiency. The calibration graphs were rectilinear for 0.1-2.4 micrograms ml-1 of SeVI and 10 ng ml-1-2.2 micrograms ml-1 of SeIV, respectively. The method was applied to the determination of Se in several Standard Reference Materials (alloy, sediments and tea), as well as in some environmental waters (tap and surface water), food samples (flour and egg), a biological sample (human hair), soil sample and in synthetic mixtures. Up to 25 samples per hour can be analysed with an RSD approximately 0.1-2%.


Insights from QM/MM Modeling the 3D Structure of the 2009 H1N1 Influenza A Virus Neuraminidase and Its Binding Interactions with Antiviral Drugs.
Control of drug release through the inhibition of neuraminidase-1 has been identified as a potential target for the treatment of H1N1 influenza; however, the drug binding mode of neuraminidase is not yet completely understood. In this work, we propose a model for a neuraminidase-1 complex based on four known X-ray structures of drug/neuraminidase-1 complexes. Specifically, H1N1 neuraminidase-1 complexed with 4 drugs (zanamivir, laninamivir, laninamivir octanoate and oseltamivir) was first investigated using a combined quantum mechanical and molecular mechanical (QM/MM) approach. Based on these structures, a model for the H1N1 neuraminidase-1 complex was proposed and simulated using the same computational protocol. Implications to drug/H1N1 neuraminidase-1 binding modes are discussed. From our simulations, the predicted binding free energies of the four drugs are in good agreement with the experimental results, with the correlation coefficient being 0.84.


Dicer associates with chromatin to repress genome activity in Schizosaccharomyces pombe.
In the fission yeast S. pombe, the RNA interference (RNAi) pathway is required to generate small interfering RNAs (siRNAs) that mediate heterochromatic silencing of centromeric repeats. Here, we demonstrate that RNAi also functions to repress genomic elements other than constitutive heterochromatin. Using DNA adenine methyltransferase identification (DamID), we show that the RNAi proteins Dcr1 and Rdp1 physically associate with some euchromatic genes, noncoding RNA genes and retrotransposon long terminal repeats, and that this association is independent of the Clr4 histone methyltransferase. Physical association of RNAi with chromatin is sufficient to trigger a silencing response but not to assemble heterochromatin. The mode of silencing at the newly identified RNAi targets is consistent with a co-transcriptional gene silencing model, as proposed earlier, and functions with trace amounts of siRNAs. We anticipate that similar mechanisms could also be operational in other eukaryotes.


Studies on the release of lysosomal enzymes from kidney lysosomes.
Incubation of kidney lysosomes at 37 degrees results in a graded release of lysosomal enzymes. The release of enzyme occurs in two stages. First the enzymes become available to the substrate but remain sedimentable. Later the amount of soluble enzyme increases and eventually is almost equal to that of the available enzyme. Morphological studies of lysosomes showed that during the process involving increasing availability of enzymes, the lysosomes remained intact. Release of the soluble enzymes was characterized ultrastructurally by a complete loss of the electron-opaque matrix contained within the lysosomal membrane. The increased release of soluble enzymes was concomitant with an increase in the number of individual lysosomes showing complete loss of contents, rather than a gradual loss or dilution of matrix density. Lysosomes which had lost their electron-opaque contents retained their outer membrane intact and were seen to contain numerous internal membranes and small vesicles.


Characterization of L-glutamine transport by a human neuroblastoma cell line.
This study characterized the Na+-dependent transport of L-glutamine by a human neuroblastoma cell line, SK-N-SH. The Na+-dependent component represented >95% of the total glutamine uptake. Kinetic studies showed a single saturable high-affinity carrier with a Michaelis constant (K(m)) of 163 +/- 23 microM and a maximum transport velocity (Vmax) of 13,713 +/- 803 pmol x mg protein(-1) x min(-1). Glutamine uptake was markedly inhibited in the presence of L-alanine, L-asparagine, and L-serine. Li+ did not substitute for Na+. These data show that L-glutamine is predominantly taken up through system ASC. Glutamine deprivation resulted in the decrease of glutamine transport by a mechanism that decreased Vmax without affecting K(m). The expression of the system ASC subtype ASCT2 decreased in the glutamine-deprived group, whereas glutamine deprivation did not induce changes in system ASC subtype ASCT1 mRNA expression. Adaptive increases in Na+-dependent glutamate, Na+-dependent 2-(methylamino)isobutyric acid, and Na+-independent leucine transport were observed under glutamine-deprived conditions, which were completely blocked by actinomycin D and cycloheximide. These mechanisms may allow cells to survive and even grow under nutrient-deprived conditions.


Rapid determination of influenza vaccine potency by an SPR-based method using subtype or lineage-specific monoclonal antibodies.
Potency testing and release of annual influenza vaccines require preparation, calibration, and distribution of reference antigens (RAs) and antisera every year, which takes an average of 8 to 12 weeks, and can be a major limiting factor in pandemic situations. Here we describe for the first time a robust Surface Plasmon Resonance (SPR)-based method that employs influenza subtype or lineage hemagglutinin (HA) specific monoclonal antibodies (mAbs) to measure the HA concentration in influenza multivalent vaccines. Implementing such an advanced test method will at the very least eliminate the rate-limiting and laborious efforts of making antisera reagents annually, and thus expedite the influenza vaccine delivery to the public by at least 6 weeks. Results demonstrate that the SPR-based method, developed using Biacore, is robust and not influenced by the type of RAs (inactivated whole virus, split, or subunit vaccine-derived materials), whether they are used as monovalent or multivalent preparations. HA concentrations obtained for monovalent drug substances (DS) or quadrivalent drug products (DP) of inactivated influenza split vaccine showed a tight correlation (the best fit value for the slope is 1.001 with R2 of 0.9815 and P-value <0.0001) with the corresponding values obtained by the current potency assay, Single Radial Immunodiffusion (SRID). Supplementary analysis of the results by the Bland-Altman plot demonstrated good agreement between the SPR and SRID methods, with no consistent bias of the SPR versus SRID method. We further demonstrate that the SPR-based method can be used to estimate HA concentrations in intermediates of the influenza vaccine manufacturing process containing varying matrices and impurity levels. Further, the results demonstrate that the method is sensitive to detecting degradation of HA caused by elevated temperature, low pH, and freezing. It is evident from this report and other published work that the advancement of analytical techniques and the early findings are encouraging for the implementation of alternate potency assays with far-reaching benefits covering both seasonal and pandemic influenza.


Application of the chick embryo chorioallantoic membrane in neurosurgery disease.
The chick embryo chorioallantoic membrane (CAM) is a highly vascularized extraembryonic membrane. Because of its ease of accessibility, extensive vascularization and immunodeficient environment, the CAM has been broadly used in the oncology, biology, pharmacy, and tissue regeneration research. The present review summarizes the application of the CAM in neurosurgery disease research. We focused on the use of the CAM as an assay for the research of glioma, vascular anomalies, Moyamoya Disease, and the blood-brain barrier.


Clinical effects of pure cyclotorsional errors during refractive surgery.
To describe the theoretical effects of cyclotorted ablations on induced aberrations and determine the limits of tolerance of cyclotorsional accuracy. A method was developed to determine the average cyclotorsion during refractive surgery without a cyclotorsion tracker. Mathematical conditions were simulated to determine the optical, visual, and absolute benefits in 76 consecutive treatments performed on right eyes. The results were evaluated as Zernike expansion of residual wavefront aberrations. Ablations based purely on Zernike decomposition but with cyclotorsion applied resulted in residual aberrations of the same Zernike modes of different magnitudes and orientations, indicating that the effect of cyclotorted compensation can be analyzed by single Zernike modes in magnitude and orientation. The effect on single Zernike modes depends on angular frequency, and not on radial order. A mean of 4.39 degrees of cyclotorsion was obtained. A theoretical optical benefit was achieved in 95% of treatments, a theoretical visual benefit in 95%, and an absolute benefit in 93% compared with 89%, 87%, and 96% of treatments achieving actual benefits, respectively. Residual aberrations resulting from cyclotorsion depend on aberrations included in the ablation and cyclotorsional error. The theoretical impact of cyclotorted ablations is smaller than that of decentered ablations or edge effects in coma and spherical aberrations. The results are valid within a single-failure condition of pure cyclotorsional errors, because no other sources of aberrations are considered. The leap from the mathematical model to the real-world outcome cannot be extrapolated without further study.


The Pharmacology of the hypotensive action of N,N-dimethyl para-methoxyphenylethylamine in rats.
N,N-dimethyl para-methoxyphenylethylamine prevents hypertension and reverses existing high blood pressure in DOCA-saline treated rats. Indomethacin prevents its hypotensive effect, therefore the suggested mechanism is increase in prostaglandin(s) synthesis. The effect of the usual receptor antagonists on the hypotensive effect of the title compound can also be fitted into the framework of this hypothesis.


Tuning the optical properties of mesoporous TiO2 films by nanoscale engineering.
The optical properties of spin-coated titanium dioxide films have been tuned by introducing mesoscale pores into the inorganic matrix. Differently sized pores were templated using Pluronic triblock copolymers as surfactants in the sol-gel precursor solutions and adjusted by varying the process parameters, such as the polymer concentration, annealing temperature, and time. The change in refractive index observed for different mesoporous anatase films annealed at 350, 400, or 450 °C directly correlates with changes in the pore size. Additionally, the index of refraction is influenced by the film thickness and the density of pores within the films. The band gap of these films is blue-shifted, presumably due to stress the introduction of pores exerts on the inorganic matrix. This study focused on elucidating the effect different templating materials (Pluronic F127 and P123) have on the pore size of the final mesoporous titania film and on understanding the relation of varying the polymer concentration (taking P123 as an example) in the sol-gel solution to the pore density and size in the resultant titania film. Titania thin film samples or corresponding titanium dioxide powders were characterized by X-ray diffraction, cross-section transmission electron microscopy, nitrogen adsorption, ellipsometery, UV/vis spectrometry, and other techniques to understand the interplay between mesoporosity and optical properties.


Economic Evaluations of Thrombophilia Screening Prior to Prescribing Combined Oral Contraceptives: A Systematic and Critical Review.
Combined oral contraceptives (COCs) increase the risk of venous thromboembolism (VTE), particularly among women with inherited clotting disorders. The World Health Organization classifies combined hormonal contraception as an "unacceptable health risk" for women with thrombogenic mutations but advises against universal thrombophilia screening before prescribing COCs given the low prevalence of thrombophilia and high screening costs. Through the lens of lifetime costs and benefits, this paper systematically and critically reviews all published economic evaluations of thrombophilia screening prior to prescribing COCs. We searched relevant databases for economic evaluations of thrombophilia screening before prescribing COCs. After extracting the key study characteristics and economic variables, we evaluated each article using the Quality of Health Economic Studies (QHES) and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) instruments. Seven economic evaluations of thrombophilia screening before prescribing COCs met our inclusion criteria. Only the two economic evaluations focusing exclusively on selective screening exceeded the 75-point threshold for high-quality economic studies based on the QHES instrument, whereas only one of these exceeded the 85% CHEERS threshold. Only three of the seven economic evaluations performed sensitivity analysis on key parameters. Most studies underestimated the benefits of thrombophilia screening by comparing one-time costs of genetic screening against benefits per person-year, thus implicitly assuming a 1-year duration of COC use, neglecting the long-term implications of VTE and/or neglecting the lifetime benefits of awareness of inherited thrombophilia. Our review highlights the lack of methodologically rigorous economic evaluations of universal thrombophilia screening before prescribing COCs.


Retroviral vector production in the National Gene Vector Laboratory at Indiana University.
The National Gene Vector Laboratory (NGVL) is a US National Institutes of Health initiative charged with providing clinical grade vectors for gene therapy trials. The program was started in 1995 and Indiana University has served as the production site for retroviral vectors and is also accepting applications for production of lentiviral vectors. The facility is designed to produce vectors for Phase I and Phase II clinical trials with the specific mandate to facilitate investigator-initiated research for academic institutions. To date, the facility has generated over 30 Master Cell Banks for gene therapy investigators throughout the United States. This required the facility to develop a system that can adapt to the varied needs of investigators, most of whom request different vector backbones, packaging cell lines, final product volumes, and media. In this review, we will illustrate some of the experiences of the Indiana University NGVL during the generation of retroviral vectors using murine-based packaging cell lines.


Skin permeation of lidocaine from crystal suspended oily formulations.
In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, Japp, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2=IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0-20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest Japp among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.


Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA).
Results of the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) show significantly lower rates of coronary and stroke events in individuals allocated an amlodipine-based combination drug regimen than in those allocated an atenolol-based combination drug regimen (HR 0.86 and 0.77, respectively). Our aim was to assess to what extent these differences were due to significant differences in blood pressures and in other variables noted after randomisation. We used data from ASCOT-BPLA (n=19 257) and compared differences in accumulated mean blood pressure levels at sequential times in the trial with sequential differences in coronary and stroke events. Serial mean matching for differences in systolic blood pressure was used to adjust HRs for differences in these events. We used an updated Cox-regression model to assess the effects of differences in accumulated mean levels of various measures of blood pressure, serum HDL-cholesterol, triglycerides and potassium, fasting blood glucose, heart rate, and bodyweight on differences in event rates. We noted no temporal link between size of differences in blood pressure and different event rates. Serial mean matching for differences in systolic blood-pressure attenuated HRs for coronary and stroke events to a similar extent as did adjustments for systolic blood-pressure differences in Cox-regression analyses. HRs for coronary events and stroke adjusted for blood pressure rose from 0.86 (0.77-0.96) to 0.88 (0.79-0.98) and from 0.77 (0.66-0.89) to 0.83 (0.72-0.96), respectively. Multivariate adjustment gave HRs of 0.94 (0.81-1.08) for coronary events (HDL cholesterol being the largest contributor) and 0.87 (0.73-1.05) for stroke events. Multivariate adjustment accounted for about half of the differences in coronary events and for about 40% of the differences in stroke events between the treatment regimens tested in ASCOT-BPLA, but residual differences were no longer significant. These residual differences could indicate inadequate statistical adjustment, but it remains possible that differential effects of the two treatment regimens on other variables also contributed to the different rates noted, particularly for stroke.


Reversible interventions for menstrual management in adolescents and young adults with gender incongruence.
The newly released World Professional Association for Transgender Health Standards of Care, 8th Edition specify that adolescents should be offered menstrual suppression as part of their treatment plans to suppress menses and alleviate dysphoria, provide contraception, or improve irregular bleeding on testosterone therapy. This is a review of current evidence-based options for reversible interventions for menstrual suppression in adolescents with gender dysphoria or incongruence. Shared decision-making should be used by the clinician at all times, and the clinician should be intentional in prioritizing the patient's stated needs and desires when offering interventions. No method should be withheld due to the experience of gender incongruence alone. Contraceptive options offering menstrual suppression include depot-medroxyprogesterone acetate, levonorgestrel intrauterine systems, progestin-only contraceptive pills, and combined hormonal contraceptives. Non-contraceptive options include norethindrone acetate, oral medroxyprogesterone acetate, gonadotropin-releasing hormone analogues/agonists, and danazol. Certain patients may also benefit from non-pharmacologic interventions, such as specialty menstrual underwear. Using medicine to stop Menstrual periods in teens with gender incongruence Summary: Newly released recommendations for the care of teens and young adults with gender dysphoria or incongruence specifically recommend using medications to get rid of menstrual periods if desired or medically necessary. Patients may ask for this to help improve dysphoria, as a feature they want in birth control, or simply because they do not want to have periods. Because temporarily getting rid of periods is something that doctors can do for any patient old enough to have periods, patients with gender dysphoria should also be able to have their periods temporarily stopped using medications if requested. Doctors should ensure that they always help the patient make a decision that is right for them instead of prescribing what they think is right without considering the patient's input. Options for temporarily getting rid of periods can include birth control, such as oral contraceptive pills, patches, or rings; intrauterine devices; or shots, and it can also be done with things that are not birth control, such a progesterone pills or puberty blockers. Finally, some patients may only need improved period hygiene with period underwear to feel better in their bodies.


Sinusitis: viral, bacterial, or fungal and what is the role of Staph?
Recently, it has been recognized that inflammation is the major cause of chronic rhinosinusitis (CRS) rather than bacterial infection. Fungi have emerged as a possible pathogenic agent that drives CRS. One clear-cut group of fungal sinusitis can be divided into invasive and noninvasive. The condition that the allergist is most likely to see is allergic fungal sinusitis. Generally, it appears in atopic, immunocompetent, adolescents and young adults and is marked by the presence of nasal polyps and allergic mucin, which includes eosinophils, Charcot-Leyden crystals, and fungal hyphae. Computer tomographic imaging shows sinus opacification with hyperdense areas. Treatment has been successful with definitive nasosinus surgery and long-term oral prednisone. There is some evidence that fungi also may account for a large percentage of the remaining CRS patients. In this instance, the immune response to common airborne fungi appears to be IgG mediated rather than IgE mediated. Promising therapeutic results have been seen with intranasal antifungal agents but larger multicenter double-blinded placebo-controlled studies are needed. Another unanswered question includes the possible role of staphylococcus-derived enterotoxins in the pathogenesis of CRS.


A polar-coordinate-based pencil beam algorithm for VMAT dose computation with high-resolution gantry angle sampling.
Most commercially available treatment planning systems (TPSs) approximate the continuous delivery of volumetric modulated arc therapy (VMAT) plans with a series of discretized static beams for treatment planning, which can make VMAT dose computation extremely inefficient. In this study, we developed a polar-coordinate-based pencil beam (PB) algorithm for efficient VMAT dose computation with high-resolution gantry angle sampling that can improve the computational efficiency and reduce the dose discrepancy due to the angular under-sampling effect. 6 MV 1 × 1 m m 2 $1 \times 1{\rm{\;m}}{{\rm{m}}^2}$ pencil beams were simulated on a uniform cylindrical phantom under an EGSnrc Monte Carlo (MC) environment. The MC-generated PB kernels were collected in the polar coordinate system for each bixel on a 40 × 40 c m 2 $40 \times 40{\rm{\;c}}{{\rm{m}}^2}$ fluence map and subsequently fitted via a series of Gaussians. The fluence was calculated using a detectors' eye view with off-axis and MLC transmission factors corrected. Doses of VMAT arc on the phantom were computed by summing the convolution results between the corresponding PB kernels and fluence for each bixel in the polar coordinate system. The convolution was performed using fast Fourier transform to expedite the computing speed. The calculated doses were converted to the Cartesian coordinate system and compared with the reference dose computed by a collapsed cone convolution (CCC) algorithm of the TPS. A heterogeneous phantom was created to study the heterogeneity corrections using the proposed algorithm. Ten VMAT arcs were included to evaluate the algorithm performance. Gamma analysis and computation complexity theory were used to measure the dosimetric accuracy and computational efficiency, respectively. The dosimetric comparisons on the homogeneous phantom between the proposed PB algorithm and the CCC algorithm for 10 VMAT arcs demonstrate that the proposed algorithm can achieve a dosimetric accuracy comparable to that of the CCC algorithm with average gamma passing rates of 96% (2%/2mm) and 98% (3%/3mm). In addition, the proposed algorithm can provide better computational efficiency for VMAT dose computation using a PC equipped with a 4-core processor, compared to the CCC algorithm utilizing a dual 10-core server. Moreover, the computation complexity theory reveals that the proposed algorithm has a great advantage with regard to computational efficiency for VMAT dose computation on homogeneous medium, especially when a fine angular sampling rate is applied. This can support a reduction in dose errors from the angular under-sampling effect by using a finer angular sampling rate, while still preserving a practical computing speed. For dose calculation on the heterogeneous phantom, the proposed algorithm with heterogeneity corrections can still offer a reasonable dosimetric accuracy with comparable computational efficiency to that of the CCC algorithm. We proposed a novel polar-coordinate-based pencil beam algorithm for VMAT dose computation that enables a better computational efficiency while maintaining clinically acceptable dosimetric accuracy and reducing dose error caused by the angular under-sampling effect. It also provides a flexible VMAT dose computation structure that allows adjustable sampling rates and direct dose computation in regions of interest, which makes the algorithm potentially useful for clinical applications such as independent dose verification for VMAT patient-specific QA.


[Drug hypersensitivity syndrome].
The drug hypersensitivity syndrome (DHS) is a drug-induced reaction of an extremely severe clinical course and serious prognosis. It poses major diagnostic problems and is frequently unrecognized by clinicians. Based on literature data, the authors have presented the information on epidemiology, etiology, pathogenesis, clinical picture, diagnostics and treatment of DHS. This is the first report in Poland concerning this clinical interdisciplinary syndrome.


Impaired development and competitive refinement of the cortical frequency map in tumor necrosis factor-α-deficient mice.
Early experience shapes sensory representations in a critical period of heightened plasticity. This adaptive process is thought to involve both Hebbian and homeostatic synaptic plasticity. Although Hebbian plasticity has been investigated as a mechanism for cortical map reorganization, less is known about the contribution of homeostatic plasticity. We investigated the role of homeostatic synaptic plasticity in the development and refinement of frequency representations in the primary auditory cortex using the tumor necrosis factor-α (TNF-α) knockout (KO), a mutant mouse with impaired homeostatic but normal Hebbian plasticity. Our results indicate that these mice develop weaker tonal responses and incomplete frequency representations. Rearing in a single-frequency revealed a normal expansion of cortical representations in KO mice. However, TNF-α KOs lacked homeostatic adjustments of cortical responses following exposure to multiple frequencies. Specifically, while this sensory over-stimulation resulted in competitive refinement of frequency tuning in wild-type controls, it broadened frequency tuning in TNF-α KOs. Our results suggest that homeostatic plasticity plays an important role in gain control and competitive interaction in sensory cortical development.


Genome-wide analysis of DNA methylation and its relationship with serum homocysteine levels in patients with hypertension.
Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases, and elevated plasma Hcy levels could aggravate vascular injury in hypertension. Hyperhomocysteinemia can change the methylation status of global DNA and specific genes. In the present study, we aim to examine the comprehensive influence of Hcy levels on DNA methylation status in patients with hypertension. Epigenome-wide methylation profiles of the peripheral leukocyte DNA of 218 patients with hypertension were analyzed using the Illumina Infinium Methylation EPIC BeadChip. Differentially methylated positions (DMPs) associated with serum Hcy levels were identified by mixed linear regression with the adjustment of potential confounders. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to determine the potential functions of the identified DMPs. The association between the methylation level of DMPs and carotid-femoral pulse wave velocity (Cf-PWV) was also analyzed. Five DMPs at cg13169662, cg03179312, cg21976560, cg25262698, and cg09433843 showed significant association with serum Hcy levels (false discovery rate-corrected P < 0.05). An additional six CpG sites met the threshold for suggestive significance ( P < 1 × 10 -6 ), among which three DMPs (cg25781123, cg26463106, and cg06679221) were annotated to THUMPD3 . Furthermore, the methylation levels of cg13169662 and cg25262698 (RPRD1A) were significantly associated with Cf-PWV. Our results suggest that Hcy could induce DNA methylation alteration in patients with hypertension. Further functional research is warranted to elucidate the concrete role of DMPs in hypertension.


Longitudinal mode competition and mode clustering in (Al,In)GaN laser diodes.
Longitudinal mode competition in (Al,In)GaN laser diodes at λ = 445nm and 515 nm with mode competition frequencies from 10 MHz to 150 MHz is observed. Up to two dozen lasing modes oscillate with the lasing mode rolling from the short wavelength edge to the long wavelength edge of the gain profile. The experimental results can be described very well with a set of multi-mode rate equations including self-, symmetric and asymmetric cross gain saturation. By tuning essential parameters of the gain saturation terms, mode competition disappears and single mode operation as well as mode clustering is found. This proves that the mechanisms of gain saturation have not only a profound impact on the complex temporal-spectral behavior but also explains mode clustering in (Al,In)GaN laser diodes, both in pulsed and continuous wave (cw) operation as a natural nonlinear effect without the necessity to add noise.


Preoperative portal vein embolization for liver malignancies.
To study effectiveness of preoperative portal vein embolization before extensive hepatic resection in patients with primary or secondary liver malignancies. Between December 1997 and May 2003, right portal vein embolization was performed in 24 patients. The indication to the procedure was a small amount (< 30%) of the future remnant liver. Ultrasound-guided percutaneous transhepatic puncture of the portal vein and embolization of its right lobar branch with Lipiodol, ethanol, gelatin sponge and/or steel coils were used. There were no complications of the procedure. In 19-56 (mean, 30) days, CT or MRI showed significant increase of the future remnant liver volume from 25% to 35% of the whole liver; the mean increase was 40%. Laparotomy was performed in 15 patients. Right, extended right hepatectomy, and repeated resection were performed in 7, 6, and 1 patient respectively, while one patient underwent only exploration because of tumor progression. Of 14 resected patients, 11 showed no postoperative liver failure. The latter was medically cured in two of three remaining patients, while one patient (future remnant liver < 30% even after the embolization) died from liver failure in 20 days after the surgery. Hepatic resection is planning in 4 of 9 non-operated patients. The 5 patients were not operated because of tumor progression. Right portal vein embolization is a safe and technically simple procedure that decreases the risk of postoperative hepatic failure after major liver resection.


[Secretion of beta-hCG in pregnancy: an artefact?].
The concentration of beta-subunit (hCG beta) cannot be exactly quantified by means of competitive immunoassay in the presence of high levels of hCG, e.g. during normal pregnancy. Although the specificity and sensitivity of immunometric assay with mixed monoclonal antibodies was much improved, false positive results of hCG beta can, however, be obtained, if a high concentration of hCG is present in the hCG beta-IRMA (Ozturk et al. 1987). In this study hCG beta was therefore measured by subtraction of the values obtained by 2 immunometric assays for hCG + hCG beta and hCG in 174 serum samples of normal pregnant women during the 4th and 20th week of pregnancy. As both values did not differ, no hCG beta activity could be confirmed. Serum samples from pregnant women or authentic substances (hCG and hCG beta) were analyzed qualitatively by means of gel filtration (Sephadex-G100 column) and measurement of hCG and hCG + hCG beta activity in the fractions. In the chromatograms of pregnant serum, only one fraction with a hCG activity was observed. No additional fraction corresponding to the hCG beta activity could be identified in these chromatograms. It is concluded that, the secretion of hCG beta in serum during pregnancy is very low (less than 1%) and that the hCG beta activity measured by means of radioimmunoassay may possibly be due to an artifact.


Substance Use Patterns Among Adolescents: A Latent Class Analysis.
BACKGROUND: Substance use among adolescents remains a major public health concern, which is correlated with mortality. AIMS: The purpose of this study was to (1) examine risk factors predisposing adolescents to substance use and (2) identify patterns of simultaneous drug exploration among adolescents. METHOD: Data (N = 15,624; collected in 2015) were drawn from the Centers for Disease Control and Prevention, National Youth Risk Behavior Survey, which is a national school-based survey of 9th- to 12th-grade students to monitor health risk behaviors. Substance use was assessed using self-reported questionnaires, and latent class analysis and logistic regression were used for data analysis. RESULTS: Five latent patterns of substance use were identified: (1) abstinent (64%); (2) 1st-step social experimenter (25%) (i.e., used alcohol, e-cigarettes, and/or marijuana); (3) 2nd-step social experimenter (6%) (i.e., used alcohol, cigarettes, e-cigarettes, marijuana, synthetic marijuana, and/or prescription pills); (4) pill experimenter (4%), (i.e., used prescription pills); (5) full experimenter (2%) (i.e., likely to use all assessed substances). Gender, race, grade, and depressive mood were strong predictors of membership in a particular substance use class. CONCLUSION: Adolescents presenting for care may possess symptoms associated with various substances beyond those being managed. Mental health nurses can leverage these results in reducing adolescent substance use through primary and secondary prevention. A longitudinal study of not only substance use patterns but also the progression to substance use disorders among adolescents is warranted.