Antibodies to gp120 and PD-1 expression on virus-specific CD8+ T cells in protection from simian AIDS.
We compared the relative efficacies against simian immunodeficiency virus (SIV) challenge of three vaccine regimens that elicited similar frequencies of SIV-specific CD4(+) and CD8(+) T-cell responses but differed in the level of antibody responses to the gp120 envelope protein. All macaques were primed with DNA plasmids expressing SIV gag, pol, env, and Retanef genes and were boosted with recombinant modified vaccinia Ankara virus (MVA) expressing the same genes, either once (1 × MVA) or twice (2 × MVA), or were boosted once with MVA followed by a single boost with replication-competent adenovirus (Ad) type 5 host range mutant (Ad5 h) expressing SIV gag and nef genes but not Retanef or env (1 × MVA/Ad5). While two of the vaccine regimens (1 × MVA and 1 × MVA/Ad5) protected from high levels of SIV replication only during the acute phase of infection, the 2 × MVA regimen, with the highest anti-SIV gp120 titers, protected during the acute phase and transiently during the chronic phase of infection. Mamu-A*01 macaques of this third group exhibited persistent Gag CD8(+)CM9(+) effector memory T cells with low expression of surface Programmed death-1 (PD-1) receptor and high levels of expression of genes associated with major histocompatibility complex class I (MHC-I) and MHC-II antigen. The fact that control of SIV replication was associated with both high titers of antibodies to the SIV envelope protein and durable effector SIV-specific CD8(+) T cells suggests the hypothesis that the presence of antibodies at the time of challenge may increase innate immune recruiting activity by enhancing antigen uptake and may result in improvement of the quality and potency of secondary SIV-specific CD8(+) T-cell responses.


Anatomical variability of the anterolateral thigh flap perforators: vascular anatomy and its clinical implications.
Anatomical variability of perforators of the anterolateral thigh flap has been reported. The authors introduce a classification based on the number, location, and origin of the cutaneous perforators to comprehensively illustrate their vascular patterns in hopes that unfavorable anatomical variations of the anterolateral thigh flap can be overcome in clinical applications. The authors enrolled and reviewed 110 anterolateral thigh flaps created between September of 2010 and January of 2013 for head and neck reconstruction after cancer ablation. The location of the perforators was defined by Yu's ABC system. Its corresponding origin from the descending or transverse branch of the lateral circumflex femoral artery was clarified by Shieh's vascular anatomical classification for the anterolateral thigh flap. Of the 110 flaps, a single perforator (A or B or C) was observed in 20 flaps (18.2 percent), double perforators (A + B or B + C or A + C) were observed in 59 flaps (53.6 percent), and triple perforators (A + B + C) in 31 flaps (28.2 percent). The origin of perforators was the descending branch in 76 flaps (69.1 percent), the transverse branch in 10 flaps (9.1 percent), and both descending and transverse branches in 24 flaps (21.8 percent). The authors observed 16 vascular patterns. The most common type was double perforators, with perforators B and C originating from the descending branch [n = 40 (36.4 percent)]. The clinical significance of each pattern is delineated, and surgical technical considerations are suggested according to flap requirements and types of vascular anatomy.


Preoperative characterization of indeterminate large adrenal masses with dual tracer PET-CT using fluorine-18 fluorodeoxyglucose and gallium-68-DOTANOC: initial results.
We aimed to evaluate the usefulness of dual tracer positron emission tomography-computed tomography (PET-CT) with flourine-18 fluorodeoxyglucose (18F-FDG) and gallium-68 [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI3-octreotide (68Ga-DOTANOC) in preoperative characterization of large indeterminate adrenal masses. Ten patients (four males, six females; median age, 35 years) with indeterminate, large (≥4 cm) adrenal masses were included in this prospective study. All patients underwent both 18F-FDG PET-CT and 68Ga-DOTANOC PET-CT within one week. Images were evaluated both visually and semi-quantitatively, with standardized uptake value (SUVmax) and SUVratio (SUVmax) of tumor/SUVmax) of mediastinum). Based on differential uptake pattern on 18F-FDG and 68Ga-DOTANOC, lesions were classified as cortical (18F-FDG>68Ga-DOTANOC), medullary (68Ga-DOTANOC>18F-FDG), or indeterminate (18F-FDG=68Ga-DOTANOC). Histopathology was taken as reference standard. Receiver operating characteristic (ROC) analysis was performed to find a cut-off of SUVmax) and SUVratio to differentiate cortical and medullary lesions. On histopathology, eight lesions were adrenocortical carcinomas, one was benign pheochromocytoma, and one was malignant pheochromocytoma. Visually, 18F-FDG PET-CT was positive in all ten lesions, while 68Ga-DOTANOC PET-CT was positive in two, both of which were pheochromocytomas. On SUVmax) based analysis, nine lesions were cortical and one was medullary. On ROC analysis, a SUVmax) cut-off of > 2.3 was obtained for 18F-FDG PET-CT and 3.6 for 68Ga-DOTANOC PET-CT for differentiating adrenal cortical and medullary lesions. The cut-off for SUVratio was 4.5 on 18F-FDG PET-CT and 11.1 on 68Ga-DOTANOC PET-CT. These preliminary results demonstrate that dual tracer PET-CT using 18F-FDG and 68Ga-DOTANOC could be informative in the preoperative characterization of large indeterminate adrenal masses.


Comparison of complications associated with induction by misoprostol versus dilation and evacuation for second-trimester abortion.
To compare the frequency of complications between medical induction with misoprostol and dilation and evacuation (D&E) for second-trimester uterine evacuation. In a retrospective cohort study, records were reviewed from all women who underwent second-trimester uterine evacuation between 14 and 24 weeks of pregnancy at an academic hospital in the USA from January 2007 to December 2008. Total complications and serious complications were compared between medical induction and D&E, and clinical covariates associated with complications were assessed. Overall, 465 women were included. At least one complication occurred in 28 (23.0%) of 122 women in the medical induction group, and 24 (7.0%) of 343 women in the D&E group (P<0.001). One or more serious complications occurred in 4 (3.3%) women undergoing medical induction and 5 (1.5%) undergoing D&E (P=0.251). Logistic regression analysis demonstrated that increasing pregnancy length (P=0.003) and medical induction (as compared with D&E; P=0.004) were associated with complications. Although D&E resulted in fewer overall complications as compared with medical induction, the rate of serious complications did not differ between the two procedures.


Risk of major depressive disorder among older persons living in HIV-endemic central and southwestern Uganda.
Major depressive disorder (MDD) is projected to become the second most common cause of disability by 2020 calling for a better understanding its antecedents across the lifespan and in diverse socio-cultural settings. In this paper we describe the risk factors of MDD among older people (50 years +) living in HIV-endemic central and southwestern Uganda. A cross-sectional study was undertaken among 471 respondents (50 years +) participating in the Wellbeing of Older People's Study cohort of the MRC/UVRI Uganda research Unit on AIDS in Uganda. Participants were from five strata: HIV negative, HIV positive on ART, HIV positive not on ART, having an adult child on ART, and having an adult child who died of HIV. Overall MDD prevalence was 9.2% (95% CI 6.7-12.2%) with a prevalence among males of 7.4% (95% CI 4.0-12.3%) and females of 10.3% (95% CI 7.0-14.3%). Factors significantly associated with MDD included: declining socio-economic status, increasing disability scores, decreasing mean grip strength, reported back pain, and not having hypertension. Marginally associated with MDD was being HIV infected and not on ART.


TGF-beta regulates pathology but not tissue CD8+ T cell dysfunction during experimental Trypanosoma cruzi infection.
Infection with the protozoan parasite Trypanosoma cruzi leads to chronic infection, with parasite persistence primarily in muscle tissue. CD8(+) T cells isolated from muscle tissue of T. cruzi-infected mice display decreased production of IFN-gamma in response to T cell receptor engagement. The expression of TGF-beta at the site of CD8(+) T cell dysfunction and parasite persistence suggested that this immunoregulatory cytokine might play a role in these processes. Mice expressing a T cell-specific dominant negative TGF-beta receptor type II (DNRII) were therefore infected with T. cruzi. Infection of DNRII mice resulted in massive CD8(+) T cell proliferation, leading to increased numbers but decreased frequencies of antigen-specific CD8(+) T cells in the spleen compared to wild-type mice. However, TGF-beta unresponsiveness failed to restore effector functions of CD8(+) T cells isolated from muscle tissue. Histological examination of skeletal muscle from T. cruzi-infected DNRII mice revealed an extensive cellular infiltrate, and DNRII mice displayed higher susceptibility to infection. Overall, while TGF-beta does not appear to be responsible for CD8(+) T cell unresponsiveness in peripheral tissue in T. cruzi-infected mice, these data suggest a role for TGF-beta in control of immunopathology in response to T. cruzi infection.


Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice.
Pyruvate dehydrogenase complex (PDC) plays an important role in energy homeostasis in the heart by catalyzing the oxidative decarboxylation of pyruvate derived primarily from glucose and lactate. Because various pathophysiological states can markedly alter cardiac glucose metabolism and PDC has been shown to be altered in response to chronic ischemia, cardiac physiology of a mouse model with knockout of the alpha-subunit of the pyruvate dehydrogenase component of PDC in heart/skeletal muscle (H/SM-PDCKO) was investigated. H/SM-PDCKO mice did not show embryonic lethality and grew normally during the preweaning period. Heart and skeletal muscle of homozygous male mice had very low PDC activity (approximately 5% of wild-type), and PDC activity in these tissues from heterozygous females was approximately 50%. Male mice did not survive for >7 days after weaning on a rodent chow diet. However, they survived on a high-fat diet and developed left ventricular hypertrophy and reduced left ventricular systolic function compared with wild-type male mice. The changes in the heterozygote female mice were of lesser severity. The deficiency of PDC in H/SM-PDCKO male mice greatly compromises the ability of the heart to oxidize glucose for the generation of energy (and hence cardiac function) and results in cardiac pathological changes. This mouse model demonstrates the importance of glucose oxidation in cardiac energetics and function under basal conditions.


Safety of conventional systemic therapies for psoriasis on reproductive potential and outcomes.
The effects of conventional systemic therapies for psoriasis on pregnancy outcomes, lactation, male fertility and mutagenicity are common concerns in the clinical setting. There is relatively little evidence to guide clinician and patient. In this study, we review the safety profile of the commonly used conventional systemic therapies used for psoriasis in individuals of reproductive potential. Safety data are derived from large-scale registries, adverse-event reporting databases, clinical trials and case reports. We assess the effect of each therapy on adverse pregnancy outcomes, including congenital malformations, and lactation with maternal administration. We also assess the effect of the therapies on male fertility and potential mutagenicity with paternal administration. We provide applicable guidance to inform clinician and patient before and after conception.


Inhibition of apoptosis by 60% oxygen: a novel pathway contributing to lung injury in neonatal rats.
During early postnatal alveolar formation, the lung tissue of rat pups undergoes a physiological remodeling involving apoptosis of distal lung cells. Exposure of neonatal rats to severe hyperoxia (≥95% O(2)) both arrests lung growth and results in increased lung cell apoptosis. In contrast, exposure to moderate hyperoxia (60% O(2)) for 14 days does not completely arrest lung cell proliferation and is associated with parenchymal thickening. On the basis of similarities in lung architecture observed following either exposure to 60% O(2), or pharmacological inhibition of physiological apoptosis, we hypothesized that exposure to 60% O(2) would result in an inhibition of physiological lung cell apoptosis. Consistent with this hypothesis, we observed that the parenchymal thickening induced by exposure to 60% O(2) was associated with decreased numbers of apoptotic cells, increased expressions of the antiapoptotic regulator Bcl-xL, and the putative antiapoptotic protein survivin, and decreased expressions of the proapoptotic cleaved caspases-3 and -7. In summary, exposure of the neonatal rat lung to moderate hyperoxia results in an inhibition of physiological apoptosis, which contributes to the parenchymal thickening observed in the resultant lung injury.


A Case of Massive Pleural Effusion: Pleurodesis by Bleomycin.
Malignant pleural effusion is a common complication of primary and metastatic pleural malignancies. Pleurodesis for the management of malignant pleural effusion is intended to achieve symphysis between parietal and visceral pleura, and to prevent relapse of pleural effusion. Many chemical agents are tried to induce inflammation and damage of the pleural mesothelial layer to achieve this symphysis. Hemorrhagic pleural effusion, especially in the right hemithorax commonly occurs as presentation of primary and metastatic pleural malignancies. This case reports massive right-sided hemorrhagic pleural effusion as the sole manifestation of primary lung cancer in a 45 year old man. Patient attended our department of thoracic surgery complaining of cough, shortness of breath and right sided chest pain. A chest X-ray and chest computer tomography (CT) radiograph shows right sided massive pleural effusion. Right sided tube thoracotomy done. Pleural fluid study was done. Fluid for cytopathology was positive for malignant cell. Computed tomography guided fine needle aspiration cytology from right lung lesion was also done. Diagnosis was as small cell carcinoma. Pleural effusion resolved after 9(th) post operative day of chest tube insertion. Bleomycin pleurodesis was done. Day after pleurodesis intra thoracic tube was removed and patient was discharged from hospital on 10(th) Post operative day with an advice to attend the oncology department for further treatment. The protocol of tube thoracostomy and chemical pleurodesis was almost always successful in giving symptomatic relief of respiratory distress for a considerable period of time. However, chemical pleurodesis is not possible in all cases of malignant pleural effusion because it has got potential complication including death.


Sociodemographic and clinical features of patients with depressive disorder in Khartoum, Sudan.
It's known worldwide that depression is becoming a major health problem and its prevalence is increasing. The main objective of this study is to find out the prevalence of depression among patients attending a general psychiatric clinic, and study their sociodemographic and clinical features. Files of patients attending a private psychiatric clinic in Khartoum in the period June 2005-June 2010 were reviewed. Only those with a diagnosis of depression were chosen, sociodemographic date and clinical features were documented and results were shown below. Total numbers of patients with depression were 137 (11.4%). Females were more than males (56.2%), the majority are between ages 41-60 (40.9%), married (65%), (14.9%) had family history of psychiatric disorders and (52%) had a previous history of psychiatric treatment. Depressed mood is the commonest symptom (98.5%), loss of interest (91.9%), reduced energy (57%), guilt feelings (17.9%) and (35.8%) of our samples expressed suicidal ideations. The commonest type of somatic symptom is generalized aches and pain (30.7%), (18%) were psychotic. The present study is a retrospective descriptive study, based on a private psychiatric clinic sample. It provided a useful baseline for more comprehensive field based studies, to try to aid planning and development of services to meet the needs of the population.


[Four year management of HIV serology at the National Center of Blood Transfusion in Conakry].
From January 1997 to December 2000, 21145 blood donations have been collected and tested for anti-HIV antibodies by the National Center of Blood Transfusion of Conakry (NCBT). 347 were positive, confirmed by Western Blot (312 HIV-1, 20 HIV-2 and 15 HIV1-2). HIV seroprevalence in tested blood donations showed a slow decrease by year: 1.87% in 1997 to 1.79% in 2000. The distribution according to donation type was 1% for volunteer donors and 2% for family donors. Seropositivity HIV rates according to sex indicate that the female donors are more infected than male donors. Among 347 seropositive, 83% were more than 20 years old. The seroprevalence is higher in soldier blood donors 3.72% (53/1422) than in student donors 0.55% (43/7712). The number of seropositive results found during these 4 years is not really representative of the HIV spreading infection in Guinean population, but their distribution according to sex and age is very close to the distribution of the AIDS cases in Guinea.


Endometriosis: Classification, pathophysiology, and treatment options.
The human endometrium is a complex hormone-target tissue consisting of two layers: the lower basalis, and the upper functionalis. The latter of the two goes through a cycle of thickening and shedding without residual scarring or loss of function. This cycle, known as the menstrual cycle, occurs on a monthly basis in most of healthy reproductive-age women. It is, however, associated with a number of reproductive diseases, endometriosis being one of them. Endometriosis is defined as the presence of endometrium at ectopic sites within the peritoneum or, more rarely, other locations outside the abdominal area. It affects around 6-10% of reproductive-age women in the world and causes debilitating pain, heavy menstrual bleeding, pain during penetrative sex, and infertility. The etiology of the disease is not yet fully understood but the generally accepted theory is that the endometriotic lesions originate from viable eutopic endometrial cells that flow back into the peritoneum through the process of retrograde menstruation. Endometriosis is usually classified into four stages: minimal, mild, moderate, and severe, though it is important to note that the presentation of symptoms does not necessarily correspond to the disease progression. The immune system plays an important role in supporting the viability and growth of ectopic endometriotic tissue, all the while promoting chronic inflammation at the lesion sites, which causes prolonged pain. There is no definitive cure for endometriosis, but there are several options for symptom management, including laparoscopy, hormonal therapy, the use of NSAIDs, dietary changes, exercise, and, in cases when all conservative treatments fail, hysterectomy.


Indophenol method for acetaminophen in serum examined.
We show that an indophenol-based colorimetric method for acetaminophen (Clin Toxicol 15: 67-73, 1979) has less than maximal sensitivity because of (a) incomplete hydrolysis, related to suboptimal acid concentration; (b) suboptimal hydrolysis time; and (c) possible deterioration of the ammonium hydroxide reagent after 2.5 months. We have modified the method by optimizing duration of hydrolysis and color development. Results by the method correlate linearly with acetaminophen concentrations to 250 mg/L (1.66 mmol/L). Moreover, the modified method is free from interference by compounds in serum from uremic patients.


Therapeutic reendothelialization by induced pluripotent stem cells after vascular injury--brief report.
Endothelial damage is an early requisite step for atherosclerosis after vascular injury. It has been reported that vascular wall cells can develop from induced pluripotent stem (iPS) cell-derived fetal liver kinase-1-positive (Flk-1(+)) cells. Here, we investigated the efficacies of intravenously administered iPS cell-derived Flk-1(+) cells on reendothelialization and neointimal hyperplasia in a mouse model of vascular injury. Femoral arteries of KSN nude mice were injured using a steel wire. Mouse iPS cell-derived Flk-1(+) or Flk-1(-) cells were intravenously injected into those mice at 24 hours after vascular injury. Delivery of iPS cell-derived Flk-1(+) cells significantly attenuated neointimal hyperplasia compared with controls. Evans blue staining of the injured vessel revealed that administration of iPS cell-derived Flk-1(+) significantly enhanced reendothelialization compared with the Flk-1(-) cell control group. Recruitment of PKH26-labeled iPS cell-derived Flk-1(+) cells to the site of injury was also detectable. Expression level of CXCR4 in iPS cell-derived Flk-1(+) cells was 7.5-fold higher than that of iPS cell-derived Flk-1(-) cells. Stromal cell-derived factor-1α treatment significantly enhanced adhesion and migration of iPS cell-derived Flk-1(+) cells to the endothelia, but these were not observed in Flk-1(-) cells. Intravenously administered iPS cell-derived Flk-1(+) cells are recruited to the site of vascular injury, thereby enhancing reendothelialization followed by suppression of neointimal hyperplasia. Administration of iPS cell-derived Flk-1(+) cells is a potentially useful therapeutic means for vascular dysfunction and prevention of restenosis after angioplasty.


Consecutive palladium-catalyzed Hiyama-Heck reactions in aqueous media under ligand-free conditions.
Symmetric and asymmetric (E)-1,2-diarylethenes are synthesized from aryl bromides by consecutive one-pot Hiyama-Heck reactions carried out in water and under air; the only additives required are sodium hydroxide, palladium acetate and poly(ethylene glycol), and the products are isolable in many cases by simple filtration of the water solution.


Rare and declining bee species are key to consistent pollination of wildflowers and crops across large spatial scales.
Biodiversity promotes ecosystem function (EF) in experiments, but it remains uncertain how biodiversity loss affects function in larger-scale natural ecosystems. In these natural ecosystems, rare and declining species are more likely to be lost, and function needs to be maintained across space and time. Here, we explore the importance of rare and declining bee species to the pollination of three wildflowers and three crops using large-scale (72 sites across 5000 km2 ), multi-year datasets. Half of the sampled bee species (82/164) were rare or declining, but these species provided only ~15% of overall pollination. To determine the number of species important to EF, we used two methods of "scaling up," both of which have previously been used for biodiversity-function analysis. First, we summed bee species' contributions to pollination across space and time and then found the minimum set of species needed to provide a threshold level of function across all sites; according to this method, effectively no rare and declining bee species were important to pollination. Second, we account for the "insurance value" of biodiversity by finding the minimum set of bee species needed to simultaneously provide a threshold level of function at each site in each year. The second method leads to the conclusion that 25 rare and eight declining bee species (36% and 53% of all rare and declining bee species, respectively) are included in the minimum set. Our findings provide some of the strongest evidence yet that rare and declining species are key to meeting threshold levels of EF, thereby providing a more direct link between real-world biodiversity loss and EF.


Effects of multi-domain interventions in (pre)frail elderly on frailty, functional, and cognitive status: a systematic review.
Frailty is an aging syndrome caused by exceeding a threshold of decline across multiple organ systems leading to a decreased resistance to stressors. Treatment for frailty focuses on multi-domain interventions to target multiple affected functions in order to decrease the adverse outcomes of frailty. No systematic reviews on the effectiveness of multi-domain interventions exist in a well-defined frail population. This systematic review aimed to determine the effect of multi-domain compared to mono-domain interventions on frailty status and score, cognition, muscle mass, strength and power, functional and social outcomes in (pre)frail elderly (≥65 years). It included interventions targeting two or more domains (physical exercise, nutritional, pharmacological, psychological, or social interventions) in participants defined as (pre)frail by an operationalized frailty definition. The databases PubMed, EMBASE, CINAHL, PEDro, CENTRAL, and the Cochrane Central register of Controlled Trials were searched from inception until September 14, 2016. Additional articles were searched by citation search, author search, and reference lists of relevant articles. The protocol for this review was registered on PROSPERO (CRD42016032905). Twelve studies were included, reporting a large diversity of interventions in terms of content, duration, and follow-up period. Overall, multi-domain interventions tended to be more effective than mono-domain interventions on frailty status or score, muscle mass and strength, and physical functioning. Results were inconclusive for cognitive, functional, and social outcomes. Physical exercise seems to play an essential role in the multi-domain intervention, whereby additional interventions can lead to further improvement (eg, nutritional intervention). Evidence of beneficial effects of multi-domain compared to mono-domain interventions is limited but increasing. Additional studies are needed, focusing on a well-defined frail population and with specific attention to the design and the individual contribution of mono-domain interventions. This will contribute to the development of more effective interventions for frail elderly.


Compact in-line floating display system using a dihedral corner reflector array.
We propose a compact type floating display system using a dihedral corner reflector array. Conventional floating displays using the dihedral corner reflector array usually have a folded configuration which makes the system bulky. The proposed technique achieves the compact in-line configuration using a pair of decentered lenses. The decentered lenses make the effective incident angle to the dihedral corner reflector array be tilted while maintaining the display panel and the dihedral corner reflector array in parallel. The ghost images are also refracted largely by the decentered lenses, being separated from the desired floating images. The proposed technique is verified by optical experiments.


Design of a pre-slit for SPring-8 undulator beamlines.
A volumetric heating method is applied to the pre-slit placed on the SPring-8 standard-undulator beamline front ends in order to handle the very intensive photon beam. A graphite block is used as the radiation-absorbing body, which is brazed to a cooling holder made of oxygen-free high-conductivity copper. Various experiments and calculations have been carried out on the strength of the brazed joint. Comparisons between the experiments and calculations show that static fracture of the joint would not occur even under the highest heat load. The outgassing properties of the graphite blocks are also presented here.


Activities of the Leeds Castle Polyposis Group.
In June 1985 an international meeting took place at Leeds Castle, England, to discuss some of the problems facing those caring for polyposis patients and conducting research in the field. From this grew the Leeds Castle Polyposis Group, comprising workers from 19 centers around the world; they agreed to cooperate initially in the collation of retrospective data with the hope that this would lead to prospective studies including comparative therapy trials. So far four retrospective pro formas have circulated. The data from these and plans for further projects will be discussed at the next meeting of the group in Washington in April 1987.


Air pollution and Parkinson's disease - evidence and future directions.
Parkinson's disease (PD) is a neurodegenerative disease of unknown etiology that is thought to be caused by a complex combination of environmental and/or genetic factors. Air pollution exposure is linked to numerous adverse effects on human health, including brain inflammation and oxidative stress, processes that are believed to contribute to the development and progression of PD. This review provides an overview of recent advances in the epidemiology of air pollution and PD, including evidence of the effects of various pollutants (ozone, PM10, PM2.5, PM2.5-10, NOx, NO2, CO, traffic air pollution, second-hand smoking) on PD risk. Based on this evidence, promising opportunities for future research are outlined, including: (1) studies of smaller particle sizes that cross the blood-brain barrier, (2) studies of the effects of air pollution on PD mortality and/or progression; (3) studies of interactions of air pollution with gene environment and other environmental factors.


A Novel Complex-Coefficient In-Band Interference Suppression Algorithm for Cognitive Ultra-Wide Band Wireless Sensors Networks.
With the rapid development of wireless communication systems and electronic techniques, the limited frequency spectrum resources are shared with various wireless devices, leading to a crowded and challenging coexistence circumstance. Cognitive radio (CR) and ultra-wide band (UWB), as sophisticated wireless techniques, have been considered as significant solutions to solve the harmonious coexistence issues. UWB wireless sensors can share the spectrum with primary user (PU) systems without harmful interference. The in-band interference of UWB systems should be considered because such interference can severely affect the transmissions of UWB wireless systems. In order to solve the in-band interference issues for UWB wireless sensor networks (WSN), a novel in-band narrow band interferences (NBIs) elimination scheme is proposed in this paper. The proposed narrow band interferences suppression scheme is based on a novel complex-coefficient adaptive notch filter unit with a single constrained zero-pole pair. Moreover, in order to reduce the computation complexity of the proposed scheme, an adaptive complex-coefficient iterative method based on two-order Taylor series is designed. To cope with multiple narrow band interferences, a linear cascaded high order adaptive filter and a cyclic cascaded high order matrix adaptive filter (CCHOMAF) interference suppression algorithm based on the basic adaptive notch filter unit are also presented. The theoretical analysis and numerical simulation results indicate that the proposed CCHOMAF algorithm can achieve better performance in terms of average bit error rate for UWB WSNs. The proposed in-band NBIs elimination scheme can significantly improve the reception performance of low-cost and low-power UWB wireless systems.


Trait selection and co-existence of phytoplankton in partially mixed systems: Trait based modelling and potential of an aggregated approach.
Trait selection and co-existence in phytoplankton communities in partially mixed water columns is investigated using trait based modelling. In the models employed, trait selection results from phytoplankton competition for two limiting resources, light and nutrients. The study employs spatially resolved models, in which the phytoplankton community is represented as a large number of trait-groups characterized by fixed trait combinations (trade-offs). Results from the trait-group resolving model (RM) are compared to results from an aggregated trait based model with adaptive traits (AM). Differences in specific production resulting from a trade-off between the half saturation constants of light and nutrients are sufficient to support evolutionary stable co-existence confirming that co-existence does not require differences in resource consumption. If abiotic conditions lead to the selection of a single trait group in RM, AM provides excellent approximations of the development of total biomass, average community trait and trait variance in the phytoplankton community. However, if selection leads to bimodal trait distributions, e.g. to co-existence of two trait groups (or species), functionally important properties of the phytoplankton community cannot be adequately represented by the aggregated information provided by AM. Because the increase in variance due to the development of bimodal trait distributions cannot be distinguished from an increase in variance due to an increase in trait diversity, the development of trait variance in AM models is not a reliable measure of trait diversity. Furthermore, AM may not provide reliable simulations of trophic interactions if the performance of the consumers depends on the traits of their resources. However, AM may support exploration of the consequences of environmental conditions and of the parameterization of species for co-existence within communities.


Integer programming for improving radiotherapy treatment efficiency.
Patients received by radiotherapy departments are diverse and may be diagnosed with different cancers. Therefore, they need different radiotherapy treatment plans and thus have different needs for medical resources. This research aims to explore the best method of scheduling the admission of patients receiving radiotherapy so as to reduce patient loss and maximize the usage efficiency of service resources. A mix integer programming (MIP) model integrated with special features of radiotherapy is constructed. The data used here is based on the historical data collected and we propose an exact method to solve the MIP model. Compared with the traditional First Come First Served (FCFS) method, the new method has boosted patient admission as well as the usage of linear accelerators (LINAC) and beds. The integer programming model can be used to describe the complex problem of scheduling radio-receiving patients, to identify the bottleneck resources that hinder patient admission, and to obtain the optimal LINAC-bed radio under the current data conditions. Different management strategies can be implemented by adjusting the settings of the MIP model. The computational results can serve as a reference for the policy-makers in decision making.


Molecular Characterization of Staphylococcus aureus Isolates From Children With Periorbital or Orbital Cellulitis.
Periorbital and orbital cellulitis cause significant pediatric morbidity. Here, we define the clinical features of and characterize isolates from children with periorbital or orbital cellulitis caused by Staphylococcus aureus at Texas Children's Hospital in Houston. Patients were identified from a prospective S aureus study database from January 2002 to July 2015. Demographic and clinical data were collected retrospectively. Isolates were genotyped by pulsed-field gel electrophoresis, and Panton-Valentine leukocidin (lukSF-PV [pvl]) genes were detected by quantitative polymerase chain reaction. Data were analyzed with the Fisher exact or Wilcoxon rank-sum test. Eighty-five patients with periorbital (n = 58) or orbital (n = 27) cellulitis were identified. We found 57 (67%) methicillin-resistant S aureus (MRSA) isolates, 72 (85%) pvl-positive (pvl+) isolates, and 66 (78%) USA300 isolates. No differences in clinical characteristics were found when we compared MRSA to methicillin-susceptible (MSSA) infections or USA300 to non-USA300 infections. Patients with orbital cellulitis were hospitalized a median of 12 days (range, 2-28 days) and received antibiotics for 21 days (range, 10-32 days). Twelve (44%) patients with orbital cellulitis received steroids. Steroid treatment did not affect the length of hospitalization or duration of antibiotic treatment. Six (7%) patients with orbital cellulitis were bacteremic. Patients with periorbital cellulitis were hospitalized for a median of 3 days (range, 0-17 days) and received antibiotics for 11 days (range, 7-32 days). According to computed tomography (CT), 19 (70%) patients with orbital cellulitis and 11 (41%) with periorbital cellulitis had sinusitis. The majority of periorbital and orbital S aureus infections at Texas Children's Hospital were caused by MRSA, and no change was observed over time. Empirical antibiotic treatment should include coverage for MRSA. PVL might be an important virulence factor in these presentations. S aureus is associated with sinusitis and its complications.


Relationships between levels of urinary podocalyxin, number of urinary podocytes, and histologic injury in adult patients with IgA nephropathy.
Podocalyxin (PCX) is present on the apical cell membrane of podocytes and is shed in urine from injured podocytes. Urinary podocalyxin (u-PCX) is associated with severity of active glomerular injury in patients with glomerular diseases. This study examined the relationship between number of urinary podocytes, levels of u-PCX, and glomerular injury in adults with IgA nephropathy (IgAN). Urine samples voided in the morning on the day of biopsy were obtained from 51 patients with IgAN (18 men and 33 women; mean age, 31 years). All renal biopsy specimens were analyzed histologically. Pathologic variables of IgAN were analyzed per Shigematsu classification, the Oxford classification of IgAN, and the Clinical Guidelines of IgAN in Japan. Levels of u-PCX were measured by sandwich ELISA. Histologic analysis based on Shigematsu classification revealed a significant correlation between levels of u-PCX and severity of acute extracapillary abnormalities (r=0.72; P<0.001), but levels of urinary protein excretion did not correlate with acute glomerular abnormalities. Levels of urinary protein excretion in patients with segmental sclerosis (n=19) were higher than in patients without (n=22) (0.49 [interquartile range (IQR), 0.20-0.88] g/g creatinine versus 0.20 [IQR, 0.10-0.33] g/g creatinine; P<0.01). The number of urinary podocytes in patients with segmental sclerosis was higher than in patients without (1.05 [IQR, 0.41-1.67] per mg creatinine versus 0.28 [IQR, 0.10-0.66] per mg creatinine; P<0.01). Levels of u-PCX and the number of urinary podocytes are associated with histologic abnormalities in adults with IgAN.


A noninvasive multianalytical approach establishment for risk assessment and gastric cancer screening.
Effective screening and early detection are critical to improve the prognosis of gastric cancer (GC). Our study aims to explore noninvasive multianalytical biomarkers and construct integrative models for preliminary risk assessment and GC detection. Whole genomewide methylation marker discovery was conducted with CpG tandems target amplification (CTTA) in cfDNA from large asymptomatic screening participants in a high-risk area of GC. The methylation and mutation candidates were validated simultaneously using one plasma from patients at various gastric lesion stages by multiplex profiling with Mutation Capsule Plus (MCP). Helicobacter pylori specific antibodies were detected with a recomLine assay. Integrated models were constructed and validated by the combination of multianalytical biomarkers. A total of 146 and 120 novel methylation markers were found in CpG islands and promoter regions across the genome with CTTA. The methylation markers together with the candidate mutations were validated with MCP and used to establish a 133-methylation-marker panel for risk assessment of suspicious precancerous lesions and GC cases and a 49-methylation-marker panel as well as a 144-amplicon-mutation panel for GC detection. An integrated model comprising both methylation and specific antibody panels performed better for risk assessment than a traditional model (AUC, 0.83 and 0.63, P < .001). A second model for GC detection integrating methylation and mutation panels also outperformed the traditional model (AUC, 0.82 and 0.68, P = .005). Our study established methylation, mutation and H. pylori-specific antibody panels and constructed two integrated models for risk assessment and GC screening. Our findings provide new insights for a more precise GC screening strategy in the future.


Enhanced catalytic activity without the use of an external light source using microwave-synthesized CuO nanopetals.
We report enhanced catalytic activity of CuO nanopetals synthesized by microwave-assisted wet chemical synthesis. The catalytic reaction of CuO nanopetals and H2O2 was studied with the application of external light source and also under dark conditions for the degradation of the hazardous dye methylene blue. The CuO nanopetals showed significant catalytic activity for the fast degradation of methylene blue and rhodamine B (RhB) under dark conditions, without the application of an external light source. This increased catalytic activity was attributed to the co-operative role of H2O2 and the large specific surface area (≈40 m2·g-1) of the nanopetals. We propose a detail mechanism for this fast degradation. A separate study of the effect of different H2O2 concentrations for the degradation of methylene blue under dark conditions is also illustrated.


Disruption of the Tff1 gene in mice using CRISPR/Cas9 promotes body weight reduction and gastric tumorigenesis.
Trefoil factor 1 (TFF1, also known as pS2) is strongly expressed in the gastrointestinal mucosa and plays a critical role in the differentiation of gastric glands. Since approximately 50% of all human gastric cancers are associated with decreased TFF1 expression, it is considered a tumor suppressor gene. TFF1 deficiency in mice results in histological changes in the antral and pyloric gastric mucosa, with severe hyperplasia and dysplasia of epithelial cells, resulting in the development of antropyloric adenoma. Here, we generated TFF1-knockout (KO) mice, without a neomycin resistant (NeoR) cassette, using the clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRSIPR/Cas9) system. Though our TFF1-KO mice showed phenotypes very similar to the previous embryonic stem (ES)-cell-based KO mice, they differed from the previous reports in that a reduction in body weight was observed in males. These results demonstrate that these newly established TFF1-KO mice are useful tools for investigating genetic and environmental factors influencing gastric cancer, without the effects of artificial gene insertion. Furthermore, these findings suggest a novel hypothesis that TFF1 expression influences gender differences.


Prevalence and Characteristics of School Services for High School Students with Attention-Deficit/Hyperactivity Disorder.
This study examines the prevalence and characteristics of services reported by school staff for 543 high school students participating in the 8 year follow-up of the multi-site Multimodal Treatment study of ADHD (MTA). Overall, 51.6% of students with a history of attention-deficit/hyperactivity disorder (ADHD) were receiving services through an Individualized Educational Plan (IEP) or a 504 plan, a rate higher than expected for this age group. Less than 5% of these had 504 plans; 35.5% attended special education classes. Very few services (except tutoring) were provided outside of an IEP or 504 plan. Almost all students with services received some type of academic intervention, whereas only half received any behavioral support or learning strategy. Less than one-fourth of interventions appear to be evidence-based. Students receiving services showed greater academic and behavioral needs than those not receiving services. Services varied based upon type of school, with the greatest number of interventions provided to students attending schools that only serve those with disabilities. Original MTA treatment randomization was unrelated to services, but cumulative stimulant medication and greater severity predicted more service receipt. Results highlight a need for accommodations with greater evidence of efficacy and for increased services for students who develop academic difficulties in high school.


Isolated rhabdomyolysis of long head of triceps mimicking upper extremity deep vein thrombosis.
Rhabdomyolysis is characterised by skeletal muscle breakdown, with release of toxic intracellular contents into the circulation. A man in his 20s presented to the emergency department with acute-onset right arm swelling, with pitting oedema extending into his forearm without clear precipitant. Initial differential diagnosis was upper extremity deep vein thrombosis, however none was identified on CT venogram. Instead, rhabdomyolysis of long head of triceps was diagnosed after multidisciplinary review of the venogram by the treating vascular surgeon and radiologist. Retrospectively, added serum creatine kinase was found to be 11 587 U/L, and together with MRI of the right arm, the diagnosis was established. Given the patient's lack of comorbidities, normal renal function and reliability, he was managed conservatively as an outpatient without hospital admission for intravenous hydration. This is the only case to our knowledge of isolated long head of triceps' rhabdomyolysis reported in Australia and the second case worldwide.


Transplantation of germ cells from glial cell line-derived neurotrophic factor-overexpressing mice to host testes depleted of endogenous spermatogenesis by fractionated irradiation.
With a novel method of eliminating spermatogenesis in host animals, male germ cells isolated from mice with targeted overexpression of glial cell line-derived neurotrophic factor (GDNF) were transplanted to evaluate their ability to reproduce the phenotype previously found in the transgenic animals. Successful depletion of endogenous spermatogenesis was achieved using fractionated ionizing irradiation. A dose of 1.5 Gy followed by a dose of 12 Gy after 24 h reduced the percentage of tubule cross-sections displaying endogenous spermatogenesis to approximately 3% and 10% as evidenced by histologic evaluation of testes at 12 and 21 wk, respectively, after irradiation. At this dose, no apparent harmful side effects were noted in the animals. Upon transplantation, GDNF-overexpressing germ cells were found to be able to repopulate the irradiated testes and to form clusters of spermatogonia-like cells resembling those found in the overexpressing donor mice. The cluster cells in transplanted host testes expressed human GDNF, as had been shown previously for clusters in donor animals, and both were strongly positive for the tyrosine kinase receptor Ret. Thus, we devised an efficient method for depleting the seminiferous epithelium of host mice without appreciable adverse effects. In these host mice, GDNF-overexpressing cells reproduced the aberrant phenotype found in the donor transgenic mice.


Environmental risk assessment of PPP application in European soils and potential ecosystem service losses considering impacts on non-target organisms.
The use of Plant Protection Products (PPPs) is leading to high exposure scenarios with potential risk to soil organisms, including non-target species. Assessment of the effects of PPPs on non-target organisms is one of the most important components of environmental risk assessment (ERA) since they play crucial functions in ecosystems, being main driving forces in different soil processes. As part of the framework, EFSA is proposing the use of the ecosystem services approach for setting specific protection goals. In fact, the services provided by soil organisms can be impacted by the misuse of PPPs in agroecosystems. The aim of this work was to assess PPPs potential risk upon ecosystem services along European soils, considering impacts on earthworms and collembola. Four well-known (2 insecticides-esfenvalerate and cyclaniliprole- and 2 fungicides - picoxystrobin and fenamidone-) worst case application (highest recommended application) were studied; exploring approaches for linked observed effects with impacts on ecosystem services, accounting for their mode of action (MoA), predicted exposure, time-course effects in Eisenia fetida and Folsomia sp. and landscape variability. The selected fungicides exerted more effects than insecticides on E. fetida, whereas few effects were reported for both pesticides regarding Folsomia sp. The most impacted ecosystem services after PPP application to crops appeared to be habitat provision, soil formation and retention, nutrient cycling, biodiversity, erosion regulation, soil remediation/waste treatment and pest and disease regulation. The main factors to be taken into account for a correct PPP use management in crops are discussed.


Factors associated with effective contraceptive use among a sample of Latina women.
Unintended pregnancy disproportionately affects Latina women. One factor contributing to unintended pregnancy among Latinas is the low rate of contraceptive use. This study examined correlates of effective contraceptive use among a sample of Latina women (n=202) at increased risk for HIV. In addition to traditional intrapersonal variables (i.e., perceived risk of pregnancy, motivation to avoid pregnancy), the present study examined the role of the male partner and relationship factors (i.e., relationship commitment, duration, pregnancy prevention decision-making) on contraceptive use. Participants were recruited from clinics and community locations in East Los Angeles and administered a 60-minute in-person interview. Multivariate logistic regression was used to compare women who consistently used effective contraceptives (36%) to women using no method or an ineffective method. Women in relationships of 1 to 2 years were nearly 3 times more likely to use an effective contraceptive compared to women in relationships of less than 1 year (odds ratio (OR)=2.7, 95% CI 1.1, 6.7). Women were more than twice as likely to use an effective method if they reported a high level of involvement in decision-making about whether to use contraception (OR=2.3, 95% CI 1.1, 4.7) or had discussed contraception with their partner (OR=2.4, 95% CI 1.03, 5.6). This study provides additional information about the importance of male partners and relationship factors in contraceptive use among Latina women. Efforts to prevent unintended pregnancy need to address the role of relationship factors in the sexual risk and protective behaviors of Latinas.


Interfacial residues of SpcS chaperone affects binding of effector toxin ExoT in Pseudomonas aeruginosa: novel insights from structural and computational studies.
ExoT belongs to the family of type 3 secretion system (T3SS) effector toxins in Pseudomonas aeruginosa, known to be one of the major virulence determinant toxins that cause chronic and acute infections in immuno-compromised individuals, burn victims and cystic fibrosis patients. Here, we report the X-ray crystal structure of the amino terminal fragment of effector toxin ExoT, in complex with full-length homodimeric chaperone SpcS at 2.1 Å resolution. The full-length dimeric chaperone SpcS has the conserved α-β-β-β-α-β-β-α fold of class I chaperones, the characteristic hydrophobic patches for binding effector proteins and a conserved polar cavity at the dimeric interface. The stable crystallized amino terminal fragment of ExoT consists of a chaperone binding domain and a membrane localization domain that wraps around the dimeric chaperone. Site-directed mutagenesis experiments and a molecular dynamics study complement each other in revealing Asn65, Phe67 and Trp88 as critical dimeric interfacial residues that can strongly influence the effector-chaperone interactions.


Risk Factors for Postpartum Disease Activity in Women With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.
Women with inflammatory bowel disease (IBD) have an increased risk of postpartum disease activity. We aimed to systematically determine the effect of various risk factors on postpartum IBD disease activity. Electronic databases were searched through January 2021 for studies that reported risk of postpartum disease activity in women with IBD. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the impact of IBD phenotype, disease activity, therapy de-escalation, mode of delivery, and breastfeeding on postpartum disease activity. Study bias was determined using the Quality in Prognostic Studies tool. Twenty-seven observational studies (3825 patients) were included, 15 of which had a high risk of confounding bias. The pooled incidence of women with postpartum active IBD was 31.9% (95% CI, 25.6-38.1). Similar results were seen with ulcerative colitis and Crohn's disease (CD; OR, 0.96; 95% CI, 0.58-1.59). Those with stricturing (OR, 3.64; 95% CI, 1.31-10.08) and penetrating (OR, 4.25; 95% CI, 1.11-16.26) CD had higher odds of postpartum active IBD. Active disease at conception (OR, 10.59; 95% CI, 1.48-76.02) and during pregnancy (OR, 4.91; 95% CI, 1.82-13.23) increased the odds of postpartum disease activity. Similarly, biologic discontinuation in the third trimester (OR, 1.77; 95% CI, 1.01-3.10) and therapy de-escalation after delivery (OR, 7.36; 95% CI, 3.38-16.0) was associated with postpartum disease activity. Complicated Crohn's disease, disease activity at conception and during pregnancy, and de-escalation of biologics during pregnancy or after delivery are associated with postpartum disease activity in women with IBD.


GPN-1/glypican and UNC-52/perlecan do not appear to function in BMP signaling to pattern the C. elegans postembryonic mesoderm.
Heparan sulfate proteoglycans (HSPGs) are diverse macromolecules consisting of a protein core modified with glycosaminoglycan (GAG) chains. HSPGs, including glypicans and perlecans, have been implicated in shaping the extracellular matrix (ECM) to affect growth factor signaling. Here, we tested if GPN-1/glypicanor UNC-52/perlecan plays a role in the bone morphogenetic protein (BMP) signaling pathway in patterning the C. elegans postembryonic mesoderm. Using the suppression of sma-9(0) (Susm)assay, we found that animals carrying mutant alleles of gpn-1 or unc-52 do not exhibit any Susm phenotype. We also tested and found that the two glypicans GPN-1 and LON-2 do not share functional redundancy in the BMP pathway. Our results suggest that GPN-1/glypican and UNC-52/perlecan do not play a major role in the C. elegans BMP pathway, at least in patterning of the postembryonic mesoderm.


Hierarchical assemblies of polypeptoids for rational design of advanced functional nanomaterials.
Polypeptoids (poly-N-substituent glycines) are a class of highly tailorable peptidomimetic polymers. Polypeptoids have identical backbones as polypeptides (poly-C-substituent glycines), but sidechains of polypeptoids are appended to backbone nitrogen rather than α-carbon of polypeptides. As a result, peptoid backbone lacks of chirality and hydrogen bond donors. This unique structure gives polypeptoids a combined merit of both high stability as synthetic polymers and biocompatibility as biopolymers. In addition, peptoid sequences can be engineered precisely to assemble specific crystalline patterns such as spheres, fibers, ribbons, tubes, and sheets, which shows promising potentials of polypeptoids for different applications such as antimicrobials, catalysts, drug delivery, and templating inorganic materials. In this review, we summarize recent investigations into hierarchical self-assembly pathways and molecular structures of peptoid crystals that are of interest as templates for fabricating functional materials for potential biomedical, biochemical, and bioengineering applications. This review provides a summary of recent experimental and computational studies of polypeptoid assembly in solution and solid-liquid interfaces, current achievements in the field, and discusses future challenges and opportunities for the rational design of self-assembled polypeptoid nanomaterials.


Demonstration of improvement in the signal-to-noise ratio of Thomson scattering signal obtained by using a multi-pass optical cavity on the Tokyo Spherical Tokamak-2.
The multi-pass Thomson scattering (TS) scheme enables obtaining many photons by accumulating multiple TS signals. The signal-to-noise ratio (SNR) depends on the accumulation number. In this study, we performed multi-pass TS measurements for ohmically heated plasmas, and the relationship between SNR and the accumulation number was investigated. As a result, improvement of SNR in this experiment indicated similar tendency to that calculated for the background noise dominant situation.


Probing the activity of NTHL1 orthologs by targeting conserved amino acid residues.
The base excision repair DNA glycosylases, EcoNth and hNTHL1, are homologous, with reported overlapping yet different substrate specificities. The catalytic amino acid residues are known and are identical between the two enzymes although the exact structures of the substrate binding pockets remain to be determined. We sought to explore the sequence basis of substrate differences using a phylogeny-based design of site-directed mutations. Mutations were made for each enzyme in the vicinity of the active site and we examined these variants for glycosylase and lyase activity. Single turnover kinetics were done on a subgroup of these, comparing activity on two lesions, 5,6-dihydrouracil and 5,6-dihydrothymine, with different opposite bases. We report that wild type hNTHL1 and EcoNth are remarkably alike with respect to the specificity of the glycosylase reaction, and although hNTHL1 is a much slower enzyme than EcoNth, the tighter binding of hNTHL1 compensates, resulting in similar kcat/Kd values for both enzymes with each of the substrates tested. For the hNTHL1 variant Gln287Ala, the specificity for substrates positioned opposite G is lost, but not that of substrates positioned opposite A, suggesting a discrimination role for this residue. The EcoNth Thr121 residue influences enzyme binding to DNA, as binding is significantly reduced with the Thr121Ala variant. Finally, we present evidence that hNTHL1 Asp144, unlike the analogous EcoNth residue Asp44, may be involved in resolving the glycosylase transition state.


Association of Histological and Clinical Chorioamnionitis With Neonatal Sepsis Among Preterm Infants: A Systematic Review, Meta-Analysis, and Meta-Regression.
Chorioamnionitis (CA) is considered a key risk factor for very preterm birth and for developing early onset sepsis (EOS) in preterm infants, but recent data suggest that CA might be protective against late onset sepsis (LOS). We performed a systematic review and meta-analysis of studies exploring the association between CA and sepsis. A comprehensive literature search was performed in PubMed/MEDLINE and EMBASE, from their inception to December 1, 2018. A random-effects model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Sources of heterogeneity were analyzed by subgroup and meta-regression analyses. The following categories of sepsis were analyzed: EOS, LOS, unspecified onset sepsis (UOS), culture-proven, and clinical sepsis. CA was subdivided into clinical and histological chorioamnionitis. Funisitis was also analyzed. We found 3,768 potentially relevant studies, of which 107 met the inclusion criteria (387,321 infants; 44,414 cases of CA). Meta-analysis showed an association between any CA and any EOS (OR 4.29, CI 3.63-5.06), any LOS (OR 1.29, CI 1.11-1.54), and any UOS (OR 1.59, CI 1.11-1.54). Subgroup analysis showed that CA was associated with culture-proven EOS (OR 4.69, CI 3.91-5.56), clinical EOS (OR 3.58, CI 1.90-6.76), and culture-proven LOS (OR 1.31, CI 1.12-1.53), but not with clinical LOS (OR 1.52, CI 0.78-2.96). The presence of funisitis did not increase the risk of either EOS or LOS when compared with CA without funisitis. CA-exposed infants had lower gestational age (-1.11 weeks, CI -1.37 to -0.84) than the infants not exposed to CA. Meta-regression analysis showed that the lower gestational age of the CA group correlated with the association between CA and LOS but not with the association between CA and EOS. In conclusion, our data suggest that the positive association between chorioamnionitis and LOS may be modulated by the effect of chorioamnionitis on gestational age.


Polymorphic ventricular tachycardia with cardiac sarcoidosis: treatment with low-dose metoprolol and cibenzoline.
A 38-year-old female had felt exertional dyspnea for six months. Physical examination and laboratory data including angiotensin-converting enzyme, failed to diagnose sarcoidosis. Her chest X-ray showed cardiomegaly but no hilar lymph node enlargement. Holter ECG showed nonsustained and sustained ventricular tachycardias, monomorphic or polymorphic tachycardia. Echocardiography and contrast left ventriculography showed left ventricular dilatation and generalized hypo- and akinesis. Endomyocardial biopsy revealed myocardial sarcoidosis. Administration of corticosteroids, metoprolol of 20 mg/day and cibenzoline of 300 mg/day was markedly effective for the treatment of ventricular tachycardia. This patient is alive for one year after treatment and the combination therapy seems to contribute to good prognosis.


The Dopamine Receptor D4 Gene (DRD4) and Financial Risk-Taking: Stimulating and Instrumental Risk-Taking Propensity and Motivation to Engage in Investment Activity.
The Dopamine receptor D4 gene (DRD4) has been previously linked to financial risk-taking propensity. Past works demonstrated that individuals with a specific variant of the DRD4 gene (7R+) are more risk-seeking than people without it (7R-). The most prominent explanation for this effect is the fact that 7R+ individuals are less sensitive to dopamine and thus seek more stimulation to generate "normal" dopaminergic activity and feel pleasure. However, results about this relationship have not been conclusive, and some revealed a lack of the relationship. In the current work, we tested if those unclear results might be explained by the motivation that underlies the risk-taking activity; i.e., if people take risks to feel excitement or if they take risk to obtain a specific goal. In our study we tested the differences in risk-taking between 7R+ and 7R- among people who are experienced in financial risk-taking (113 investors) and non-experienced financial decision makers (104 non-investors). We measured risk-taking propensity with the Holt-Laury test and the Stimulating-Instrumental Risk Inventory. Moreover, we asked investors about their motivations for engaging in investment activity. Our study is the next one to report a lack of differences in risk-taking between 7R+ and 7R- individuals. As well, our results did not indicate any differences between the 7R+ and 7R- investors in motivation to engage in investment activity. We only observed that risk-taking propensity was higher among investors than non-investors and this was noticed for all measures. More research is needed to better understand the genetic foundations of risk-taking, which could answer the question about the substantial variation in the domain of risky financial decisions.


Second-career baccalaureate nursing students: a lived experience.
Second-career baccalaureate nursing programs and the students enrolled in them have been a topic of interest since these programs were first introduced into the academic setting in the 1970s. The purpose of this phenomenological inquiry was to develop an understanding of the meaning of the lived experience of being a second-career baccalaureate nursing student. Five second-career baccalaureate nursing students participated in unstructured, in-depth, face-to-face interviews. Data analysis was guided by the phenomenological method of van Manen. The themes identified were Questioning One's Place in the World; Seeing One's Place in the World in Another Way; Preparing for the Plunge; Trying Transitions; A Bundle of Emotions; Faculty Control, Student Imbalance; and Almost There and Scared. Implications of this research related to curriculum revision are presented.


[Expert consensus on the diagnosis and treatment of intrahepatic cholestasis (2021 edition)].
Intrahepatic cholestasis is a clinical syndrome due to the defect of bile acid synthesis, abnormal bile excretion, and mechanical or functional disturbance of intrahepatic bile flows caused by hepatic parenchymal cell and/or intrahepatic bile duct diseases. It commonly occurs as cholestatic liver diseases, intrahepatic cholestasis of pregnancy, and genetic/metabolic-related cholestatic diseases. In recent years, new information and progress in diagnosis and treatment of intrahepatic cholestatic diseases have been achieved. In order to provide updated clinical reference and guidance for clinicians, we organized experts to compile the Expert Consensus on the Diagnosis and Treatment of Intrahepatic Cholestasis (2021), on the basis of the 2015 edition.


MOR1, the Arabidopsis thaliana homologue of Xenopus MAP215, promotes rapid growth and shrinkage, and suppresses the pausing of microtubules in vivo.
MOR1, the Arabidopsis thaliana homologue of the Xenopus microtubule-associated protein MAP215, is required for spatial organization of the acentrosomal microtubule arrays of plant cells. To determine how loss of MOR1 function affects microtubule dynamics, we compared various parameters of microtubule dynamics in the temperature-sensitive mor1-1 mutant at its permissive and restrictive temperatures, 21 degrees C and 31 degrees C, respectively. Dynamic events were tracked in live cells expressing either GFP-tagged beta-tubulin or the plus end tracking EB1. Microtubule growth and shrinkage velocities were both dramatically reduced in mor1-1 at 31 degrees C and the incidence and duration of pause events increased. Interestingly, the association of EB1 with microtubule plus ends was reduced in mor1-1 whereas side wall binding increased, suggesting that MOR1 influences the association of EB1 with microtubules either by modulating microtubule plus end structure or by interacting with EB1. Although mor1-1 microtubules grew and shrank more slowly than wild-type microtubules at 21 degrees C, the incidence of pause was not altered, suggesting that pause events, which occur more frequently at 31 degrees C, have a major detrimental role in the spatial organization of cortical microtubules. Extensive increases in microtubule dynamics in wild-type cells when shifted from 21 degrees C to 31 degrees C underline the importance of careful temperature control in live cell imaging.


WNT8 and BMP2B co-regulate non-axial mesoderm patterning during zebrafish gastrulation.
During vertebrate mesoderm formation, fates are established according to position in the dorsoventral (D/V) axis of the embryo. Initially, maternal signaling divides nascent mesoderm into axial (dorsal) and non-axial (ventral) domains. Although the subsequent subdivision of non-axial mesoderm into multiple D/V fate domains is known to involve zygotic Wnt8 and BMP signaling as well as the Vent/Vox/Ved family of transcriptional repressors, how levels of signaling activity are translated into differential regulation of fates is not well understood. To address this question, we have analyzed zebrafish embryos lacking Wnt8 and BMP2b. Zebrafish wnt8; swr (bmp2b) double mutants display a progressive loss of non-axial mesoderm and a concomitant expansion of axial mesoderm during gastrulation. Mesoderm induction and specification of the axial domain occur normally in wnt8; swr mutants, but dorsal mesoderm genes eventually come to be expressed throughout the mesoderm, suggesting that the establishment of non-axial mesoderm identity requires continual repression of dorsal mesoderm factors, including repressors of ventral genes. Loss-of-function for Vent, Vox, and Ved phenocopies the wnt8; swr mutant phenotype, consistent with Wnt8 and BMP2b maintaining non-axial mesoderm identity during gastrulation through the regulation of these three transcriptional repressors. We postulate that timely differentiation of the mesoderm requires the maintenance of non-axial mesoderm identity by Wnt8 and BMP2b at the onset of gastrulation followed by subdivision of the non-axial mesoderm into different functional domains during gastrulation.


Seed longevity and cryobiotechnology in the orchid genus cattleya.
Orchid seeds are reputed to be relatively short-lived, although comparative studies across a wide range of storage temperatures and moisture contents are few. To explore how a wide range of temperature and moisture contents affects seed longevity in the orchid genus Cattleya. Seeds of three Brazilian orchid species in the genus Cattleya (C. amethystoglossa, C. kautskyana and C. tigrina) were subjected to controlled deterioration (CD) and seeds at three moisture levels were stored for up to 270 days at temperatures as low as -196 degree C. Seed ageing curves were constructed and seed quality assessed as germination level and speed index in vitro, and by tetrazolium staining. Seed morphometry, lipid content and composition were also determined. Seeds were found to be lipid rich (54-70% DW) and short-lived under CD, with P50s varying less than two-fold (42 to 69 h) at 41 degree C. At cold (5 degree C) to ultracold (-196 degree C) temperatures longevity was greatest after pre-drying seeds to 15% RH, with germination varying by c. 6% after 270 days storage at these temperature limits. However, storage at -20 degree C resulted in a 5-46% reduction in germination, indicating a dry-seed sensitivity to conventional seed bank temperature. Ultra-dry (silica gel) and high humidity (82% RH) storage, in combination with various temperatures, compromised viability in one or more species. Overall, seed longevity in C. kautskyana > C. tigrina > C. amethystoglossa, which also reflected the pattern of embryo volume. The prospect that the generally shorter lifespans in orchid seeds may relate to stochastic processes the negative impact of which reach criticality sooner in smaller embryos requires further testing. Further evidence is provided that cryobiotechnology provides a biobanking option for orchid seeds with relatively short lifespans.


Immunological responses to complex salts of platinum. I. Specific IgE antibody production in the rat.
Ammonium tetrachloroplatinate II ([NH4]2 PtCl4) was used in free and conjugated forms with ovalbumin in an attempt to elicit specific antibody directed against either the free platinum (Pt) salt or the platinum moiety of ovalbumin-Pt conjugates in the hooded Lister rat. Immunization with free Pt salt via intraperitoneal, intramuscular, intradermal, subcutaneous, intratracheal and footpad routes over a wide range of doses (1 microgram-1 mg) employing both B. pertussis and/or aluminium hydroxide gel as adjuvants failed to induce specific IgE antibody, either primary or secondary, as shown by direct skin, PCA test or RAST. Conjugation of (NH4)2 PtCl4 with ovalbumin produced conjugates, with between two and 10 haptenic Pt groups per ovalbumin molecule, capable of inducing IgE antibody directed against the Pt moiety as determined by heterologous PCA challenge, where carrier cross-reactivity was excluded, and by specific RAST, confirmed by RAST inhibition.


Exchange splitting of the interaction energy and the multipole expansion of the wave function.
The exchange splitting J of the interaction energy of the hydrogen atom with a proton is calculated using the conventional surface-integral formula Jsurf[Φ], the volume-integral formula of the symmetry-adapted perturbation theory JSAPT[Φ], and a variational volume-integral formula Jvar[Φ]. The calculations are based on the multipole expansion of the wave function Φ, which is divergent for any internuclear distance R. Nevertheless, the resulting approximations to the leading coefficient j0 in the large-R asymptotic series J(R) = 2e(-R-1)R(j0 + j1R(-1) + j2R(-2) + ⋯) converge with the rate corresponding to the convergence radii equal to 4, 2, and 1 when the Jvar[Φ], Jsurf[Φ], and JSAPT[Φ] formulas are used, respectively. Additionally, we observe that also the higher jk coefficients are predicted correctly when the multipole expansion is used in the Jvar[Φ] and Jsurf[Φ] formulas. The symmetry adapted perturbation theory formula JSAPT[Φ] predicts correctly only the first two coefficients, j0 and j1, gives a wrong value of j2, and diverges for higher jn. Since the variational volume-integral formula can be easily generalized to many-electron systems and evaluated with standard basis-set techniques of quantum chemistry, it provides an alternative for the determination of the exchange splitting and the exchange contribution of the interaction potential in general.


The Mallory body: morphological, clinical and experimental studies (Part 1 of a literature survey).
To aid understanding of markers of disease and predictors of outcome in alcohol-exposed systems, we undertook a literature survey of more than 700 articles to view the morphological characteristics and the clinical and experimental epidemiology of the Mallory body. Mallory bodies are filaments of intermediate diameter that contain intermediate filament components (e.g., cytokeratins) observable by conventional light microscopy or immunohistochemical methods, identical in structure regardless of initiating factors or putative pathogenesis. Although three morphological types can be identified under electron microscopy (with fibrillar structure parallel, random or absent), they remain stereotypical manifestations of hepatocyte injury. A summary of the conditions associated with Mallory bodies in the literature and their validity and potential etiological relationships is presented and discussed, including estimates on the combined light microscopic and immunohistochemical prevalences and kinetics. Emphasis is placed on proper confounder control (in particular, alcohol history), which is highly essential but often inadequate. These conditions include (mean prevalence of Mallory bodies in parentheses): Indian childhood cirrhosis (73%), alcoholic hepatitis (65%), alcoholic cirrhosis (51%), Wilson's disease (25%), primary biliary cirrhosis (24%), nonalcoholic cirrhosis (24%), hepatocellular carcinoma (23%), morbid obesity (8%) and intestinal bypass surgery (6%). Studies in alcoholic hepatitis strongly suggest a hit-and-run effect of alcohol, whereas other chronic liver diseases show evidence of gradual increase in prevalence of Mallory bodies with severity of hepatic pathology. Mallory bodies in cirrhosis do not imply alcoholic pathogenesis. Obesity, however, is associated with alcoholism and diabetes, and Mallory bodies are only present in diabetic patients if alcoholism or obesity complicates the condition. In addition, case studies on diseases in which Mallory bodies have been identified, along with pharmacological side effects and experimental induction of Mallory bodies by various antimitotic and oncogenic chemicals, are presented. Mallory bodies occur only sporadically in abetalipoproteinemia, von Gierke's disease and focal nodular hyperplasia and during hepatitis due to calcium antagonists or perhexiline maleate. Other conditions and clinical drug side effects are still putative. Finally, a variety of experimental drugs have been developed that cause Mallory body formation, but markedly different cell dynamics and metabolic pathways may raise questions about the relevance of such animal models for human Mallory body formation. In conclusion, the Mallory body is indicative but not pathognomonic of alcohol involvement. A discussion on theories of development and pathological significance transcending the clinical frameworks will be presented in a future paper.


Model of break-bone fever via beta-derivatives.
Using the new derivative called beta-derivative, we modelled the well-known infectious disease called break-bone fever or the dengue fever. We presented the endemic equilibrium points under certain conditions of the physical parameters included in the model. We made use of an iteration method to solve the extended model. To show the efficiency of the method used, we have presented in detail the stability and the convergence of the method for solving the system (2). We presented the uniqueness of the special solution of system (2) and finally the numerical simulations were presented for various values of beta.


Atmospheric Chemistry of NH2SO3H in Polluted Areas: An Unexpected Isomerization of NH2SO3H in Acid-Polluted Regions.
NH2SO3H is an effective nucleation agent for the formation of atmospheric aerosols and cloud particles. So, the ammonolysis of SO3 to form NH2SO3H without and with neutral (H2O) and basic (NH3) trace gases has been extensively investigated. However, the acidic trace gas X (X = H2SO4 and CH3SO3H)-assisted ammonolysis of SO3 is still up for debate. In this work, a comprehensive theoretical investigation of X-assisted ammonolysis of SO3 and its reverse reaction (the isomerization of NH2SO3H to form SO3-···NH3+) was carried out in the gas phase and at the air-water interface. The gas-phase results show that X-assisted isomerization of NH2SO3H to form SO3-···NH3+ is more energetically and kinetically favorable than its reverse reaction and the isomerization of NH2SO3H in the presence of H2O and NH3. Such unexpected findings revealed that gas-phase NH2SO3H is highly reactive in the presence of acidic trace gas in contrast to the high stability of NH2SO3H in neutral and basic conditions. At the air-water interface, the X-assisted isomerization reaction of NH2SO3H involves multiple water molecules. The loop structure of the reaction center (X···NH2SO3H···3H2O) promotes the transfer of protons in the water molecules to form the SO3-···NH3+ ion pair, which can then interact with several interfacial water molecules to form ammonium bisulfate. These interfacial reaction channels follow a stepwise mechanism and proceed at the picosecond time-scale. The findings of this study will contribute to a better understanding of the atmospheric behavior of NH2SO3H in polluted acidic trace gases.


Genomic organization of the translationally controlled tumor protein (TCTP) gene from shrimp Marsupenaeus japonicus.
The shrimp translationally controlled tumor protein (TCTP) gene was previously found up-regulated in response to viral infection. In order to further understand the transcriptional regulation of TCTP gene expression under viral challenge, the 5'-flanking promoter region of the TCTP gene in shrimp Marsupenaeus japonicus (Mj-TCTP) was cloned by using genomic walking method. The sequence shows that this region contains many important potential binding sites for transcription factors, such as activator protein1 (AP1), cAMP response element binding protein (CREB), Ets like transcription factor-1 (Elk-1), suggesting its expression is highly regulated. The promoter activity of this 5'-flanking region was confirmed by fusing to the enhanced green fluorescence protein (EGFP) gene and testing in Trichoplusia ni High Five cell line. Along with the introns and exons cloned in this study, the Mj-TCTP DNA sequence was reported here as the first TCTP gene with complete genomic organization in crustaceans.


Chemical knockdown of protein-tyrosine phosphatase 1B by 1,2-naphthoquinone through covalent modification causes persistent transactivation of epidermal growth factor receptor.
1,2-Naphthoquinone (1,2-NQ), an atmospheric contaminant, causes the contraction of guinea pig trachea through the activation of epidermal growth factor receptor (EGFR) by inhibiting protein-tyrosine phosphatases (PTPs). Phosphorylation of EGFR is negatively regulated by PTPs, but details of the mechanism by which 1,2-NQ inhibits PTPs have not been elucidated. Results described in this report demonstrate that 1,2-NQ forms covalent bonds with PTP1B after exposure to human epithelial A431 cells. In this study, a concentration-dependent phosphorylation of EGFR was found to be coupled to the reduction of PTP activity in the cells. The reduction in PTP activity was due to the irreversible modification of PTP1B, and when PTP1B was overexpressed by the cells, the 1,2-NQ-mediated EGFR phosphorylation was suppressed. Studies with purified PTP1B and 1,2-NQ showed that the reduction in enzyme activity was due to a nucleophilic attack by the quinone on the enzyme, to form covalent bonds. Matrix-assisted laser desorption and ionization time-of-flight mass spectrometry analysis and mutation experiments revealed that PTP1B inactivation was primarily due to covalent attachment of the quinone to Cys-121 of the enzyme, with binding to His-25 and Cys-215 as well. Collectively, the results show that covalent attachment of 1,2-NQ to PTP1B is at least partially responsible for the reduction of PTP activity, which leads to prolonged transactivation of EGFR in the cells.


Monoclonal antibodies against a specific surface determinant on malarial (Plasmodium knowlesi) merozoites block erythrocyte invasion.
Twelve hybridoma cell lines secreting monoclonal antibodies against Plasmodium knowlesi merozoites have been produced. Antibodies from 3 of the 12 lines agglutinated merozoites. The 2 monoclonal antibodies (13C11 and 16F8) that markedly agglutinated merozoites blocked merozoite invasion of erythrocytes. Of these 2 lines, the one that induced the most agglutination also blocked invasion most effectively. The third monoclonal antibody (53B3) caused minimal agglutination of merozoites and did not block invasion, nor did the other 9 nonagglutinating antibodies. The 2 blocking monoclonal antibodies bound to antigens around the entire surface of merozoites, as demonstrated by immunoelectron microscopy, and precipitated a single biosynthetically labeled protein of apparent m.w. of 250,000. None of the nonagglutinating lines precipitated this protein. Monoclonal antibodies 13C11 and 16F8 reacted with a common antigenic determinant on a Malaysian and a Philippine strain of P. knowlesi in that they blocked invasion and precipitated a 250,000 m.w. protein from both. Sera from immune monkeys also precipitated this 250,000 m.w. protein.


Risks and implications for health and the environment associated with products and waste containing nanomaterials: regulatory and management issues in the European framework.
Nanomaterials can revolutionize everyday products, but there are still many unanswered questions about the risks they may pose to human health and the environment. Inconsistent definitions and metrological issues are still of concern for manufacturers, importers and distributors who are demanded to comply with strict regulations. It is also likely that the increasing number of nanomaterial-containing products available on the market will vary the chemical and physical properties of the waste produced, which is currently treated in traditional plants without any particular differentiation. Treatment efficiency for nanomaterials-containing waste should then be addressed and the risks of uncontrolled emissions considered. Finally, the risks associated with the use of nanomaterials-containing products may not be sufficiently characterized as current exposure estimation models are not designed for estimating exposure to nanomaterials and they are likely to be affected by large uncertainties. Hence, it would be important for national and international institutions to provide, as soon as possible, harmonized regulations covering all aspects of the life cycle of products and waste containing nanomaterials. This paper is proposed as a starting point for reflection on the main regulatory and management issues associated with products and waste containing nanomaterials, focusing mainly on the European framework.


Assessing the effects of endocrine disruptors in the National Children's Study.
Children are uniquely vulnerable to toxic chemicals in the environment. Among the environmental toxicants to which children are at risk of exposure are endocrine disruptors (EDs)--chemicals that have the capacity to interfere with hormonal signaling systems. EDs may alter feedback loops in the brain, pituitary, gonads, thyroid, and other components of the endocrine system. They can affect development. Effects of EDs have been described in wildlife populations, in animals exposed experimentally, and to a more limited extent in humans. Mechanisms of action of EDs are increasingly being elucidated, and genetic polymorphisms that convey differential susceptibility to EDs are beginning to be explored. It is hypothesized that in utero and early childhood exposures to EDs may be responsible, at least in part, for decreases in semen quality; increasing incidence of congenital malformations of the reproductive organs, such as hypospadias; increasing incidence of testicular cancer; and acceleration of onset of puberty in females. The National Children's Study (NCS) will provide a unique opportunity to test the validity of these hypotheses in the context of a large prospective multi-year epidemiologic investigation. It will be essential in the NCS to assess exposures to a range of putative natural and synthetic EDs, to assess outcomes possibly due to ED exposure, to examine the potential interplay between EDs and genetic polymorphisms, and to seek links between ED exposures in early life and endocrine, reproductive, neurobehavioral, and other outcomes throughout the life span.


Visualizing L-glutamate fluxes in acute hippocampal slices with glutamate oxidase-immobilized coverslips.
We used a glutamate oxidase (GluOx)-immobilized glass coverslip for reducing diffusional blur and improving the temporal resolution of visualizing L-glutamate fluxes in acute brain slices. The immobilization of GluOx on an avidin modified glass coverslips was achieved by optimized the amine coupling method. The GluOx coverslip was applied to the imaging of L-glutamate fluxes in acute hippocampal slices under hypoxia and KCl stimulation. A slice from mouse brain was loaded with horseradish peroxidase (HRP) and substrate DA-64, and placed on the GluOx coverslip for stimulation. The regional distribution of hypoxia-induced L-glutamate fluxes was analyzed. The maximum flux at 3 min after the onset of hypoxia increased in the order CA1>CA3>DG. The time-courses of the L-glutamate fluxes at CA1 and DG were biphasic, while that at CA3 decreased monotonously. The KCl-stimulated release of L-glutamate in the presence of the DL-TBOA uptake inhibitor was imaged. While no noticeable change was observed in the absence of DL-TBOA, L-glutamate fluxes in the presence of the inhibitor increased in the order CA1>CA3>DG, reflecting the effect of uptake processes. The present approach suppressed diffusional blur of the glutamate signal and improved the temporal resolution as compared with the BSA-HRP membrane method described earlier.


Crystal structures of a bioactive 6'-hydroxy variant of sisomicin bound to the bacterial and protozoal ribosomal decoding sites.
Parasitic infections recognized as neglected tropical diseases are a source of concern for several regions of the world. Aminoglycosides are potent antimicrobial agents that have been extensively studied by biochemical and structural studies in prokaryotes. However, the molecular mechanism of their potential antiprotozoal activity is less well understood. In the present study, we have examined the in vitro inhibitory activities of some aminoglycosides with a 6'-hydroxy group on ring I and highlight that one of them, 6'-hydroxysisomicin, exhibits promising activity against a broad range of protozoan parasites. Furthermore, we have conducted X-ray analyses of 6'-hydroxysisomicin bound to the target ribosomal RNA A-sites in order to understand the mechanisms of both its antibacterial and antiprotozoal activities at the molecular level. The unsaturated ring I of 6'-hydroxysisomicin can directly stack on G1491, which is highly conserved in bacterial and protozoal species, through π-π interaction and fits closer to the guanidine base than the typically saturated and hydroxylated ring I of other structurally related aminoglycosides. Consequently, the compound adopts a lower energy conformation within the bacterial and protozoal A-sites and makes pseudo pairs to either A or G at position 1408. The A-site-selective binding mode strongly suggests that 6'-hydroxysisomicin is a potential lead for the design of next-generation aminoglycosides targeting a wide variety of infectious diseases.


Hepatocellular carcinoma: important biomarkers and their significance in molecular diagnostics and therapy.
The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world because of two major reasons: firstly, HCC is one of the most lethal form of malignancies with less than 10% survival rate and secondly, a lack of prudent diagnostics makes early detection of HCC nearly impossible. The poor prognosis of HCC accentuates the need to develop new diagnostic markers and therapeutic approaches. In this review we discuss recent advances made in the discovery of molecular biomarkers and their significance in the detection of HCC. We focus on three major classes of biomarkers: serological, tumor, peri-tumoral tissue and cancer stem cell markers. Considerable progress has been made recently in our understanding of HCC at the molecular level increasing the potential of molecular targeted therapy. A number of molecular targets have been identified that have been showing promising results. Of particular interest is Sorafenib, a multi-tyrosine kinase inhibitor that has been approved for the HCC treatment. Inhibitors of other molecular targets such as VEGF, EGFR, mTOR etc. are emerging as plausible therapeutic agents for the treatment of HCC and are discussed in this review.


[Multiple dose pharmacokinetic and bioavailability studies of oral sustained release and conventional formulations of isosorbide-5-mononitrate in healthy volunteers].
The pharmacokinetics of a new sustained release tablets (40 mg, qd) of isosorbide-5-mononitrate (IS-5-MN) was investigated together with a conventional preparation (20 mg, bid) after multiple oral administration in ten healthy human subjects using an open, randomized two-way crossover experimental design. Based on three statistical analyses of the area under the plasma concentration-time curve (AUC), the two tablet formulations are judged to be bioequivalent (P > 0.1), with a relative bioavailability of 108.95% for the IS-5-MN sustained release formulation. Pharmacokinetic data showed that the sustained release formulation reached mean peak plasma levels significantly later and lower minimum plasma concentration (Cmin), compared with the conventional preparation. But no statistically significant difference was found for other pharmacokinetic parameters including peak plasma levels (Cmax), AUC, elimination constant (Ke), elimination half-life (T1/2) and fluctuation index (FI) between the two preparations (P > 0.05).


Simvastatin attenuates cisplatin-induced kidney and liver damage in rats.
Statins have anti-inflammatory effects that are not directly related to their cholesterol-lowering activity. This study aimed to investigate the effect of simvastatin on the extent of tissue damage in cisplatin-induced nephrotoxicity and hepatotoxicity. The rats received a single intravenous injection of 2.5mgkg(-1) cisplatin. Other groups received either simvastatin (1mgkg(-1)) or the vehicle (ethanol:saline) intraperitoneally for 10 days beginning 5 days prior to cisplatin injection. All animals were decapitated 5 days after cisplatin administration. Trunk blood was collected and analyzed for blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), albumin, and total bilirubin levels. The urine samples were used for the calculation of creatinine clearance levels. The kidney and liver samples were stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content or were processed for histopathological examinations. Formation of reactive oxygen species in tissue samples was monitored by using chemiluminescence method. Simvastation reduced the extent of both kidney and liver damage and preserved both kidney and liver functions (p<0.01-0.001). Increase in liver MDA level with a concomitant reduction in GSH in the cisplatin group was attenuated by simvastatin treatment (p<0.05-0.01). Increase in tissue collagen content and chemiluminescence levels in the kidney and liver samples of the cisplatin group was also reversed by simvastatin (p<0.001). In conclusion, simvastatin is beneficial in cisplatin-induced kidney and liver dysfunction and organ damage in rats via prevention of lipid peroxidation and tissue fibrosis, preservation of antioxidant glutathione, and suppression of neutrophil infiltration.


Comparison of calycosin and irbesartan for their impact on renin angiotensin system in human umbilical vein endothelial cell.
The aim of this paper was to compare the efficacy of in vitro calycosin and irbesartan for the treatment of angiotensin II (AngII)-induced renin angiotensin system (RAS) disorder in human umbilical vein endothelial cells (HUVECs). Cultured HUVECs were randomly divided into several groups: control, AngII 1×10-6 mol) alone, Ang II (1×10-6 mol) plus calycosin (0.1, 1, 10 mg/L) and Ang II (1×10-6 mol) plus Irbesartan (10 μmol). Morphology of vascular endothelial cells was studied by using a light microscope with hematoxylin and eosin double staining. Changes in both protein and gene expression of Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) were detected by immunohistochemistry analysis and reverse transcription polymerase chain reaction (RT-PCR) techniques, respectively. In comparison to control, AngII significantly promoted both protein and gene expressions of ACE while inhibited those of ACE2 in HUVECs. Interestingly, Calycosin was able to inhibit the effect of AngII in a concentration dependent manner, and its effect at concentration of 35 μmol was equal to that of positive control Irbesartan (10μmol). Calycosin from Radix Astragali from Gansu province could protect HUVECs from AngII induced RAS disorder by downregulation of ACE expression and increased ACE2 expression, which is similar to irbesartan. These results suggest that calycosin may be a promising candidate for treatment of endothelial dysfunction.


Effects of a high-fiber diet on hepatocyte apoptosis and liver regeneration after partial hepatectomy in rats with fatty liver.
The morbidity and mortality that accompany fatty liver may occur as a result of increased apoptosis of hepatocytes and decreased liver regeneration. We determined the effects of a high-fiber diet on hepatocyte apoptosis and liver regeneration after partial hepatectomy in rats with fatty liver. Fatty liver was induced in male Wistar rats weighing around 200 g through feeding of a high-fat diet for 4 weeks. The rats were then randomly assigned to 3 groups that received a high-fat diet, a normal diet, or a high-fiber diet for another 4 weeks. Partial hepatectomy (around 70%) was performed, and rats were killed 6, 24, 48, or 72 hours after hepatectomy. We then measured (1) the ratio of remnant liver weight to body weight and assessed the histology of the remnant liver as indicators of fatty liver, (2) caspase-3 activity and in situ cell death detection of DNA fragmentation as indicators of apoptosis, and (3) 5-bromo-2-deoxyuridine (BrdU) activity and (4) ornithine decarboxylase (ODC) contents in remnant livers as markers of regeneration. We found that (1) a high-fat diet for 4 weeks can markedly induce fatty liver, (2) apoptosis of hepatocytes is greater in fatty liver than in normal liver (98 +/- 19 vs 36 +/- 7) at 6 hours after partial hepatectomy (p < .05), (3) the capacity of liver regeneration decreases significantly (BrdU index: 30 +/- 5 vs 12 +/- 3, and ODC contents: 604 +/- 48 vs 390 +/- 42 mg/dL) in fatty liver 24 hours after partial hepatectomy (p < .05), (4) a normal diet can partially reverse the effects of fatty liver; (5) a high-fiber diet can significantly reverse the effects of fatty liver (p < .05). A high-fiber diet can reverse the negative effects of fatty liver on apoptosis and regenerative capacity after partial hepatectomy.


Traumatic Right Diaphragmatic Hernia; A Delayed Presentation.
Diaphragmatic rupture following blunt or penetrating thoraco-abdominal trauma is frequently missed. It presents years later with herniation of abdominal viscera. Surgical treatment should be sought for when diagnosed. A 56 year old female presented to emergency with traumatic right diaphragmatic hernia, road traffic accident 8 years ago when she sustained multiple rib fractures on the right side. Upon diagnosis, successful primary hernia repair was performed. Non-specific clinical and radiological features of diaphragmatic hernia (diminished breath sounds, respiratory distress, orthopnoea, dyspnoea, hydro-pneumothorax, and mediastinal shift and lung collapse) lead to delayed or missed diagnosis. Patients present months to years later with complications. By including it in the differentials while managing a trauma patient along with collaboration of the radiology department, the chances of missing this finding would be lowered substantially.