Anti-inflammatory and chondroprotective activity of (+)-α-pinene: structural and enantiomeric selectivity.
Previous studies have suggested that α-pinene, a common volatile plant metabolite, may have anti-inflammatory effects in human chondrocytes, thus exhibiting potential antiosteoarthritic activity. The objective of this study was to further characterize the potential antiosteoarthritic activity of selected pinene derivatives by evaluating their ability to modulate inflammation and extracellular matrix remodeling in human chondrocytes and to correlate the biological and chemical properties by determining whether the effects are isomer- and/or enantiomer-selective. To further elucidate chemicopharmacological interactions, the activities of other naturally occurring monoterpenes with the pinane nucleus were also investigated. At noncytotoxic concentrations, (+)-α-pinene (1) elicited the most potent inhibition of the IL-1β-induced inflammatory and catabolic pathways, namely, NF-κB and JNK activation and the expression of the inflammatory (iNOS) and catabolic (MMP-1 and -13) genes. (-)-α-Pinene (2) was less active than the (+)-enantiomer (1), and β-pinene (3) was inactive. E-Pinane (4) and oxygenated pinane-derived compounds, pinocarveol (5), myrtenal (6), (E)-myrtanol (7), myrtenol (8), and (Z)-verbenol (9), were less effective or even completely inactive and more cytotoxic than the pinenes tested (1-3). The data obtained show isomer- and enantiomer-selective anti-inflammatory and anticatabolic effects of α-pinene in human chondrocytes, (+)-α-pinene (1) being the most promising for further studies to determine its potential value as an antiosteoarthritic drug.


Cataract Services are Leaving Widows Behind: Examples from National Cross-Sectional Surveys in Nigeria and Sri Lanka.
The Sustainable Development Goals aim to leave no one behind. We explored the hypothesis that women without a living spouse-including those who are widowed, divorced, separated, and never married-are a vulnerable group being left behind by cataract services. Using national cross-sectional blindness surveys from Nigeria (2005-2007; n = 13,591) and Sri Lanka (2012-2014; n = 5779) we categorized women and men by marital status (married/not-married) and place of residence (urban/rural) concurrently. For each of the eight subgroups we calculated cataract blindness, cataract surgical coverage (CSC), and effective cataract surgical coverage (eCSC). Not-married women, who were predominantly widows, experienced disproportionate cataract blindness-in Nigeria they were 19% of the population yet represented 56% of those with cataract blindness; in Sri Lanka they were 18% of the population and accounted for 54% of those with cataract blindness. Not-married rural women fared worst in access to services-in Nigeria their CSC of 25.2% (95% confidence interval, CI 17.8-33.8%) was far lower than the best-off subgroup (married urban men, CSC 80.0% 95% CI 56.3-94.3); in Sri Lanka they also lagged behind (CSC 68.5% 95% CI 56.6-78.9 compared to 100% in the best-off subgroup). Service quality was also comparably poor for rural not-married women-eCSC was 8.9% (95% CI 4.5-15.4) in Nigeria and 37.0% (95% CI 26.0-49.1) in Sri Lanka. Women who are not married are a vulnerable group who experience poor access to cataract services and high cataract blindness. To "leave no one behind", multi-faceted strategies are needed to address their needs.


Mapping and microsatellite marker development for the porcine leukemia inhibitory factor receptor (LIFR) and epidermal growth factor receptor (EGFR) genes.
Leukemia inhibitory factor receptor (LIFR), epidermal growth factor receptor (EGFR), and their respective ligands have been implicated in regulating growth and development of the early pig conceptus. We isolated a PAC clone containing the porcine gene for LIFR and a BAC clone with the porcine EGFR gene, respectively. On each of these clones one microsatellite marker was identified by sequencing a collection of subclones. These gene-associated markers were evaluated by genotyping of 202 unrelated boars of four different breeds. Based on fluorescence in situ hybridization and radiation hybrid mapping, the porcine LIFR gene was assigned to SSC16q13-->q14. The EGFR gene mapped to SSC9q26.


Meta-analysis of coinfection and coexposure with Borrelia burgdorferi and Anaplasma phagocytophilum in humans, domestic animals, wildlife, and Ixodes ricinus-complex ticks.
Anaplasma phagocytophilum, which causes granulocytic anaplasmosis, and Borrelia burgdorferi, the agent of Lyme borreliosis, are transmitted in multiple Holarctic regions by the same Ixodes sp. tick vectors and maintained in sylvatic cycles with the same rodent reservoirs. Coinfection of humans, domestic animals, wildlife, and ticks with both B. burgdorferi and A. phagocytophilum appears to be common, yet the pathologic mechanisms and ecology remain poorly understood compared with single-agent infection. We compiled available literature describing experimental and naturally occurring coinfection with B. burgdorferi and A. phagocytophilum in I. ricinus-complex ticks and host species, including wildlife, humans, livestock, and pets; calculated odds ratios for coinfection risks; evaluated the hypotheses that odds ratios for coinfection differ significantly between different tick life stages, ticks and vertebrate hosts, and reservoir and nonreservoir hosts; and finally, calculated the predicted coinfection prevalence based on the probability of each pathogen alone and compared this to the reported coinfection prevalence. Sixty-one manuscripts referenced coinfection or coexposure between these pathogens, with prevalence estimates for coinfection up to 67% in vertebrates and 28% in ticks. Of 61 different reports of coinfection or coexposure, 18 had odds ratios for coinfection significantly higher than 1. The combined odds ratios for coinfection in vertebrates and ticks were 1.9 and 1.28, respectively, with statistically significant variability among host and tick species in odds ratios. The overall predicted coexposure prevalence for vertebrates was 3.1% compared with an observed 8.9% prevalence. Odds ratios were not significantly different among classes of vertebrate hosts, species of ticks, stages of ticks, or ticks compared with hosts. We confirm a considerable level of coinfection and coexposure with these pathogens, although not predictably across host or tick species or geographical region.


Single-lung transplantation with ABO-compatible donors results in excellent outcomes.
The goal of this study was to determine if carefully selected ABO-compatible donors in single-lung transplantation results in acceptable outcomes. The United Network for Organ Sharing database was reviewed for adult single-lung transplant recipients from May 2005 to December 2011. Recipients of lungs from ABO-compatible donors were compared with those of ABO-identical donors. Mortality was examined with risk-adjusted multivariable Cox proportional hazards regression using significant univariate predictors. Of 3,572 single-lung transplants, 342 (9.6%) were from ABO-compatible donors. The two groups were evenly matched in recipient age (60.8 vs 60.2 years, p = 0.28), male gender (61.8% vs 58.2%, p = 0.10), lung allocation score (43.4 vs 42.6, p = 0.32), forced expiratory volume in 1 second (FEV1; 41.2% vs 40.8%, p = 0.32), and ischemic time (4.2 vs 4.0 hours, p = 0.09), and donor age (34.4 vs 32.9, p = 0.07) and male gender (61.5 vs 65.5, p = 0.14). ABO-compatible donors were less likely to be race mismatched (58.3% vs 50.9%, p = 0.01). Median survival was not different (1,284.0 vs 1,540 days, p = 0.39). On multivariate analysis, lungs from ABO-compatible donors were not associated with mortality (hazard ratio, 1.02; 95% confidence interval, 0.85-1.22; p = 0.86). Prolonged ischemic time, increasing recipient creatinine, increasing recipient age, race mismatch, class I plasma reactive antigen panel > 10%, and the use of mechanical ventilation or extracorporeal membrane oxygenation were associated with mortality. Peak post-transplant FEV1 (64.5% vs 64.0%, p = 0.69) and decrement in FEV1 over time were similar (p = 0.82). This large multi-institutional analysis of ABO-compatible donors in single-lung transplantation demonstrates that careful selection of ABO-compatible donors results in excellent outcomes.


[Value of the analysis of new cases of arterial hypertension in an organized population for the purpose of planning primary prevention programs].
Within the framework of the 5-year program for the control of arterial hypertension, "detriment" to the population program caused by the lack of preventive work among the so-called healthy portion of the population was estimated at a Moscow machine-building plant. The proportion of patients in whom arterial hypertension was successfully reduced or controlled was matched against the proportion of those whose arterial BP went up above the normal or marginal level during the same period. The study demonstrated the possibility of identifying high-risk individuals in need of primary preventive care within a population, and timely and purposive planning of preventive programs.


Curcumin and liver cancer: a review.
Primary liver cancer, also known as hepatocellular carcinoma (HCC), is one of the most lethal cancers having worldwide prevalence. Although most HCC cases are reported in the developing countries of Asia and Africa, there has been an alarming increase in HCC cases in Western Europe as well as United States. Chronic liver diseases, viral hepatitis, alcoholism as well as dietary carcinogens, such as aflatoxins and nitrosoamines, contribute to HCC. Liver transplantation as well as surgical resection at best offer limited treatment options. Thus, there exists a critical need to investigate and evaluate possible alternative chemopreventive and therapeutic strategies which may be effective in the control of liver cancer. HCC, most often, develops and progresses in a milieu of oxidative stress and inflammation. Phytochemicals, such as dietary polyphenols endowed with potent antioxidant as well as anti-inflammatory properties, provide a suitable alternative in affording alleviation of HCC. Curcumin, the principal polyphenolic curcuminoid, obtained from the turmeric rhizome Curcuma longa has long been used to cure several chronic ailments, such as neoplastic and neurodegenerative diseases. Studies suggest that curcumin may have antitumor, antioxidant, and anti-inflammatory properties. This article reviews the effects of curcumin in preclinical in vitro and in vivo models of HCC with particular emphasis to its antioxidant, apoptotic and anti-inflammatory effects as well as involvement in various molecular signaling mechanisms. This review also discusses potential challenges involved in the use of curcumin in HCC, such as bioavailability, pharmacokinetics, drug delivery as well as paucity of clinical studies.


The formation, elements of success, and challenges in managing a critical care program: Part I.
Leaders of critical care programs have significant responsibility to develop and maintain a system of intensive care. At inception, those clinician resources necessary to provide and be available for the expected range of patient illness and injury and throughput are determined. Simultaneously, non-ICU clinical responsibilities and other expectations, such as education of trainees and participation in hospital operations, must be understood. To meet these responsibilities, physicians must be recruited, mentored, and retained. The physician leader may have similar responsibilities for nonphysician practitioners. In concert with other critical care leaders, the service adopts a model of care and assembles an ICU team of physicians, nurses, nonphysician providers, respiratory therapists, and others to provide clinical services. Besides clinician resources, leaders must assure that services such as radiology, pharmacy, the laboratory, and information services are positioned to support the complexities of ICU care. Metrics are developed to report success in meeting process and outcomes goals. Leaders evolve the system of care by reassessing and modifying practice patterns to continually improve safety, efficacy, and efficiency. Major emphasis is placed on the importance of continuity, consistency, and communication by expecting practitioners to adopt similar practices and patterns. Services anticipate and adapt to evolving expectations and resource availability. Effective services will result when skilled practitioners support one another and ascribe to a service philosophy of care.


Multi-organ toxicity induced by fine particulate matter PM2.5 in zebrafish (Danio rerio) model.
The fine particulate matter (PM2.5) in air pollution is a major public health concern and now known to contribute to severe diseases, therefore, a comprehensive understanding of PM2.5-induced adverse effects in living organisms is needed urgently. This study was aimed to evaluate the toxicity of PM2.5 on multi-organ systems in a zebrafish (Danio rerio) model. The embryonic toxicity induced by PM2.5 was demonstrated by an increase in mortality and inhibition of hatching rate, in a dose- and time-dependent manner. PM2.5 caused the pericardial edema, as well as reducing heart rate and cardiac output. The area of sub-intestinal vessels (SIVs) was significant reduced in Tg(fli-1:EGFP) transgenic zebrafish lines. Morphological defects and yolk sac retention were associated with hepatocyte injury. In addition, PM2.5 disrupted the axonal integrity, altering of axon length and pattern in Tg(NBT:EGFP) transgenic lines. Genes involved in cardiac function (spaw, supt6h, cmlc1), angiogenesis (vegfr2a, vegfr2b), and neural function (gabrd, chrna3, npy8br) were markedly down-regulated; while genes linked to hepatic metabolism (cyp1a, cyp1b1, cyp1c1) were significantly up-regulated by PM2.5. In summary, our data showed that PM2.5 induced the cardiovascular toxicity, hepatotoxicity and neurotoxicity in zebrafish, suggested that PM2.5 could cause multi-organ toxicity in aquatic organism.


Ten years of respiratory cytopathology at Duke University Medical Center. II. The cytopathologic diagnosis of lung cancer during the years 1970 to 1974, with a comparison between cytopathology and histopathology in the typing of lung cancer.
In 1975 Duke University Medical Center, a retrospective and prospective survey of respiratory cytopathologic specimens was undertaken for the ten-year period 1970 to 1979. The purpose of this study was to document the role of cytopathology in the diagnosis of lung cancer at this institution. This paper presents the results of the cytopathologic and histopathologic typing of cases of lung cancer seen at Duke University Medical Center from 1970 to 1974. During this period, 9,892 cytologic specimens from the lower respiratory tract were processed. Cytopathologic diagnoses of cancer with tissue confirmation were made on 483 specimens from 232 patients. Because original cytologic diagnoses, but not histopathologic diagnoses, had been made in conformity with a modified WHO classification of lung neoplasms, all histopathologic material was reviewed and reclassified when necessary. This was carried out by one of the authors (E.H.B.) as a blind review without benefit of knowledge of either preexisting cytopathologic or histopathologic diagnoses. Twenty-six patients were excluded from the current study because of lack of satisfactory histologic material. In 94 patients classified by histopathology as having squamous cell carcinoma, 76.4% of the positive cytologic specimens were also called squamous cell carcinoma; 18.6% were interpreted as large cell undifferentiated carcinoma. In 39 patients classified by tissue as having large cell undifferentiated carcinoma, the cytology agreed in 42.4% of the positive specimens. For the 29 patients thought histologically to have small cell undifferentiated carcinoma, the same diagnosis was rendered in 95.5% of the cytologically positive specimens from these patients. For the adenocarcinoma group of 43 patients, a cytopathologic diagnosis of adenocarcinoma was made in 67.8% of the positive specimens.


The long arm of mentoring: a counterfactual analysis of natural youth mentoring and employment outcomes in early careers.
Young people often develop natural mentoring relationships with nonparental adults during adolescence and young adulthood. While much has been learned about the benefits of natural mentoring for more proximate outcomes such as mental health and education, relatively little is known about the causal impact of youth mentoring relationships on career opportunities. This study uses data from the National Longitudinal Study of Adolescent Health (Add Health) survey to explore the effects of different kinds of natural mentoring relationships on employment outcomes during the early career years (when workers are in their late twenties and early thirties). Whereas traditional methods of causal conditioning show a broad range of employment benefits from being mentored, results from counterfactual analysis using propensity score matching reveal that the benefits of mentoring are confined to intrinsic job rewards. The findings imply that mentors help steer youth toward intrinsically rewarding careers.


An examination of camptocormia assessment by dynamic quantification of sagittal posture.
Camptocormia is a disabling pathology of the axial system that debilitates patients in their daily life. To date, there have been no studies evaluating the impact of camptocormia on walking performance. This study presents a new method for assessing sagittal posture under walking conditions in patients with camptocormia. The severity of camptocormia was evaluated by measuring sagittal inclination, represented indirectly by the horizontal distance between the C7 and S1 markers (C7 sagittal arrow; C7-SAR). Sagittal inclination was measured under various behavioural conditions using clinical, radiological and kinematic approaches. Forty-three patients were included in the study (17 with Parkinson's disease and 26 with idiopathic camptocormia). Under static conditions, C7-SAR could be assessed using different methods. During walking, there was a dramatic increase in C7-SAR values. Correlation analysis revealed a relationship between functional impairment and dynamic C7-SAR values, but not with radiological C7-SAR values. PATIENTS with Parkinson's disease behaved differently from idiopathic patients, suggesting the involvement of different underlying physiopathological mechanisms. Monitoring sagittal inclination during walking is more accurate than radiological measurements to determinine the detrimental effects of camptocormia and its consequences for quality of life.


Radioactive labelling of ribosomal proteins with reductive alkylation and its use in studying ribosome-cytosol interactions.
Mouse brain ribosomes were radioactively labelled by a cell-free reductive alkylation reaction with NaBH4 and [14C]formaldehyde. The radioactivity was largely associated with ribosomal proteins, but little, if any, of the rRNA was radioactive after the alkylation procedure. Both ribosomal structural proteins and loosely associated components were successfully labelled by this procedure. The sedimentation properties of the ribosomes were unaltered and their ability to carry out poly(U)-directed protein synthesis, although decreased, was largely retained. Incubation of 14C-labelled ribosomes with brain cytosol resulted in a 17% loss of radioactivity, although treatment of the ribosomes with 1.0 m-KCl to remove the loosely associated factors rendered the ribonucleoprotein particles resistant to cytosol effects. The ribosome-cytosol interactions did not appear to be related to an exchange process, since the released radioactivity was largely degraded to acid-soluble material. In addition, the incubation of native ribosomes with brain cytosol resulted in an almost complete loss in the ability of the ribosomes to participate in cell-free protein synthesis.


Bilateral brachial plexopathy as an initial presentation in a newly-diagnosed, uncontrolled case of diabetes mellitus.
A 55-year-old Indian woman with newly-diagnosed diabetes mellitus presented with acute onset right upper limb proximal weakness. This was followed three weeks later by pain, weakness and sensory loss in the left upper limb. Electrodiagnosis showed patchy multiple proximal and distal axonal neuropathies in both upper limbs, consistent with bilateral brachial neuritis. Laboratory investigations, cerebrospinal fluid analysis, and imaging studies were normal except for an antinuclear antibody titre of 1:640. Sural nerve and quadriceps biopsy did not show vasculitis. Brachial plexopathy has seldom been associated with diabetes mellitus and could represent a rare subtype of the diabetic neuropathies.


Depression in adolescents and young adults--polysomnographic and neuroendocrine aspects.
The comparison of polysomnographic data between a group of nine major depressive adolescents, 12 minor depressive adolescents and 12 controls showed a significant difference in sleep efficiency index and in percentage of awakenings. Sleep efficiency was reduced in major depressive adolescents and the percentage of awakenings was increased. Pubertal stage did not appear to have any effect on sleep EEG recordings. The administration of dexamethasone provoked a suppression of cortisol secretion in 50% of major depressive adolescents. Pubertal stage did not appear to have any significant effect on cortisol level after DST.


Pathogenesis of infection with varicella vaccine.
Because of its exanthem, the disease varicella has been known since antiquity. Even late in the 19th century, however, there remained considerable confusion between mild smallpox and chickenpox. The name varicella itself is an irregular diminutive form of variola. Yet, early in the 20th century, detailed histologic studies began to differentiate the exanthems. The investigation of the varicella vesicle by Tyzzer 90 years ago remains a classic example (see Fig. 2). Although the pathogenesis of varicella vaccine virus infection appears to mimic that of wt VZV infection, a vaccine virus-related exanthem is more common in immunized children with an underlying immunosuppressive condition, such as leukemia, than in normal children. Those immunized children who never develop a rash presumably have an abrogated infection in which the host immune response has eliminated the virus prior to a major viremic spread. There may be a correlation between the presence of an exanthem and the ability of an immunized child to spread the varicella vaccine virus. The differences in capsid structure and assembly may explain in part the attenuation of the vaccine strain. Because the majority of varicella vaccine virus particles in the nucleus have aberrant cores lacking an electron-dense center, they are never enveloped. Therefore, they do not become infectious virions. In a recent article, Grose et al applied the technique of three-dimensional (3-D) computer modeling in an attempt to reconstruct an aberrant VZV capsid with the hubcap or pinwheel core. Each 3-D model was then sliced by computer to obtain a series of two-dimensional models that represented the images commonly seen by traditional electron microscopy. The 3-D model that best represented the capsid with a pinwheel core contained particulate matter in each of the 12 vertices of the icosahedral capsid (Fig. 14). This model strongly suggested that VZV may form in the nucleus an intermediary or end-stage capsid with an aberrant distribution of assembly protein or viral DNA within its core. Herpes simplex viral particles with pinwheel cores are rarely seen in cell culture, so this type of aberrant capsid appears to be associated mainly with VZV replication. Thus, the strategy of Takahashi and colleagues to serially passage the varicella vaccine virus in human embryonic lung cells, guinea pig embryo cells, and Wistar Institute strain 38 (WI-38) cells may have exploited in as yet unknown ways the profound cell-associated nature of VZV to achieve an end product with attenuated pathogenic potential.


Hospital mortality is associated with ICU admission time.
Previous studies have shown that patients admitted to the intensive care unit (ICU) after "office hours" are more likely to die. However these results have been challenged by numerous other studies. We therefore analysed this possible relationship between ICU admission time and in-hospital mortality in The Netherlands. This article relates time of ICU admission to hospital mortality for all patients who were included in the Dutch national ICU registry (National Intensive Care Evaluation, NICE) from 2002 to 2008. We defined office hours as 08:00-22:00 hours during weekdays and 09:00-18:00 hours during weekend days. The weekend was defined as from Saturday 00:00 hours until Sunday 24:00 hours. We corrected hospital mortality for illness severity at admission using Acute Physiology and Chronic Health Evaluation II (APACHE II) score, reason for admission, admission type, age and gender. A total of 149,894 patients were included in this analysis. The relative risk (RR) for mortality outside office hours was 1.059 (1.031-1.088). Mortality varied with time but was consistently higher than expected during "off hours" and lower during office hours. There was no significant difference in mortality between different weekdays of Monday to Thursday, but mortality increased slightly on Friday (RR 1.046; 1.001-1.092). During the weekend the RR was 1.103 (1.071-1.136) in comparison with the rest of the week. Hospital mortality in The Netherlands appears to be increased outside office hours and during the weekends, even when corrected for illness severity at admission. However, incomplete adjustment for certain confounders might still play an important role. Further research is needed to fully explain this difference.


Genetic background-dependent effects of murine micro RNAs on circadian clock function.
MicroRNAs (miRs) are important regulators of a wide range of biological processes. Antagomir studies suggest an implication of miR-132 in the functionality of the mammalian circadian clock. miR-212 and miR-132 are tandemly processed from the same transcript and share the same seed region. We found the clock modulator miR-132 and miR-212 to be expressed rhythmically in the central circadian clock. Consequently, mRNAs implicated in circadian functions may likely be targeted by both miRs. To further characterize the circadian role we generated mice with stable deletion of the miR-132/212 locus and compared the circadian behavior of mutant and wild-type control animals on two genetic backgrounds frequently used in chronobiological research, C57BL/6N and 129/Sv. Surprisingly, the wheel-running activity phenotype of miR mutant mice was highly background specific. A prolonged circadian free-running period in constant darkness was found in 129/Sv, but not in C57BL/6N miR-132/212 knockout mice. In contrast, in C57BL/6N, but not in 129/Sv miRNA-132/212 knockout mice a lengthened free-running period was observed in constant light conditions. Furthermore, miR-132/212 knockout mice on 129/Sv background exhibited enhanced photic phase shifts of locomotor activity accompanied by reduced light induction of Period gene transcription in the SCN. This phenotype was absent in miRNA-132/212 knockout mice on a C57BL/6N background. Together, our results reveal a strain and light regimen-specific function of miR-132/212 in the circadian clock machinery suggesting that miR-132 and miR-212 act as background-dependent circadian rhythm modulators.


A key role for matrix metalloproteinases and neutral sphingomyelinase-2 in transplant vasculopathy triggered by anti-HLA antibody.
Outcomes for organ transplantation are constantly improving because of advances in organ preservation, surgical techniques, immune clinical monitoring, and immunosuppressive treatment preventing acute transplant rejection. However, chronic rejection including transplant vasculopathy still limits long-term patient survival. Transplant vasculopathy is characterized by progressive neointimal hyperplasia leading to arterial stenosis and ischemic failure of the allograft. This work sought to decipher the manner in which the humoral immune response, mimicked by W6/32 anti-HLA antibody, contributes to transplant vasculopathy. Studies were performed in vitro on cultured human smooth muscle cells, ex vivo on human arterial segments, and in vivo in a model consisting of human arterial segments grafted into severe combined immunodeficiency/beige mice injected weekly with anti-HLA antibodies. We report that anti-HLA antibodies are mitogenic for smooth muscle cells through a signaling mechanism implicating matrix metalloproteinases (MMPs) (membrane type 1 MMP and MMP2) and neutral sphingomyelinase-2. This mitogenic signaling and subsequent DNA synthesis are blocked in smooth muscle cells silenced for MMP2 or for neutral sphingomyelinase-2 by small interfering RNAs, in smooth muscle cells transfected with a vector coding for a dominant-negative form of membrane type 1 MMP, and after treatment by pharmacological inhibitors of MMPs (Ro28-2653) or neutral sphingomyelinase-2 (GW4869). In vivo, Ro28-2653 and GW4869 reduced the intimal thickening induced by anti-HLA antibodies in human mesenteric arteries grafted into severe combined immunodeficiency/beige mice. These data highlight a crucial role for MMP2 and neutral sphingomyelinase-2 in vasculopathy triggered by a humoral immune response and open new perspectives for preventing transplant vasculopathy with the use of MMP and neutral sphingomyelinase inhibitors, in addition to conventional immunosuppression.


Gingival epithelial cell signalling and cytoskeletal responses to Porphyromonas gingivalis invasion.
Porphyromonas gingivalis, an oral pathogen, can internalize within primary gingival epithelial cells (GECs) through an invasion mechanism mediated by interactions between P. gingivalis fimbriae and integrins on the surface of the GECs. Fimbriae-integrin-based signalling events were studied by fluorescence microscopy, and the subcellular localization of integrin-associated signalling molecules paxillin and focal adhesion kinase (FAK), and the architecture of the actin and microtubule cytoskeleton were examined. GECs infected with P. gingivalis for 30 min demonstrated significant redistribution of paxillin and FAK from the cytosol to cell peripheries and assembly into focal adhesion complexes. In contrast, a fimbriae-deficient mutant of P. gingivalis did not contribute substantially to activation of paxillin or FAK. After 24 h, the majority of paxillin and FAK had returned to the cytoplasm with significant co-localization with P. gingivalis in the perinuclear region. Wild-type P. gingivalis induced nucleation of actin filaments forming microspike-like protrusions and long stable microfilaments distributed throughout the cells. Fimbriae mutants promoted a rich cortical actin meshwork accompanied by membrane ruffling dispersed along the cell membrane. Remarkable disassembly and nucleation of the actin and microtubule filamentous network was observed following 24 h infection with either wild-type or fimbriae-deficient mutants of P. gingivalis. The results show that fimbriated P. gingivalis cells induce formation of integrin-associated focal adhesions with subsequent remodelling of the actin and tubulin cytoskeleton.


Optimal temporal interpolation filter for motion-compensated frame rate up conversion.
Frame rate up conversion (FRUC) methods that employ motion have been proven to provide better image quality compared to nonmotion-based methods. While motion-based methods improve the quality of interpolation, artifacts are introduced in the presence of incorrect motion vectors. In this paper, we study the design problem of optimal temporal interpolation filter for motion-compensated FRUC (MC-FRUC). The optimal filter is obtained by minimizing the prediction error variance between the original frame and the interpolated frame. In FRUC applications, the original frame that is skipped is not available at the decoder, so models for the power spectral density of the original signal and prediction error are used to formulate the problem. The closed-form solution for the filter is obtained by Lagrange multipliers and statistical motion vector error modeling. The effect of motion vector errors on resulting optimal filters and prediction error is analyzed. The performance of the optimal filter is compared to nonadaptive temporal averaging filters by using two different motion vector reliability measures. The results confirm that to improve the quality of temporal interpolation in MC, the interpolation filter should be designed based on the reliability of motion vectors and the statistics of the MC prediction error.


[Neurocirculatory dystonia (does this disease exist?)].
Difficulties of diagnostics of neurocirculatory dystonia are discussed. Definition based on Myasnikov's ideas about hyperreactivity, that is inadequate cardiovascular responses to psychoemotional stress, is proposed. Peculiarities of classification and therapy of neurocirculatory dystonia are presented.


Mac387: its non-specificity as a tumour marker or marker of histiocytes.
A commercially available monoclonal antibody which detects histiocytes in paraffin sections, Mac387, was reacted with 148 soft tissue sarcomas, 29 carcinomas and 10 malignant melanomas. The soft tissue sarcomas had been previously immunophenotyped. All categories of sarcomas, with the exception of angiosarcomas, were positive. Most showed staining in less than 50% of the tumour cells. Six of 10 adenocarcinomas and three of nine basal cell carcinomas were positive, while squamous carcinomas and malignant melanomas were negative. Normal squamous mucosa and epidermis were also positive. The results of this study suggest that Mac387 is of little value in the differential diagnosis of soft tissue tumours, nor is it a specific histiocytic marker.


Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells.
Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.


Atenolol: once-daily cardioselective beta blockade for angina pectoris.
The physiology, pharmacokinetics and efficacy of atenolol, a cardioselective beta-adrenergic blocking agent, were evaluated in 10 patients with stable angina pectoris in a single-blind, dose-ranging study. After a 1-month control placebo period, atenolol was administered once daily at dosages of 25, 50, 100 and 200 mg for 2-week periods. All patients had fewer anginal attacks and consumed fewer nitroglycerin tablets than mg for 2-week periods. All patients had fewer anginal attacks and consumed fewer nitroglycerin tablets than during the placebo period. Twenty-four-hour ambulatory ECG recordings showed a decrease in mean hourly heart rate throughout the dosing period, with preservation of diurnal variation. Maximal, symptom-limited, treadmill exercise tests performed 3 hours after drug ingestion showed significantly increased exercise time and decreased double products for all doses, but especially with 100-mg and 200-mg doses. Exercise time 24 hours after drug ingestion continued to show a decrease in maximum heart rate and double product, with 100-mg and 200-mg doses again being most effective. Atenolol serum levels correlated with percent reduction in exercise heart rate and increased exercise time. Serum levels rose linearly, with an average elimination half-life of about 10 hours after chronic oral dosing. Thus, atenolol was an effective antianginal agent and suppressed resting and exercise-stressed heart rate for 24 hours after ingestion when given in a 100-mg or 200-mg dose once daily.


Prevalence and Characteristics of Adolescents with Autism Spectrum Disorder in the New York-New Jersey Metropolitan Area.
Almost all epidemiologic studies estimating autism spectrum disorder (ASD) prevalence have focused on school-age children. This study provides the first population-based data on the prevalence and expression of ASD among adolescents in a large US metropolitan region. Active multiple source ASD surveillance of adolescents aged 16-years was conducted according to the Autism and Developmental Disabilities Monitoring (ADDM) Network method in a four-county New Jersey metropolitan region. Prevalence estimates are provided, characteristics are described and comparison of the distribution and characteristics of ASD is offered for this cohort, at 8 and 16-years. ASD prevalence was 17.7 per 1000 (95% CI: 16.3-19.2)]. One-in-55 males and one in 172 females were identified with ASD. High-SES was positively associated with ASD and White adolescents had higher ASD prevalence (22.2 per 1000) than Hispanic adolescents (13.1 per 1000). One in four study-confirmed individuals with ASD did not have an ASD diagnosis. A majority of ASD adolescents (58.8%) had a co-occurring neuropsychiatric disorder. White and High-SES individuals had greater likelihood of co-occurring disorder. The demographic distribution and functional profile of ASD was similar in this cohort at 8 and 16-years. Approximately one-in-55 adolescents in our area had ASD, in 2014, and one-in-4 16-year-olds with ASD was not diagnosed. A majority (3-in-5) of the adolescents with ASD had a co-occurring neuropsychiatric disorder. ASD under-identification and the high frequency of co-disorders in adolescents with ASD pose significant challenges to care and support.


Clinical practice breastfeeding recommendations for primary care: applying a tri-core breastfeeding conceptual model.
Promotional practice efforts are needed in primary care to support and foster breastfeeding as the first and natural choice of nutrition for all infants regardless of race, ethnicity, educational, or income demographics in the United States. Societal awareness is increasing with regard to the significant protective qualities that human milk bestows upon public health. An estimated 75% of American mothers attempt to breastfeed, but according to the Centers for Disease Control and Prevention, just 13% are able to exclusively breastfeed by 6 months. Early identification of lactation issues is crucial to establishing and sustaining breastfeeding for the first 6 to 12 months of the child's life and beyond. We propose a set of primary care guidelines, applying a Tri-Core Model approach, to promote and foster breastfeeding efforts in the postpartum period. Breastfeeding promotion is a fundamental public health endeavor, and pediatric nurse practitioners and other advanced practice registered nurses (APRNs) are uniquely qualified to become specialists and experts in lactation care and management. Lactation support, which should be an integral facet of an APRN's practice and education, will aid in improving national breastfeeding rates and patient care outcomes. Application of the Tri-Core Model approach will help APRNs develop and implement evidence-based practice efforts that incorporate the mother-baby dyad and other multiprofessionals who are vested in successful breastfeeding outcomes. The goal of pediatric health care is provide safe and effective health care to all infants, children, and adolescents, and lactation care is an integral and crucial component of this effort.


Chemical and biological studies of a new cigarette that primarily heats tobacco. Part 1. Chemical composition of mainstream smoke.
A new-technology cigarette has been developed. While the new cigarette burns some tobacco, it does not use tobacco as the fuel to sustain combustion and provide heat to the cigarette. Rather, the new cigarette primarily heats tobacco thereby reducing products of smoke formation mechanisms such as tobacco combustion, tobacco pyrolysis and pyrosynthesis. The mainstream smoke composition from a cigarette based on the new design (TOB-HT) has been characterized in comparative chemical testing with two reference cigarettes using the FTC puffing regimen. Thermal properties, UV absorption characteristics, elemental composition and materials balance studies all suggest a simplified smoke aerosol. Twenty-five smoke constituents ("target compounds") identified by the scientific community as compounds that may contribute to the diseases statistically associated with smoking have also been measured. Mainstream smoke concentrations of most target compounds are significantly lower with the TOB-HT cigarette when compared with reference cigarettes in the ultra-light "tar" and light "tar" categories. Taken together, chemical analysis results suggest simplified TOB-HT smoke chemistry with marked reductions in specific chemicals reported to be biologically active.


La protein has a positive effect on the translation of TOP mRNAs in vivo.
In vertebrates, the mRNAs encoding ribosomal proteins, as well as other proteins implicated in translation, are characterized by a 5'-untranslated region (5'-UTR), including a stretch of pyrimidines at the 5'-end. The 5'-terminal oligopyrimidine (5'-TOP) sequence, which is involved in the growth-dependent translational regulation characteristic of this class of genes (so-called TOP genes), has been shown to specifically bind the La protein in vitro, suggesting that La might be implicated in translational regulation in vivo. In order to substantiate this hypothesis, we have examined the effect of La on TOP mRNA translational control in both stable and transient transfection experiments. In particular we have constructed and analyzed three stably transfected Xenopus cell lines inducible for overexpression of wild-type La or of putative dominant negative mutated forms. Moreover, La-expressing plasmids have been transiently co-transfected together with a plasmid expressing a reporter TOP mRNA in a human cell line. Our results suggest that in vivo La protein plays a positive role in the translation of TOP mRNA. They also suggest that the function of La is to counteract translational repression exerted by a negative factor, possibly cellular nucleic acid binding protein (CNBP), which has been previously shown to bind the 5'-UTR downstream from the 5'-TOP sequence.


Cyclooxygenase inhibition and baroreflex sensitivity in humans.
Animal studies suggest that prostanoids (i.e., such as prostacyclin) may sensitize or impair baroreceptor and/or baroreflex responsiveness depending on the site of administration and/or inhibition. We tested the hypothesis that acute inhibition of cyclooxygenase (COX), the rate-limiting enzyme in prostanoid synthesis, impairs baroreflex regulation of cardiac period (R-R interval) and muscle sympathetic nerve activity (MSNA) in humans and augments pressor reactivity. Baroreflex sensitivity (BRS) was determined at baseline (preinfusion) and 60 min after (postinfusion) intravenous infusion of a COX antagonist (ketorolac; 45 mg) (24 +/- 1 yr; n = 12) or saline (25 +/- 1 yr; n = 12). BRS was assessed by using the modified Oxford technique (bolus intravenous infusion of nitroprusside followed by phenylephrine). BRS was quantified as the slope of the linear portion of the 1) R-R interval-systolic blood pressure relation (cardiovagal BRS) and 2) MSNA-diastolic blood pressure relation (sympathetic BRS) during pharmacological changes in arterial blood pressure. Ketorolac did not alter cardiovagal (19.4 +/- 2.1 vs. 18.4 +/- 2.4 ms/mmHg preinfusion and postinfusion, respectively) or sympathetic BRS (-2.9 +/- 0.7 vs. -2.6 +/- 0.4 arbitrary units.beat(-1).mmHg(-1)) but significantly decreased a plasma biomarker of prostanoid generation (plasma thromboxane B2) by 53 +/- 11%. Cardiovagal BRS (21.3 +/- 3.8 vs. 21.2 +/- 3.0 ms/mmHg), sympathetic BRS (-3.4 +/- 0.3 vs. -3.2 +/- 0.2 arbitrary units.beat(-1).mmHg(-1)), and thromboxane B2 (change in -1 +/- 12%) were unchanged in the control (saline infusion) group. Pressor responses to steady-state incremental (0.5, 1.0, and 1.5 microg.kg(-1).min(-1)) infusion (5 min/dose) of phenylephrine were not altered by ketorolac (n = 8). Collectively, these data indicate that acute pharmacological antagonism of the COX enzyme does not impair BRS (cardiovagal or sympathetic) or augment pressor reactivity in healthy young adults.


6-Gingerol reduces Pseudomonas aeruginosa biofilm formation and virulence via quorum sensing inhibition.
Pseudomonas aeruginosa is a well-known pathogenic bacterium that forms biofilms and produces virulence factors via quorum sensing (QS). Interfering with normal QS interactions between signal molecules and their cognate receptors is a developing strategy for attenuating its virulence. Here we tested the hypothesis that 6-gingerol, a pungent oil of fresh ginger, reduces biofilm formation and virulence by antagonistically binding to P. aeruginosa QS receptors. In silico studies demonstrated molecular binding occurs between 6-gingerol and the QS receptor LasR through hydrogen bonding and hydrophobic interactions. Experimentally 6-gingerol reduced biofilm formation, several virulence factors (e.g., exoprotease, rhamnolipid, and pyocyanin), and mice mortality. Further transcriptome analyses demonstrated that 6-gingerol successfully repressed QS-induced genes, specifically those related to the production of virulence factors. These results strongly support our hypothesis and offer insight into the molecular mechanism that caused QS gene repression.


Livelihood security and adherence to antiretroviral therapy in low and middle income settings: a systematic review.
We sought to examine the association between livelihood security and adherence to antiretroviral therapy (ARVs) in low- and middle-income countries (LIMC). Performing a systematic review, we searched, independently and in duplicate, 7 electronic databases and 2 conference websites for quantitative surveys that examined the association between indicators of livelihood security and adherence to ARVs in LIMC between 2000-2010. Criteria for relevance were applied to complete papers (quantitative study with estimates of associations) and quality assessment was conducted on those deemed relevant. We performed three regressions to measure the association between each type of livelihood and adherence. Twenty original studies and 6 conference abstracts were included, the majority from Africa (n = 16). Seventeen studies and 3 conference abstracts were cross-sectional and 3 studies and 3 abstracts were prospective clinical cohort studies, with considerable variation in quality for studies of each design type. Among the diverse populations represented, we observed considerable variation in associations between measurements of livelihood indicators and increasingly accepted adherence measures, irrespective of study design or quality. A financial capital indicator, financial constraints/payment for ARV medication, was more commonly associated with non-adherence (3/5 studies). A human capital indicator, educational level, was most commonly associated with adherence (11/20 studies). Additional better quality research examining livelihood security is required to inform provision of optimal supports for adherence and mitigation of the impacts of HIV/AIDS.


Iron, zinc and copper in the Alzheimer's disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion.
Dysfunctional homeostasis of transition metals is believed to play a role in the pathogenesis of Alzheimer's disease (AD). Although questioned by some, brain copper, zinc, and particularly iron overload are widely accepted features of AD which have led to the hypothesis that oxidative stress generated from aberrant homeostasis of these transition metals might be a pathogenic mechanism behind AD. This meta-analysis compiled and critically assessed available quantitative data on brain iron, zinc and copper levels in AD patients compared to aged controls. The results were very heterogeneous. A series of heavily cited articles from one laboratory reported a large increase in iron in AD neocortex compared to age-matched controls (p<0.0001) while seven laboratories failed to reproduce these findings reporting no significant difference between the groups (p=0.76). A more than three-fold citation bias was found to favor outlier studies reporting increases in iron and this bias was particularly prominent among narrative review articles. Additionally, while zinc was not significantly changed in the neocortex (p=0.29), copper was significantly depleted in AD (p=0.0003). In light of these findings, it will be important to re-evaluate the hypothesis that transition metal overload accounts for oxidative injury noted in AD.


A meta-analytic review of the relationship of cancer coping self-efficacy with distress and quality of life.
Self-efficacy for coping with cancer is a specific construct that refers to behaviors that occur in the course of dealing with a cancer diagnosis, cancer treatments, and transitioning to survivorship. One of the more widely used measures of self-efficacy for coping strategies with cancer is the Cancer Behavior Inventory. The following general questions provide a framework for this research: 1. Is self-efficacy for coping with cancer related to distress and quality of life of a cancer patient?. 2. Do self-efficacy for coping with cancer and the target psychological outcomes (i.e., distress and quality of life) change in longitudinal studies, with or without intervention? One-hundred eighty studies cited the different versions of the Cancer Behavior Inventory and 47 used the scale. Result showed an inverse relationship between self-efficacy for coping with cancer and distress, and a positive relationship between self-efficacy for coping with cancer and Quality of Life, both with a large effect size. The strong relationship of self-efficacy and outcomes, resulted of the specificity of the instrument, which targets specific coping strategies that are closely aligned with positive outcomes in adjusting to cancer. However, the results are consistent with the theory, which states that compared to those with low efficacy, highly efficacious people demonstrate less anxiety and better adjustment in stressful situations and consistent with prior results in which self-efficacy is positively related to quality of life.


Management of basilar fenestration aneurysms: a systematic review with an illustrative case report.
Basilar artery (BA) fenestration aneurysm (BAFA) is a rare phenomenon commonly accompanying other aneurysms. Treatment is challenging, and few cases have been reported. This review investigated the management outcomes of BAFAs. Publication databases were searched to identify studies evaluating outcomes of endovascular treatment (EVT) and microsurgical treatment of BAFAs from inception through 2021. Outcomes (clinical, angiographic, postoperative complications, and retreatment rates) were collected and analyzed. The authors present their case of a patient treated for a BAFA. Including the authors' case, 184 patients with 209 BAFAs were reported in 68 studies. Most patients (130/175; 74.3%) presented with ruptured aneurysms, most commonly involving the proximal segment of the BA. Most BAFAs were small (52/103, 50.5%) and saccular (119/143, 83.2%). Most patients underwent EVT (143/184, 77.7%); the rest underwent microsurgery. Postoperative complications after EVT occurred in 10 (8.3%) of 120 patients, with 4 of the 10 experiencing strokes. At clinical follow-up, most EVT patients (74/86, 86.0%) showed good outcomes; 3.9% (2/51) had died. Most aneurysms managed with EVT (56/73, 76.7%) showed complete occlusion at follow-up; 7.3% (8/109) were retreated. Postoperative complications occurred in 62.2% (23/37) of microsurgical patients; 5 (21.7%) of the 23 experienced strokes. All patients showed good clinical outcomes at follow-up. Most aneurysms (22/28, 78.6%) treated microsurgically showed complete occlusion at angiographic follow-up, with no retreatment required. BAFAs are often symptomatic; thus, treatment is challenging. By the 2000s, treatment had moved from microsurgical to endovascular modalities, with good clinical and angiographic outcomes.


Effects of oxygen on anoxic biodegradation of benzoate during continuous culture.
In this study, various amounts of oxygen were added to denitrifying chemostats receiving benzoate to mimic the input of oxygen to anoxic zones of biological nutrient removal systems. The effect of oxygen on the biodegradative capability of the mixed-microbial culture for benzoate was investigated. The anoxic benzoate biodegradative capability of the culture was not significantly changed as the mass flowrate of oxygen was increased to 40% of the input benzoate chemical oxygen demand (COD) mass flowrate, but was decreased approximately 70% when the mass flowrate of oxygen was increased to 70% of the input benzoate COD mass flowrate. The decrease in the anoxic benzoate biodegradative capability was due primarily to the loss of the denitrifying enzymes (measured by the anoxic pyruvate-degrading ability) and not to the loss of the key anoxic catabolic enzyme (benzoyl-coenzyme A reductase). The proportional increase in the concentration of nitrate as the residual terminal electron acceptor and the lack of synthesis of aerobic ring-cleavage enzymes as the oxygen input to the chemostat was increased suggest that the mixed microbial culture preferred oxygen to nitrate as the terminal electron acceptor, but degraded benzoate using the anoxic metabolic pathway. The concentration of the mixed microbial culture increased as the oxygen input to the chemostat was increased, suggesting that the oxygen was used by cytochrome cbb3 rather than quinol oxidase because the energetic yield of cytochrome cbb3 is higher than that of quinol oxidase or the nitrogen oxide reductases.


Current trends in the incidence of neural tube defects.
To verify and investigate the reported decline of neural tube defects (NTDs) in the last decade, data from three different sources were examined: the Birth Defects Monitoring Program (BDMP), composed of newborn discharge diagnoses; the population-base Metropolitan Atlanta Congenital Defects Program (MACDP); and the National Center for Health Statistics (NCHS), whose data include only live births. Although the three systems use different methods of ascertaining cases, all data bases showed a decreasing trend in NTD rates, with annual percent decreases of 3.1% for NCHS, 5.7% for BDMP, and 7.7% for MACDP. The decrease was noted in all variables examined: race, sex, and birth status for each defect. NTD rates appear to be declining more rapidly in females than in males. Further, the rate among stillborn infants decreased more than the rate among live-born infants. The exclusion of stillbirths in the NCHS data may contribute to its low rate of decline for female anencephalics. Data from England showed a larger average annual decrease (10.6%) than did data from the United States. Although reasons for the overall decline are not verifiable, a variety of explanations are suggested for this decline and for the difference in NTD rate decline noted between live births and stillbirths. The overall decline in NTD rates should be investigated with respect to etiology; recognition of the decline is useful for planning and evaluating health care programs.


Requirements for localization of p130cas to focal adhesions.
p130cas (Cas) is an adapter protein that has an SH3 domain followed by multiple SH2 binding motifs in the substrate domain. It also contains a tyrosine residue and a proline-rich sequence near the C terminus, which are the binding sites for the SH2 and SH3 domains of Src kinase, respectively. Cas was originally identified as a major tyrosine-phosphorylated protein in v-Crk- and v-Src-transformed cells. Subsequently, Cas was shown to be inducibly tyrosine phosphorylated upon integrin stimulation; it is therefore regarded as one of the focal adhesion proteins. Using an immunofluorescence study, we examined the subcellular localization of Cas and determined the regions required for its localization to focal adhesions. In nontransformed cells, Cas was localized predominantly to the cytoplasm and partially to focal adhesions. However, in 527F-c-Src-transformed cells, Cas was localized mainly to podosomes, where the focal adhesion proteins are assembled. The localization of Cas to focal adhesions was also observed in cells expressing the kinase-negative 527F/295M-c-Src. A series of analyses with deletion mutants expressed in various cells revealed that the SH3 domain of Cas is necessary for its localization to focal adhesions in nontransformed cells while both the SH3 domain and the C-terminal Src binding domain of Cas are required in 527F-c-Src-transformed cells and fibronectin-stimulated cells. In addition, the localization of Cas to focal adhesions was abolished in Src-negative cells. These results demonstrate that the SH3 domain of Cas and the association of Cas with Src kinase play a pivotal role in the localization of Cas to focal adhesions.


Altered expression of cell cycle regulators p21, p27, and p53 in tumors of salivary glands and paranasal sinuses.
CIP/KIP family proteins entitled p21(WAF1/CIP1) and p27(KIP1) have key positions in cell cycle regulation leading to an arrest of cell proliferation. They are supposed to enable a repair process of DNA damage. In several human tumors, a loss of these proteins is associated with poor clinical outcome. The role of these cell cycle regulators in tumors of salivary gland and paranasal sinus origin is still unclear. In this study it was intended to demonstrate and compare the expression of p21, p27, and p53 in benign and malignant tumors of salivary glands and paranasal sinuses. Protein expression was detected by conventional immunohistochemistry (IHC). Additionally, we performed tyramide signal amplified immunohistochemistry (TSA-IHC) for p21 and p53 levels. Nine adenoid cystic carcinomas, 5 adenocarcinomas, 4 cylindrical cell carcinomas, as well as 30 pleomorphic adenomas and 26 inverted papillomas, were studied. In 78% of all adenoid cystic carcinomas a complete loss of p27 expression could be identified, whereas 60% of the adenocarcinomas overexpressed the protein. The majority of cylindrical cell carcinomas showed distinct cytoplasmic accumulation of p27. All malignant tumors turned out to be positive for p21 after performing TSA-IHC, although 72% of those samples had shown weak to negative protein levels in conventional immunostaining. Immunohistochemical results of CIP/KIP proteins were compared to p53 expression as well as to main clinical parameters. The study sheds new light upon the role of CIP/KIP protein family in tumors of salivary glands and paranasal sinuses. Furthermore, it is the first description of p21 and p53 TSA-IHC in these tumor types.


A pilot randomized controlled trial using EEG-based brain-computer interface training for a Chinese-speaking group of healthy elderly.
There is growing evidence that cognitive training (CT) can improve the cognitive functioning of the elderly. CT may be influenced by cultural and linguistic factors, but research examining CT programs has mostly been conducted on Western populations. We have developed an innovative electroencephalography (EEG)-based brain-computer interface (BCI) CT program that has shown preliminary efficacy in improving cognition in 32 healthy English-speaking elderly adults in Singapore. In this second pilot trial, we examine the acceptability, safety, and preliminary efficacy of our BCI CT program in healthy Chinese-speaking Singaporean elderly. Thirty-nine elderly participants were randomized into intervention (n=21) and wait-list control (n=18) arms. Intervention consisted of 24 half-hour sessions with our BCI-based CT training system to be completed in 8 weeks; the control arm received the same intervention after an initial 8-week waiting period. At the end of the training, a usability and acceptability questionnaire was administered. Efficacy was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which was translated and culturally adapted for the Chinese-speaking local population. Users were asked about any adverse events experienced after each session as a safety measure. The training was deemed easily usable and acceptable by senior users. The median difference in the change scores pre- and post-training of the modified RBANS total score was 8.0 (95% confidence interval [CI]: 0.0-16.0, P=0.042) higher in the intervention arm than waitlist control, while the mean difference was 9.0 (95% CI: 1.7-16.2, P=0.017). Ten (30.3%) participants reported a total of 16 adverse events - all of which were graded "mild" except for one graded "moderate". Our BCI training system shows potential in improving cognition in both English- and Chinese-speaking elderly, and deserves further evaluation in a Phase III trial. Overall, participants responded positively on the usability and acceptability questionnaire.


Contrast-enhanced multislice pneumo-CT-cystography in the evaluation of urinary bladder neoplasms.
To evaluate the accuracy of contrast-enhanced multislice CT (MSCT) in the study of urothelial tumors after distension of the bladder with air. We evaluated 43 consecutive patients with endoscopically proven bladder lesions. After air distension of the bladder, unenhanced pelvic and enhanced abdomino-pelvic scans were obtained with the following protocol: thickness 2.5mm x 4mm, increment 1mm, scan delay 40'' and 7-10 min. For each patient we considered the number, size, aspect (papillary or sessile) and contrast enhancement of lesions. Ureteral involvement and the presence of synchronous lesions in the excretory scan were also evaluated. MPR and virtual endoscopy images were reviewed in all cases. Bladder lesions were visualized in 39/43 cases. Compared to conventional cystoscopy, MSCT recognized single lesions in 31/33 patients, two lesions in 4/6, three in 2/2 and more than five foci in 2/2 patients. A papillary aspect was described in 44 cases while 11 lesions were sessile. Conventional Cystoscopy recognized six more lesions as compared with MSCT (four flat and two small papillary lesions). The detection rate for protruding lesions was 100% (52/52) for lesions>5mm and 60% (3/5%) for lesions<5mm. In four patients hydronephrosis was present, while in one case a synchronous lesion was evident in the renal pelvis. Contrast-enhanced MSCT with air distension of the urinary bladder is a safe and complete investigation to evaluate the local stage of bladder cancer and to evaluate the ureteral extension of the tumor, as well as the presence of synchronous lesions.


Increased plasma miR-370-3p expression in poor-outcome patients with pancreatic ductal adenocarcinoma.
To determine whether circulating microRNAs (miRNAs) can be used as prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC (N = 120) who underwent surgical resection at Hiroshima University Hospital between November 2006 and January 2020 were enrolled in this study and grouped based on their overall survival (OS) into two groups: favorable prognosis group (F group; OS ≥ 18 months) and unfavorable prognosis group (U group; OS < 18 months). Blood plasma samples were collected prior to surgery. To identify candidate prognostic miRNAs, next-generation sequencing (NGS) analysis was used to evaluate the expression levels of miRNAs in seven of the plasma samples. Using quantitative real-time PCR (qRT-PCR), the expression levels of the selected miRNAs were determined in the remaining 113 patient plasma samples, and the relationship between miRNA expression and survival was statistically evaluated. NGS analysis and qRT-PCR revealed significantly upregulated plasma miR-370-3p expression in the U group compared to that in the F group (p = 0.028 and p = 0.005, respectively). Moreover, miR-370-3p expression and lymph node metastasis showed a statistically significant association (p = 0.028). In a multivariate analysis of OS and recurrence-free survival (RFS), the upregulation of miR-370-3p expression in plasma was identified as an independent risk factor for poor OS (HR2.13, p = 0.004) and RFS (HR1.84, p = 0.015). Plasma miR-370-3p expression upregulation correlates with poor prognosis in patients with PDAC.


Experimental evidence for short-pulse laser heating of solid-density target to high bulk temperatures.
Heating efficiently solid-density, or even compressed, matter has been a long-sought goal in order to allow investigation of the properties of such state of matter of interest for various domains, e.g. astrophysics. High-power lasers, pinches, and more recently Free-Electron-Lasers (FELs) have been used in this respect. Here we show that by using the high-power, high-contrast "PEARL" laser (Institute of Applied Physics-Russian Academy of Science, Nizhny Novgorod, Russia) delivering 7.5 J in a 60 fs laser pulse, such coupling can be efficiently obtained, resulting in heating of a slab of solid-density Al of 0.8 µm thickness at a temperature of 300 eV, and with minimal density gradients. The characterization of the target heating is achieved combining X-ray spectrometry and measurement of the protons accelerated from the Al slab. The measured heating conditions are consistent with a three-temperatures model that simulates resistive and collisional heating of the bulk induced by the hot electrons. Such effective laser energy deposition is achieved owing to the intrinsic high contrast of the laser which results from the Optical Parametric Chirped Pulse Amplification technology it is based on, allowing to attain high target temperatures in a very compact manner, e.g. in comparison with large-scale FEL facilities.


Symbolic metal bit and saddlebag fastenings in a Middle Bronze Age donkey burial.
Here we report the unprecedented discovery of the skeleton of a ritually interred donkey with a metal horse bit in association with its teeth and saddlebag fastenings on its back. This discovery in the Middle Bronze Age III sacred precinct (1700/1650-1550 BCE) at Tel Haror, Israel, presents a unique combination of evidence for the early employment of equid harnessing equipment, both for chariot bridling (horse bit) and pack animals (saddlebags). The ritually deposited donkey with its unique accoutrements advances our understanding of the broad social and religious significance of equids in the Levantine Bronze Age, previously known mainly from textual and iconographical sources.


The role of estrogen and estrogen receptors in chemoresistance.
Drug resistance is one of the major obstacles limiting the success of cancer chemotherapy. Biological mechanisms contributing to drug resistance may be present de novo and related to inherent features or may be raised after exposure to anticancer drugs. In recent years, both clinical observations and experimental studies suggested that steroid hormones and their receptors might also affect the therapeutic efficacy of antineoplastic drugs. Estrogens and estrogen receptors (ER) are well-known for their critical roles in the development and progression of breast tumors. It has long been known that breast tumors expressing ERα protein (ERα+) behave in a fundamentally different fashion than ERα-negative (ERα-) tumors with regard to their responses to hormonal therapy. Data obtained from both laboratory and clinical investigations suggested that some chemotherapeutic agents are clearly less effective in ERα+ tumors than ERα- tumors, although the mechanisms of ERα-mediated chemoresistance are not entirely clear. Moreover, recent studies from our laboratory and others demonstrated that the combination of antiestrogenic agents with chemotherapeutic drugs is of significant therapeutic benefit in ERα+ breast cancer over chemotherapy alone. In addition, the ERα-derived peptides, microRNAs specifically targeting ERα, as well as agents targeting estrogen-related receptors (ERRs) may hold promise to sensitize ERα+ breast tumors to chemotherapy. Considering that ERs are expressed in ˜ 65% of human breast cancer, the ERα-mediated chemoresistance has become a big challenge for clinical treatment. The hope to overcome this drug resistance relies on further clarification of specific pathways or molecules contributing to the resistance. More exhaustive and systematic studies are essential to reach deeper understandings on the underlying mechanisms and to develop novel approaches to sensitize ERα+ breast tumors to chemotherapy.


Assessing the Environmental Effects Related to Quantum Dot Structure, Function, Synthesis and Exposure.
Quantum dots (QDs) are engineered semiconductor nanocrystals with unique fluorescent, quantum confinement, and quantum yield properties, making them valuable in a range of commercial and consumer imaging, display, and lighting technologies. Production and usage of QDs are increasing, which increases the probability of these nanoparticles entering the environment at various phases of their life cycle. This review discusses the major types and applications of QDs, their potential environmental exposures, fates, and adverse effects on organisms. For most applications, release to the environment is mainly expected to occur during QD synthesis and end-product manufacturing since encapsulation of QDs in these devices prevents release during normal use or landfilling. In natural waters, the fate of QDs is controlled by water chemistry, light intensity, and the physicochemical properties of QDs. Research on the adverse effects of QDs primarily focuses on sublethal endpoints rather than acute toxicity, and the differences in toxicity between pristine and weathered nanoparticles are highlighted. A proposed oxidative stress adverse outcome pathway framework demonstrates the similarities among metallic and carbon-based QDs that induce reactive oxygen species formation leading to DNA damage, reduced growth, and impaired reproduction in several organisms. To accurately evaluate environmental risk, this review identifies critical data gaps in QD exposure and ecological effects, and provides recommendations for future research. Future QD regulation should emphasize exposure and sublethal effects of metal ions released as the nanoparticles weather under environmental conditions. To date, human exposure to QDs from the environment and resulting adverse effects has not been reported.


Influence of high-resolution data on the assessment of forest fragmentation.
Remote sensing has been a foundation of landscape ecology. The spatial resolution (pixel size) of remotely sensed land cover products has improved since the introduction of landscape ecology in the United States. Because patterns depend on spatial resolution, emerging improvements in the spatial resolution of land cover may lead to new insights about the scaling of landscape patterns. We compared forest fragmentation measures derived from very high resolution (1 m2) data with the same measures derived from the commonly used (30 m × -30 m; 900 m2) Landsat-based data. We applied area-density scaling to binary (forest; non-forest) maps for both sources to derive source-specific estimates of dominant (density ≥ 60%), interior (≥ 90%), and intact (100%) forest. Switching from low- to high-resolution data produced statistical and geographic shifts in forest spatial patterns. Forest and non-forest features that were "invisible" at low resolution but identifiable at high resolution resulted in higher estimates of dominant and interior forest but lower estimates of intact forest from the high-resolution source. Overall, the high-resolution data detected more forest that was more contagiously distributed even at larger spatial scales. We anticipate that improvements in the spatial resolution of remotely sensed land cover products will advance landscape ecology through reinterpretations of patterns and scaling, by fostering new landscape pattern measurements, and by testing new spatial pattern-ecological process hypotheses.


Protective Role of a New Polysaccharide Extracted from Lonicera japonica Thunb in Mice with Ulcerative Colitis Induced by Dextran Sulphate Sodium.
Lonicera japonica Thunb is a traditional Chinese herbal medicine for treating intestinal inflammation. The extraction method of Lonicera japonica Thunb polysaccharide (LJP) has been developed previously by our research group. In this study, a Fourier transform infrared spectrometer (FT-IR) was used to perform a qualitative analysis of LJP and a precolumn derivatization high-performance liquid chromatography (HPLC) ((Palo Alto, CA, USA) method was used to explore the monosaccharide composition of LJP. Then, we studied the effect of LJP on the intestinal flora and immune functions of dextran sulfate sodium- (DSS-) induced colitis ulcerative mouse models. The results showed that LJP was consisted of 6 types of monosaccharides and had the characteristic absorption of typical polysaccharides. LJP can increase significantly the weight, organ index, serum cytokines (interleukin, tumor necrosis factor, and interferon-γ), secretory immunoglobulin A (SIgA) concentration, and natural killer (NK) cell and cytotoxic lymphocyte (CTL) activities in DSS-treated mice. The results of intestinal flora showed that a high dose (150 mg kg-1) of LJP had the best effects on improving the intestinal probiotics (Bifidobacterium and Lactobacilli) and antagonizing the pathogenic bacteria (Escherichia coli and Enterococcus). In addition, the measurement results of the spleen lymphocyte apoptosis confirmed from another perspective that LJP had protective effects of immune cells for DSS-treated mice.


[Technical guidelines for the prevention, diagnosis and treatment of Zika virus infection].
Infection Zika virus is an emerging disease in the Americas region, which is caused by Zika virus (ZIKV), an arbovirus of the flavivirus genus. The ZIKV is transmitted by the bite of Aedes mosquitoes, both in urban and jungle area. After the mosquito bite, the disease symptoms usually appear after an incubation period of three to twelve days. The infection may be asymptomatic or presented with fever and not purulent conjunctivitis, headache, myalgia, arthralgia, asthenia, maculopapular rash, edema in lower limbs and, less frequently, retro-orbital pain, anorexia, vomiting, diarrhea or pain abdominal. Symptoms last for 4-7 days and are self-limiting. Neurological and autoimmune complications are rare. Since 2014 it has been detected native circulation of Zika virus in the Americas. So far, there is no specific antiviral treatment or effective vaccine, so it's giving priority symptomatic and supportive treatment for the acute phase and make an early diagnosis of atypical and severe forms.


[Antifertility actions of gossypol derivatives and analogues].
This paper reports the results of 32 gossypol derivatives and analogues. Among 12 compounds screened by oral administration to male rats, only dipotassium gossypolate (NC030) exhibited an antifertility activity similar to gossypol. Among 24 compounds screened by injecting into pouches of cauda epididymides of rats, 10 exhibited spermicidal activities.


A structural-chemical explanation of fungal laccase activity.
Fungal laccases (EC 22.214.171.124) are multi-copper oxidases that oxidize a wide variety of substrates. Despite extensive studies, the molecular basis for their diverse activity is unclear. Notably, there is no current way to rationally predict the activity of a laccase toward a given substrate. Such knowledge would greatly facilitate the rational design of new laccases for technological purposes. We report a study of three datasets of experimental Km values and activities for Trametes versicolor and Cerrena unicolor laccase, using a range of protein modeling techniques. We identify diverse binding modes of the various substrates and confirm an important role of Asp-206 and His-458 (T. versicolor laccase numbering) in guiding substrate recognition. Importantly, we demonstrate that experimental Km values correlate with binding affinities computed by MMGBSA. This confirms the common assumption that the protein-substrate affinity is a major contributor to observed Km. From quantitative structure-activity relations (QSAR) we identify physicochemical properties that correlate with observed Km and activities. In particular, the ionization potential, shape, and binding affinity of the substrate largely determine the enzyme's Km for the particular substrate. Our results suggest that Km is not just a binding constant but also contains features of the enzymatic activity. In addition, we identify QSAR models with only a few descriptors showing that phenolic substrates employ optimal hydrophobic packing to reach the T1 site, but then require additional electronic properties to engage in the subsequent electron transfer. Our results advance our ability to model laccase activity and lend promise to future rational optimization of laccases toward phenolic substrates.


Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance.
To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, β cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). β cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 ± 3.2 μg/mL [2.7-fold] vs. 12.7 ± 1.4 μg/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 ± 0.0071 vs. 0.0138 ± 0.021 g/cm2). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults.


Role of the IkappaB kinase complex in oncogenic Ras- and Raf-mediated transformation of rat liver epithelial cells.
NF-kappaB/Rel factors have been implicated in the regulation of liver cell death during development, after partial hepatectomy, and in hepatocytes in culture. Rat liver epithelial cells (RLEs) display many biochemical and ultrastructural characteristics of oval cells, which are multipotent cells that can differentiate into mature hepatocytes. While untransformed RLEs undergo growth arrest and apoptosis in response to transforming growth factor beta1 (TGF-beta1) treatment, oncogenic Ras- or Raf-transformed RLEs are insensitive to TGF-beta1-mediated growth arrest. Here we have tested the hypothesis that Ras- or Raf-transformed RLEs have altered NF-kappaB regulation, leading to this resistance to TGF-beta1. We show that classical NF-kappaB is aberrantly activated in Ras- or Raf-transformed RLEs, due to increased phosphorylation and degradation of IkappaB-alpha protein. Inhibition of NF-kappaB activity with a dominant negative form of IkappaB-alpha restored TGF-beta1-mediated cell killing of transformed RLEs. IKK activity mediates this hyperphosphorylation of IkappaB-alpha protein. As judged by kinase assays and transfection of dominant negative IKK-1 and IKK-2 expression vectors, NF-kappaB activation by Ras appeared to be mediated by both IKK-1 and IKK-2, while Raf-induced NF-kappaB activation was mediated by IKK-2. NF-kappaB activation in the Ras-transformed cells was mediated by both the Raf and phosphatidylinositol 3-kinase pathways, while in the Raf-transformed cells, NF-kappaB induction was mediated by the mitogen-activated protein kinase cascade. Last, inhibition of either IKK-1 or IKK-2 reduced focus-forming activity in Ras-transformed RLEs. Overall, these studies elucidate a mechanism that contributes to the process of transformation of liver cells by oncogene Ras and Raf through the IkappaB kinase complex leading to constitutive activation of NF-kappaB.


Solution structure and function of an essential CMP kinase of Streptococcus pneumoniae.
Streptococcus pneumoniae is a major human pathogen that causes high mortality and morbidity and has developed resistance to many antibiotics. We show that the gene product from SP1603, identified from S. pneumoniae TIGR4, is a CMP kinase that is essential for bacterial growth. It represents an attractive drug target for the development of a novel antibiotic to overcome the problems of drug resistance development for this organism. Here we describe the three-dimensional solution structure of the S. pneumoniae CMP kinase as determined by NMR spectroscopy. The structure consists of eight alpha-helices and two beta-sheets that fold into the classical core domain, the substrate-binding domain, and the LID domain. The three domains of the protein pack together to form a central cavity for substrate-binding and enzymatic catalysis. The S. pneumoniae CMP kinase resembles the fold of the Escherichia coli homolog. An insertion of one residue is observed at the beta-turn in the substrate-binding domain of the S. pneumoniae CMP kinase when compared with the E. coli homolog. Chemical shift perturbations caused by the binding of CMP, CDP, and ATP revealed that CMP or CDP binds to the junction between the core and substrate-binding domains, whereas ATP binds to the junction between the core and LID domains. From NMR relaxation studies, we determined that the loops in the LID domain are highly mobile. These mobile loops could aid in the closing/opening of the LID domain during enzyme catalysis.


A child with Beckwith-Wiedemann syndrome and posterior urethral valves.
Beckwith-Wiedemann syndrome is a somatic overgrowth syndrome characterized by a variable incidence of congenital anomalies, including hemihypertrophy, omphalocele, macroglossia and renal malformations. We report a child with Beckwith-Wiedemann syndrome and posterior urethral valves. Urethral valve resection was successfully performed under general anesthesia after voiding cystourethrography. This is the first report of Beckwith-Wiedemann syndrome associated with posterior urethral valves.


An improved anti-leukemic effect achieved with donor progenitor cell infusion for relapse patients after allogeneic bone marrow transplantation.
To observe the antileukemic effect in relapse patients by infusion of donor immunocompetent cells with or without granulocyte colony-stimulating factor (G-CSF) mobilization. Twenty patients with leukemia in relapse after allogeneic bone marrow transplantation (allo-BMT) were treated with chemotherapy followed by donor-derived lymphocytes (DDL) without G-CSF mobilization (Group A, n = 11), or donor peripheral blood progenitor cells (PBPCs) with G-CSF mobilization (Group B, n = 9). Five patients in Group A were in hematologic relapse. After DDL infusion, 3 of 5 patients had a temporary complete remission (CR) and relapsed after 3, 7 and 10 months, respectively. One achieved partial remission and died of interstitial pneumonia; and the other one showed no response. Another 6 patients in Group A were in cytogenetic relapse or central nerve system (CNS) leukemia, and all achieved CR and remained in disease free survival (DFS) for 10 to 98 months after DDL infusion. All 9 patients in group B were in hematologic relapse. Three patients with chronic myeloid leukemia (CML) had cytogenetic and molecular remission for 16, 35 and 51 months, respectively after PBPC infusion; and 5 patients with acute lymphoid leukemia (ALL) had CR and were still in CR for 10 to 18 months except 1 patient relapsed soon. And the other one with AML showed no response to the therapy. Donor immunocompetent cells infusion is an effective therapy for relapsed leukemia after allo-BMT, especially for the patients with early (molecular and cytogenetic) or CNS relapse. Infusion of donor PBPC mobilized by G-CSF seems to have more potentiated graft-versus-leukemia (GVL) effect than DDL infusion.


The influence of finite aperture and frequency response of ultrasonic hydrophone probes on the determination of acoustic output.
The influence of finite aperture and frequency response of piezoelectric ultrasonic hydrophone probes on the Thermal and Mechanical Indices was investigated using a comprehensive acoustic wave propagation model. The experimental verification of the model was obtained using a commercially available, 8 MHz, dynamically focused linear array and a single element, 5 MHz, focused rectangular source. The pressure-time waveforms were recorded using piezoelectric polymer hydrophone probes of different active element diameters and bandwidths. The nominal diameters of the probes ranged from 50 to 500 microm and their usable bandwidths varied between 55 and 100 MHz. The Pulse Intensity Integral (PII), used to calculate the Thermal Index (TI), was found to increase with increasing bandwidth and decreasing effective aperture of the probes. The Mechanical Index (MI), another safety indicator, was also affected, but to a lesser extent. The corrections needed were predicted using the model and successfully reduced the discrepancy as large as 30% in the determination of PII. The results of this work indicate that by accounting for hydrophones' finite aperture and correcting the value of PII, all intensities derived from the PII can be corrected for spatial averaging error. The results also point out that a caution should be exercised when comparing acoustic output data. In particular, hydrophone's frequency characteristics of the effective diameter and sensitivity are needed to correctly determine the MI, TI, and the total acoustic output power produced by an imaging transducer.


Analysis of the pseudoautosomal X-linked gene SYBL1in bipolar affective disorder: description of a new candidate allele for psychiatric disorders.
The absence of father-to-son transmission has been observed in a subset of families with bipolar disorder (BPD), suggestive of a susceptibility gene on the sex-linked portion of the X chromosome. This is supported by some genetic linkage studies that have provided evidence for a susceptibility locus near Xq28. We have analyzed one candidate gene on Xq28, SYBL1, which maps to the Xq pseudoautosomal region (PAR). SYBL1 encodes a member of the synaptobrevin family of proteins that is involved in synaptic vesicle docking and membrane transport. Genes in the PAR generally escape X-chromosome inactivation and have an active homolog on the Y chromosome, which would result in an increase in same-sex concordance in paternal transmitted traits. However, SYBL1 is neither expressed on the Y chromosome nor the inactive X chromosome and would therefore be expected to show typical sex-linked transmission. We have screened SYBL1 for mutations that could be tested as candidate alleles in the development of BPD. Following single-strand conformation polymorphism (SSCP) analysis and DNA sequencing, four single nucleotide polymorphisms were detected: a silent mutation at codon 108, two intron mutations without any obvious biological significance, and a G-->C transversion in the polypyrimidine tract at the 3' splice acceptor site preceding exon 8. This polymorphism, which creates a perfect 16/16 stretch of pyrimidines, was analyzed in 110 patients with BPD not selected for sex-linked transmission and 119 control subjects. The results show a statistical trend toward an increase in the frequency of the C allele in males with BPD but not females. Males: chi(2) = 3.46, 1 df, p =.06; Females: chi(2) =.20, 1 df, p =.66.


Typing of Pneumocystis carinii f. sp. hominis by PCR-SSCP to indicate a high frequency of co-infections.
Broncho-alveolar lavage specimens from patients with Pneumocystis carinii pneumonia were investigated by PCR-single strand conformation polymorphism (SSCP) analysis of four genomic regions for P. carinii f. sp. hominis. In all, 32% of specimens produced two bands (one allele) for each of the four genomic regions, suggesting an infection with a single P.c. hominis type. The other specimens displayed more than two bands for at least one of the four genomic regions, suggesting several theoretical possibilities: co-infections, heterozygosity of diploid or polyploid organisms, or multicopy genes. Quantification of the different alleles and analysis of mixtures of specimens showed that different alleles of a genomic region were most often present in different proportions in a given specimen. In contrast, experiments with plasmid insertion of two alleles resulted in the detection of identical proportions of the two alleles. This suggests that neither heterozygosity of diploid organisms nor multicopy genes are responsible for the presence of two alleles. Unequal proportions are most likely explained by the occurrence of co-infections. The putative co-infecting types could be identified in the majority of specimens.


[Diagnosis and treatment of non-parasitic cysts of the spleen in children].
The experience with the treatment of non-parasitic cysts of the spleen in children has shown that although careful assessment of the clinical and case-history data facilitate the correct diagnosis the leading role should be given to laparoscopy fulfilled if necessary in combination with splenoportography or puncture of the splenic cyst. Splenectomy is the operation of choice for cysts of the spleen in children.


The Expanding Role of Mitochondria, Autophagy and Lipophagy in Steroidogenesis.
The fundamental framework of steroidogenesis is similar across steroidogenic cells, especially in initial mitochondrial steps. For instance, the START domain containing protein-mediated cholesterol transport to the mitochondria, and its conversion to pregnenolone by the enzyme P450scc, is conserved across steroidogenic cells. The enzyme P450scc localizes to the inner mitochondrial membrane, which makes the mitochondria essential for steroidogenesis. Despite this commonality, mitochondrial structure, number, and dynamics vary substantially between different steroidogenic cell types, indicating implications beyond pregnenolone biosynthesis. This review aims to focus on the growing roles of mitochondria, autophagy and lipophagy in cholesterol uptake, trafficking and homeostasis in steroidogenic cells and consequently in steroidogenesis. We will focus on these aspects in the context of the physiological need for different steroid hormones and cell-intrinsic inherent features in different steroidogenic cell types beyond mitochondria as a mere site for the beginning of steroidogenesis. The overall goal is to provide an authentic and comprehensive review on the expanding role of steroidogenic cell-intrinsic processes in cholesterol homeostasis and steroidogenesis, and to bring attention to the scientific community working in this field on these promising advancements. Moreover, we will discuss a novel mitochondrial player, prohibitin, and its potential role in steroidogenic mitochondria and cells, and consequently, in steroidogenesis.


Smoking, cessation and expenditure in low income Chinese: cross sectional survey.
This study was carried-out to explore smoking behaviour and smoking expenditure among low income workers in Eastern China to inform tobacco control policy. A self-completion questionnaire was administered to 1958 urban workers, 1909 rural workers and 3248 migrant workers in Zhejiang Province, Eastern China in 2004. Overall 54% of the men and 1.8% of all women were current smokers (at least 1 cigarette per day). Smoking was least common in migrant men (51%), compared with 58% of urban workers and 64% rural inhabitants (P < 0.0001). Forty-nine percent of rural males smoke more than 10 cigarettes/day, and 22% over 20/day. The prevalence of smoking increased with age. Overall 9% of the males had successfully quit smoking. Reasons for quitting were to prevent future illness (58%), current illness (31%), family pressures (20%) and financial considerations (20%). Thirteen percent of current smokers had ever tried to quit (cessation for at least one week) while 22% intended to quit, with migrants most likely to intend to quit. Almost all (96%) were aware that smoking was harmful to health, though only 25% were aware of the dangers of passive smoking. A mean of 11% of personal monthly income is spent on smoking rising to a mean of 15.4% in rural smokers. This expenditure was found to have major opportunity costs, including in terms of healthcare access. The prevalence of smoking and successful quitting suggest that smoking prevalence in low income groups in Eastern China may have peaked. Tobacco control should focus on support for quitters, on workplace/public place smoking restrictions and should develop specific programmes in rural areas. Health education messages should emphasise the opportunity costs of smoking and the dangers of passive smoking.


A PET-study of [11C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug-treated patients.
We recently developed [11C]FLB 457 a substituted benzamide with the very high affinity of 20 pM for D2-dopamine receptors in vitro. The aim of the present exploratory study was to examine the anatomical distribution of [11C]FLB 457 binding in the human brain and to determine extrastriatal D2-receptor occupancy in antipsychotic drug-treated patients. [11C]raclopride was used to obtain reference values for D2-dopamine receptor occupancy in the putamen. After IV injection of [11C]FLB 457 there was a high concentration of radioactivity, not only in the caudate putamen but also in the thalamus and the temporal cortex. The concentration of radioactivity in the frontal cortex, the substantia nigra and the colliculi was slightly higher than in the cerebellum. Pretreatment with haloperidol and fluphenazine indicated that [11C]FLB 457 binding in extrastriatal regions to a high degree represent specific binding to D2-dopamine receptors. The D2-occupancy in antipsychotic drug-treated patients was on the same level in the thalamus and the temporal cortex as that determined with [11C]raclopride in the putamen. The study shows that [11C]FLB 457 has potential for quantitative PET-examination of D2-dopamine receptors in man.


[Radiological aspects of pulmonary lesions due to Mycoplasma pneumoniae. A report of 70 cases (author's transl)].
Radiological appearance in 70 cases of pulmonary affection due to Mycoplasma pneumoniae are described. The most frequently seen radiological images are those in which a focus of bronchopneumonia sometimes associated with areas of atelectasis is observed. Reticulonodular lesions are observed less frequently but pseudomiliary or even pseudotumoral images may be present. Pleurisy was found in 17.1% of the cases, which is contrary to the data of the published literature, but no mediastinal or hilar adenopathy was observed. The authors emphasize the frequent unilateral localization of the lesions in the lower pulmonary zone, but stress that the classical migratory character of the lesions is difficult to evaluate in an affection which often involves multiple lesions.


Medical students' views on selection tools for medical school--a mixed methods study.
It is important to ensure that the tools used in Medical School selection are acceptable to students and applicants. A questionnaire was administered to year 1 medical students in 2010 to determine the suitability of a variety of selection tools and the acceptability of HPAT-Ireland in particular. There were 291 respondents a 77% response rate representing approximately one third of all school leaver entrants that year. While the majority 285 (98%) were in favour of using school leaving examinations there was also support for the use of interviews 215 (74%) and other tools. Three quarters of Irish respondents 159 (76%) agreed that HPAT-Ireland is a fair test overall however section 3 (non-verbal reasoning) appeared less acceptable and relevant than other sections. A little over half had taken a preparatory HPAT-Ireland course 112 (54%). Medical school applicants appear to accept the use of non-traditional tools in the selection process.