Enantio- and Diastereoselective Formal Hetero-Diels-Alder Reactions of Trifluoromethylated Enones Catalyzed by Chiral Primary Amines.
Enantioselective formal hetero-Diels-Alder reactions of trifluoromethylated enones and 2-amino-1,3-butadienes generated in situ from aliphatic acyclic enones and chiral primary amines are reported. The corresponding tetrahydropyran-4-ones are formed in up to 94 % yield and with up to 94 % ee. The reaction was carried out through a stepwise mechanism, including initial aminocatalytic aldol condensation of 2-amino-1,3-butadiene to the trifluoromethylated carbonyl group followed by an intramolecular oxa-Michael addition. Both NMR investigation and theoretical calculations on the transition state indicate that the protonated tertiary amine could effectively activate the carbonyl group of the trifluoromethyl ketone to promote the addition process through hydrogen-bonding interaction of N-H⋅⋅⋅F and N-H⋅⋅⋅O simultaneously, and thus provide a chiral environment for the approach of amino-1,3-butadienes to the activated trifluoromethyl ketone, resulting in high enantioselectivity.


Rapid PCR using nested primers of the 16S rRNA and the hippuricase (hip O) genes to detect Campylobacter jejuni and Campylobacter coli in environmental samples.
Identification of sources Campylobacter infection in the poultry houses is in general problematic due to the lack of reliable methods to detect campylobacteria in environmental samples. Detection of campylobacteria in environmental samples by conventional culture methods is difficult and of limited sensitivity due to the use of selective media, the low number of bacteria in the samples and possibly also due to the presence of non-culturable or sub-lethally injured stages of the bacteria. The present paper describes a rapid PCR assay using nested primers of the 16S rRNA or the hippuricase (hip O) genes to detect Campylobacter jejuni and Campylobacter coli in environmental samples. The sensitivity of the nested PCR was determined to be 0.01 pg/PCR, corresponding to 2-3 colony forming units (cfu) per ml. The nested PCR assays were applied to detect C. jejuni and C. coli in 269 environmental samples collected from ten broiler farms. The sensitivity, specificity and the usefulness of the PCR assay for detection of C. jejuni and C. coli in environmental samples are presented and discussed.


Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1, 4-Bis[2-(3,5-Dichloropyridyloxy)] benzene.
We have previously demonstrated that hepatocyte proliferation induced by the mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) is independent of changes in cytokines, immediate early genes, and transcription factors that are considered to be necessary for regeneration of the liver after partial hepatectomy (PH) or necrosis. To further investigate the differences between mitogen-induced mouse hepatocyte proliferation and liver regeneration after PH, we have measured the expression of cyclin D1, cyclin D3, cyclin E, and cyclin A and of the cyclin-dependent kinases CDK2, CDK4, and CDK6. The involvement of the cyclin-dependent kinase inhibitors p21 and p27 and of the oncosuppressor gene p53 was also examined at different times after stimulation of hepatocyte proliferation. Results showed that a single administration of TCPOBOP caused a very rapid increase in the levels of cyclin D1, a G1 protein, when compared with two thirds PH (8 hours versus 30 hours). The early increase in cyclin D1 protein levels was associated with a faster onset of increased expression of S-phase-associated cyclin A (24 hours versus 36 hours with PH mice). Accordingly, measurement of bromodeoxyuridine (BrdU) incorporation revealed that, although approximately 8% of hepatocytes were BrdU-positive as early as 24 hours after TCPOBOP, no significant changes in BrdU incorporation were observed at the same time point after two thirds PH. The expression of other proteins involved in cell cycle control, such as cyclin-dependent kinases (CDK4, CDK2, CDK6), was also analyzed. Results showed that expression of CDK2 was induced much more rapidly in TCPOBOP-treated mice (2 hours) than in mice subjected to PH (36 hours). A different pattern of expression in the two models of hepatocyte proliferation, although less dramatic, was also observed for CDK4 and CDK6. Expression of the CDK inhibitors p21 and p27 and the oncosuppressor gene p53 variably increased after two thirds PH, whereas basically no change in protein levels was found in TCPOBOP-treated mice. The results demonstrate that profound differences in many cell cycle-regulatory proteins exist between direct hyperplasia and compensatory regeneration. Cyclin D1 induction is one of the earlier events in hepatocyte proliferation induced by the primary mitogen TCPOBOP and suggests that a direct effect of the mitogen on this cyclin may be responsible for the rapid onset of DNA synthesis observed in TCPOBOP-induced hyperplasia.


Measurement of cervical range of motion (CROM) by electronic CROM goniometer: a test of reliability and validity.
To investigate the reliability and validity of the Electronic Cervical Range of Motion (CROM) Goniometer in measurement of cervical spine mobility in adults with and without neck pain. A cross-sectional reliability study was conducted on 54 subjects (26 neck pain and 26 non-neck pain) aged from 20-70 years old. The Numerical Pain Rating Scale and Chinese version of Northwick Park Neck Pain Questionnaire were used to assess neck pain severity and disability respectively. The CROM was measured in sitting position except left to right rotation was measured in supine lying. All the cervical active movements were measured by using the Electronic CROM Goniometer from ARCON TM Functional Capacity Evaluation (FCE) systems. The intra-tester and inter-tester reliability were high in both normal and chronic neck pain groups with ICC coefficients ranged from 0.75-*0.92. There was significant difference in the total CROM between the normal (374.7°) and chronic neck pain group (292.6°). The ACRON cervical goniometer was found to be reliable for measuring cervical mobility in 3 planes for both normal and patient subjects. Construct validity of the goniometer was supported as the test's result documented significant difference in CROM between the control and the neck pain groups.


Outcome of transanal endorectal pull-through in patients with Hirschsprung's disease.
Various outcomes following transanal endorectal pull-through (TERPT) in patients with Hirschsprung's disease (HD) have been reported. In this study, the postoperative course and functional outcome after TERPT in 25 patients with HD is evaluated. Patient records of children who underwent TERPT for HD between 2002 and 2007 were reviewed retrospectively. Age at surgery, sex, associated malformations, length of follow-up, presence of colostomy, indication for laparotomy, length of the aganglionic segment, result of rectal examination under general anaesthesia 6 weeks after surgery, necessity of a dilatation program or reoperation were investigated. In addition, standardised interviews were performed to collect the following data: bowel movement per day, faecal continence in potty-trained children or in patients older than 3 years, incidence of diarrhoea or problems with micturition and the necessity for laxative therapy. Between 2002 and 2007, 25 patients underwent TERPT for HD. Median age at the time of surgery was 3.5 months. Median follow-up was 35 months. Calibration of the anus showed a normal age-related diameter of the anus in 12/20 children and a markedly reduced diameter in 8/20 children at 6 weeks postoperatively. Seven of the latter children underwent a dilatation program. A redo pull-through procedure was performed in 3 patients due to stenosis at the colo-anal anastomosis (n=1), a constricting muscle cuff (n=1) and a twisted pull-through (n=1). Two children developed enterocolitis. The median frequency of bowel movements was 3/day (1-5/day). Laxative treatment was required in only one patient (4.5%). None of the patients had diarrhoea. Nineteen children (86%) were potty-trained, being older than 3 years. Eighteen of them were continent (95%). One patient (5%) with trisomy 21 suffered from intermittent non-retentive faecal incontinence. None of the patients showed signs of neurogenic bladder dysfunction. The functional outcome in most patients after TERPT is satisfactory. We suggest that routine rectal digital examination and anal calibration under anaesthesia 6 weeks postoperatively might detect occult anodermal stenosis and allow early initiation of an anorectal dilatation program, which could decrease the incidence of enterocolitis, persistent constipation and the necessity for further surgical intervention.


Acute respiratory distress syndrome: performance of ventilator at simulated altitude.
Ventilation of Acute Respiratory Distress Syndrome (ARDS) is a challenge, and there is definitely a need for lack of variations between delivered and set tidal volume (Vt). We have assessed the ability of the ventilator T-birdVS02 and LTV-1000 to deliver to a lung model with ARDS a set Vt at different simulated altitudes. We used a decompression chamber to mimic the hypobaric environment at a range of simulated cabin altitudes of 1,500, 2,500, and 3,000 m (4,000, 6,670, and 8,000 feet, respectively). Ventilators were tested with realistic parameters. Vt was set at 400 mL and 250 mL in an ARDS lung model. Comparisons of preset to actual measured values were accomplished using a t test for each altitude. The T-birdVS02 showed a decrease in the volume delivered. Comparisons of actual delivered Vt and set Vt demonstrated a significant difference starting at 1,500 m for a Vt set of 400 mL and at 2,500 m for Vt set of 250 mL. At these altitudes, the variations between Vt set and delivered were more than 10%. With decreasing barometric pressure, the LTV-1000 showed mostly an increase in volume delivered. Comparisons of actual delivered Vt and set Vt demonstrated a significant difference at 2,500 m for a Vt set of 400 mL and at 3,000 m for Vt set of 250 mL. The delivered Vt remained within 10% of the set Vt. Clinicians involved in aerial evacuations must keep in mind the performance and limitations of their ventilator system.


Contrasting of Lowicryl K4M thin sections.
A method is presented for increasing the contrast of cellular structures on ultrathin sections from tissues embedded in Lowicryl K4M. The method, designated UA/MC adsorption staining, is based on the uranyl acetate/methyl cellulose staining of thawed cryosections. Ultrathin Lowicryl K4M sections were exposed to a uranyl acetate/methyl cellulose solution and the excess solution was removed with filter paper, leaving the remainder to air dry on the section. Sections on the grids were then directly observed in the electron microscope. Parameters such as methyl cellulose and uranyl acetate concentrations, duration of staining, temperature and pH were all assessed for their effect on subsequent contrast formation. Conditions were achieved which yielded intense contrast of cellular membranes, basement membranes and extracellular matrix components usually not apparent in Lowicryl K4M thin sections routinely counter-stained with uranyl acetate and lead acetate. The enhancement of the contrast of these structures does not obscure colloidal gold particles used for immunocytochemistry or lectin labeling, thus making the UA/MC adsorption staining method useful for increasing membrane contrast in routine post-embedding immuno- and lectin cytochemistry on Lowicryl K4M thin sections.


Forming transmembrane channels using end-functionalized nanotubes.
Using dissipative particle dynamics (DPD) simulations, we examine the interaction between amphiphilic nanotubes and lipid bilayer membranes. The nanotubes are represented by a hydrophobic shaft that is end-functionalized with hydrophilic groups. Nanotubes that are capped by a monolayer of hydrophilic beads or also encompass hydrophilic "hairs" on just one end of the shaft are found to spontaneously penetrate and assume a transmembrane position; the process, however, depends critically on the membrane tension. On the other hand, nanotubes that include hydrophilic hairs at both ends of the hydrophobic shaft are not observed to spontaneously self-organize into the bilayer. When the membrane is stretched to form a pore, the nanotubes with two hairy ends adsorb on the edge of the pore and become localized in the membrane, thus forming a transmembrane channel. The findings from these studies provide guidelines for creating biomimetic nanotube channels that are capable of selectively transporting molecules through the membrane in response to changes in the local environment.


[Chronotropic insufficiency in patients with ischemic heart disease].
A study is presented of 80 patients with ischemic heart disease (IHD): 37 patients with a low reaction of the cardiac rhythm to physical load--chronotropic insufficiency (CHI) and 43 patients with an adequate reaction of the cardiac rhythm to loads. Physical working capacity was evaluated by the strength of threshold load, pulsepressure double product, rest quotient, oxygen pulse, oxygen consumption per 1 kgm of work. Interval between the 1 and 2 examination--6.5 years. It was shown that CHI in IHD does not influence the prognosis of the disease and does not reflect the grade of its severity. They are, however, the marker of involvement of the atria. Chronic insufficiency in ischemic heart disease makes it difficult to objectively evaluate the physical working capacity.


Quality assurance and standardization: summary of the satellite meeting, Turku, Finland, 11-12 June 1999.
The Quality Assurance (QA) and Standardization satellite meeting addressed five major issues in newborn screening: (i) Pre- and post-analytical phases are important in the overall quality of screening, and quality assurance programs should include these aspects. (ii) It is possible to run a single screening program using laboratories on more than one site, as is done in Europe, California and Cuba. Special quality assurance procedures are necessary for success. (iii) It is possible to achieve improved analytical quality and international comparison of results by use of common reference materials such as the amino acid materials developed in Europe and the US. It will be important to use tested paper with defined performance characteristics. (iv) It is appropriate for newborn screening programs to be accredited, but it will also be important to develop criteria for pre- and post-analytic phases of screening. (v) A new QA program is being developed for Latin America. The Australasian QA program now includes amino acids and acylcarnitines in a form suitable for tandem mass spectrometry blind QA. The European Society for Paediatric Endocrinology has developed guidelines for CAH screening.


Unusual Clinical Manifestations and Outcome of Multisystem Inflammatory Syndrome in Children (MIS-C) in a Tertiary Care Hospital of North India.
Till date, there is paucity of published literature on clinical manifestations of Coronavirus disease 2019 (COVID-19) in children from low-middle-income countries (LMIC). Most of the reports are from Europe, USA or China. Our study aimed to capture data on varied and unusual clinical presentation and management of MIS-C (Multisystem Inflammatory Syndrome in Children) with COVID-19 and compare the MIS-C and non-MIS-C children. This was a single-centre cohort study of 41 COVID positive children 0-12 years age hospitalized between 1 April 2020 and 31 July 2020. Data were entered into standardized WHO Case Report Form and analysed using strata 15.0 statistical software. Twenty out of 41 children fulfilled the criteria of MIS-C. Male-to-female ratio in the cohort was 1.73:1. In MIS-C cases, predominant clinical manifestation was fever (100%), neurological manifestations (80%), lower respiratory tract infection (50%), rash (35%) and acute gastroenteritis (25%). They were categorized into Acute Encephalitis-like illness in 35%, Kawasaki-like disease, Toxic Shock-like syndrome and Comorbidity with systemic complications in 20% each. Ninety percent of MIS-C cases required oxygen supplementation with odds ratio (OR) 18 (3.22-100.48), whereas 65% required mechanical ventilation with OR 37.14 (4.08-338.10). Most of them had raised inflammatory markers and hepatic enzymes derangement. Steroids, Intravenous immunoglobulin and supportive therapy were mainstay of management for MIS-C group. Most MIS-C group children had multisystem involvement with predominant neurological manifestations at time of presentation. Delay in diagnosis and referral may have adversely affected the prognosis and outcome.


Embryonic stem cell development in a chemically defined medium.
Vertebrate germ layer development is an intricately interwoven process with the organism operating as an integrated whole. To examine these processes we have used embryonic stem (ES) cell in vitro differentiation in a serum-free, chemically defined medium (CDM). In CDM, ES cells differentiate as embryoid bodies to neuroectoderm with upregulation of pax-6, without commensurate expression of Brachyury. In the presence of Activin A, pax-6 and Brachyury mRNAs are readily detectable, suggestive of both neuroectoderm and mesoderm formation, while in the presence of BMP-4 a process resembling primitive streak formation at the molecular level occurs. Neuroectoderm development in CDM alone is consistent with the view that this process can occur by default, as reported in Xenopus, due to the absence or sequestration of mesoderm-inducing factors. Additionally, these data show that BMP-4 alone is capable of instigating a process resembling primitive streak formation in ES cells and possibly in vivo.


[Cytogenetic investigations in 817 dysmorphic babies].
By means of G-, C-, and Q-banding techniques 817 dysmorphic children under 1 year of age were cytogenetically investigated. 184 cases of Down's syndrome, 54 cases of various numerical or structural autosomal aberrations, and 29 cases of gonosomal aberration were discovered. The criteria of dysmorphia are the following: intra-, and/or extrauterine retardation, occurrence of minor and/or major malformations, dysfunction of the central nervous system, and the ambiguity of the external genitals, respectively. The proper evaluation of the dysmorphic signs markedly increases the efficiency of the cytogenetical studies. According to the results, the principles applied in 16 patients the background of the dysmorphic features of a pericentric inversion of chromosome No 9 could be disclosed. This phenomenon earlier regarded as polymorphism or normal variant seems to be playing an important role in the etiology of unspecified dysmorphic syndromes. The early detection of a chromosomal aberration ensures the correct judgment of the diagnosis and the prognosis of the patient and by tracking down the carrier family members helps in the prevention, too.


[Intraoperative ERCP for therapy of common bile duct stones during laparoscopic cholecystectomy].
The data of 166 patients that underwent laparoscopic cholecystectomy between November 1989 and December 1997 are given. In all cases intraoperative ERC and extraction of bile duct stones within the laparoscopic surgery were performed. The results show that by intraoperative simultaneous ERC bile duct stones can be removed with a success rate of 98.8% and a mortality rate of 0%. Intraoperative ERC is a secure and economic kind of treatment, especially the patient profits from this minimal invasive procedure.


Integrative development of a short screening questionnaire of highly processed food consumption (sQ-HPF).
Recent lifestyle changes include increased consumption of highly processed foods (HPF), which has been associated with an increased risk of non-communicable diseases (NCDs). However, nutritional information relies on the estimation of HPF consumption from food-frequency questionnaires (FFQ) that are not explicitly developed for this purpose. We aimed to develop a short screening questionnaire of HPF consumption (sQ-HPF) that integrates criteria from the existing food classification systems. Data from 4400 participants (48.1% female and 51.9% male, 64.9 ± 4.9 years) of the Spanish PREDIMED-Plus ("PREvention with MEDiterranean DIet") trial were used for this analysis. Items from the FFQ were classified according to four main food processing-based classification systems (NOVA, IARC, IFIC and UNC). Participants were classified into tertiles of HPF consumption according to each system. Using binomial logistic regression, food groups associated with agreement in the highest tertile for at least two classification systems were chosen as items for the questionnaire. ROC analysis was used to determine cut-off points for the frequency of consumption of each item, from which a score was calculated. Internal consistency of the questionnaire was assessed through exploratory factor analysis (EFA) and Cronbach's analysis, and agreement with the four classifications was assessed with weighted kappa coefficients. Regression analysis identified 14 food groups (items) associated with high HPF consumption for at least two classification systems. EFA showed that items were representative contributors of a single underlying factor, the "HPF dietary pattern" (factor loadings around 0.2). We constructed a questionnaire asking about the frequency of consumption of those items. The threshold frequency of consumption was selected using ROC analysis. Comparison of the four classification systems and the sQ-HPF showed a fair to high agreement. Significant changes in lifestyle characteristics were detected across tertiles of the sQ-HPF score. Longitudinal changes in HPF consumption were also detected by the sQ-HPF, concordantly with existing classification systems. We developed a practical tool to measure HPF consumption, the sQ-HPF. This may be a valuable instrument to study its relationship with NCDs. Retrospectively registered at the International Standard Randomized Controlled Trial Registry ( ISRCTN89898870 ) on July 24, 2014.


Apelin-13 protects against myocardial infarction-induced myocardial fibrosis.
Myocardial infarction is a serious health threat. Apelin is an endogenous ligand of angiotensin II receptor-like 1 (APJ) and the apelin/APJ system is associated with various types of heart disease. However, whether apelin protects against myocardial infarction‑induced myocardial fibrosis remains unclear. The present study aimed to investigate the function of apelin‑13 during myocardial infarction‑induced myocardial fibrosis, and to determine the mechanism underlying the effects of apelin‑13. Apelin‑13 was demonstrated to improve left ventricular function and results of hematoxylin and eosin staining, Masson's trichrome staining and western blotting showed that apelin‑13 attenuated myocardial fibrosis. Further mechanistic investigation was performed by enzyme‑linked immunosorbent assay, western blotting and electrophoretic mobility shift assay. The results demonstrated that apelin‑13 inhibited the activation of nuclear factor (NF)‑κB signaling in vitro and in vivo. To the best of our knowledge, the present study was the first to demonstrate that apelin‑13 may attenuate myocardial infarction‑induced myocardial fibrosis, and that this protective function may be mediated by inhibition of NF‑κB signaling. The present study suggests a theoretical basis for the effects of apelin‑13 and provides insight into the potential clinical application of apelin-13.


[Continuous support during childbirth to reduce cesarean sections: evidence brief for policy].
Cesarean section rates have increased globally in the last 30 years, representing more than 56% of total births in Brazil. Considering the impacts of elective cesarean sections in maternal and child health, this review aimed to present an option to reduce these rates. We used the SUPPORT tools to summarize the best evidence. We included systematic reviews published in English, Portuguese, or Spanish, which focused on non-clinical interventions. Continuous support during labor and birth was described in four systematic reviews as an option to reduce cesarean rates (down to -51%). It also decreased unnecessary clinical interventions during labor, the duration of labor, and the likelihood of delivering a baby with a low Apgar score at five minutes. Moreover, continuous support improved breastfeeding, postpartum recovery of women during the puerperium period, and increased women's satisfaction with the birth experience and the possibility of spontaneous vaginal deliveries. The continuous support was beneficial for women and newborns. The intervention fosters respect, safety, and quality during birth, besides reducing hospital costs. Therefore, it is an effective strategy that should be adopted in hospitals and other health services to improve women's access to their rights.


Current research on immunopathology of melanoma: analysis of lymphocyte populations in relation to antigen expression and histological features of melanoma.
Immunoperoxidase localization of monoclonal antibodies in sections of melanoma has been used to identify histological features which may be of prognostic importance in melanoma, in particular whether certain structures on melanoma cells may determine the degree and nature of lymphoid infiltrates and whether these may be related to prognosis. Monoclonal antibodies to lymphocyte subpopulations were used to identify and quantitate lymphoid infiltrates in 15 primary melanomas and 8 cutaneous metastases. These were correlated with histological features identified in routine sections. There was a wide variation in the numbers of mononuclear cells associated with both primary and metastatic melanoma. T cells and to a lesser extent macrophages accounted for the majority of the cells, B cells and natural killer (NK) cells for only 2% of the infiltrates. The Leu 3a (helper) T cell subpopulation predominated in primary tumours, OKT8 positive (suppressor/cytotoxic) cells in metastases. Infiltrates in which OKT8 cells predominated were associated with ulceration, a high mitotic rate and thick primary tumours. The converse applied to Leu 3a infiltrates. Infiltrates with a high proportion of Leu 3a positive cells tended to be associated with Thy-1 positive, DR antigen negative tumours. Thy-1 antigens were predominantly expressed on primary tumours and rarely on metastases whereas the converse applied to expression of the acute lymphoblastic leukemia antigen (CALLA) on melanoma cells. These findings suggest that certain melanoma antigens may be related to the nature of the lymphoid infiltrate associated with melanoma and possibly with the behaviour of the tumour in the host. They further suggest that identification of cell surface structures and lymphoid infiltrates by these techniques may be a valuable extension of routine histopathological assessment of prognosis in melanoma.


Paradoxical effects of overexpression of the type I insulin-like growth factor (IGF) receptor on the responsiveness of human breast cancer cells to IGFs and estradiol.
Estrogens increase the proliferative response of estrogen-responsive breast cancer cells to insulin-like growth factors (IGFs). The mechanisms involved are unclear, but the observation that estradiol increases type I IGF receptor levels in MCF-7 breast cancer cells has suggested that the increased response may be due to increased expression of type I IGF receptor. The purpose of this study was to investigate this hypothesis by using a retroviral expression vector to constitutively over-express the type I IGF receptor in estrogen-responsive breast cancer cells. We isolated clones of infected MCF-7 cells that expressed up to 4.5-fold more receptor than the estradiol-induced level in cells infected with a control vector. Hybridization of a type I IGF receptor complementary DNA probe to RNA extracted from these clones showed that most of the receptor RNA was transcribed from the retroviral provirus. Estrogen receptor continued to be expressed in clones overexpressing type I IGF receptor, and overexpression had little effect on the induction of an estrogen-regulated gene by estradiol and the proliferative response to IGFs alone or estradiol alone. Overexpression did, however, alter the proliferative response to IGFs in the presence of estradiol. The three clones analyzed showed an increased sensitivity to low IGF-I concentrations and a paradoxical attenuation of the synergistic effect between estradiol and IGF-I at high IGF-I concentrations. Collectively, these experiments show that the level of expression of the type I IGF receptor is an important determinant in the responsiveness of breast cancer cells to estrogen, but the observation that the response of cells to estradiol alone is not affected by constitutive overexpression of the type I IGF receptor suggests that estrogens stimulate the proliferation of breast cancer cells by regulating the expression of genes in addition to the type I IGF receptor.


Widespread and long-lasting alterations in GABA(A)-receptor subtypes after focal cortical infarcts in rats: mediation by NMDA-dependent processes.
Impairment of inhibitory neurotransmission has been reported to occur in widespread, structurally intact brain regions after focal ischemic stroke. These long-lasting alterations contribute to the functional deficit and influence long-term recovery. Inhibitory neurotransmission is primarily mediated by gamma-aminobutyric acid (GABA)A receptors assembled of five subunits that allow a variety of adaptive changes. In this study, the regional distribution of five major GABA(A)-receptor subunits (alpha1, alpha2, alpha3, alpha5, and gamma2) was analyzed immunohistochemically 1, 7, and 30 days after photochemically induced cortical infarcts. When compared with sham-operated controls, a general and regionally differential reduction in immunostaining was found within the cortex, hippocampus, and thalamus of both hemispheres for almost all subunits. Within ipsilateral and contralateral neocortical areas, a specific pattern of changes with a differential decrease of subunits alpha1, alpha2, alpha5, and gamma2 and a significant upregulation of subunit alpha3 was observed in the contralateral cortex homotopic to the infarct. This dysregulation was most prominent at day 7 and still present at day 30. Interestingly, a single application of the noncompetitive N-methyl-D-aspartate-receptor antagonist MK-801 during lesion induction completely blocked these bihemispheric alterations. Cortical spreading depressions induced by topical application of KCl do not change GABA(A)-receptor subunit expression. As alterations in subtype distribution crucially influence inhibitory function, ischemia-induced modifications in GABA(A)-receptor subtype expression may be of relevance for functional recovery after stroke.


Lasers in refractive surgery: history, present, and future.
The history of laser refractive surgery is reviewed, followed by an overview of the current state of the field as well as a look at promising future developments.


Long-term metabolic evolution of brain metastases with suspected radiation necrosis following stereotactic radiosurgery: longitudinal assessment by F-DOPA PET.
The evolution of radiation necrosis (RN) varies depending on the combination of radionecrotic tissue and active tumor cells. In this study, we characterized the long-term metabolic evolution of RN by sequential PET/CT imaging with 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (F-DOPA) in patients with brain metastases following stereotactic radiosurgery (SRS). Thirty consecutive patients with 34 suspected radionecrotic brain metastases following SRS repeated F-DOPA PET/CT every 6 months or yearly in addition to standard MRI monitoring. Diagnoses of local progression (LP) or RN were confirmed histologically or by clinical follow-up. Semi-quantitative parameters of F-DOPA uptake were extracted at different time points, and their diagnostic performances were compared with those of corresponding contrast-enhanced MRI. Ninety-nine F-DOPA PET scans were acquired over a median period of 18 (range: 12-66) months. Median follow-up from the baseline F-DOPA PET/CT was 48 (range 21-95) months. Overall, 24 (70.6%) and 10 (29.4%) lesions were classified as RN and LP, respectively. LP occurred after a median of 18 (range: 12-30) months from baseline PET. F-DOPA tumor-to-brain ratio (TBR) and relative standardized uptake value (rSUV) increased significantly over time in LP lesions, while remaining stable in RN lesions. The parameter showing the best diagnostic performance was rSUV (accuracy = 94.1% for the optimal threshold of 1.92). In contrast, variations of the longest tumor dimension measured on contrast-enhancing MRI did not distinguish between RN and LP. F-DOPA PET has a high diagnostic accuracy for assessing the long-term evolution of brain metastases following SRS.


The effect of resilience and self-efficacy on nurses' compassion fatigue: A cross-sectional study.
To measure the prevalence of compassion fatigue among Chinese clinical nurses and to examine the effects of resilience and self-efficacy on compassion fatigue. A cross-sectional descriptive survey was conducted in accordance with the STROBE guidelines. Participants were recruited from three tertiary hospitals in central China from October 3 to December 15, 2019, using convenience sampling. Clinical nurses (n = 992) from different nursing departments completed the General Information Questionnaire, Professional Quality of Life Scale, Connor-Davidson Resilience Scale, and General Perceived Self-Efficacy Scale. Descriptive statistics, t-tests, one-way analysis of variance, Pearson or Spearman's correlation analyses, and multiple linear regression models were used. Nurses experienced moderate levels of compassion fatigue (burnout and secondary traumatic stress). Resilience and self-efficacy were significantly negatively correlated with burnout but not with secondary traumatic stress. Linear regression analysis showed that resilience, self-efficacy, exercise, and physical conditions were the main predictors of burnout. Only physical conditions and marital status significantly predicted secondary traumatic stress. Nurses are vulnerable to compassion fatigue in China. Resilience and self-efficacy significantly negatively predicted nurses' compassion fatigue. Physical conditions, healthy lifestyles, and social support are also important factors for compassion fatigue. Our findings can be used to generate targeted intervention and coping strategies for nurses to improve their resilience and self-efficacy to alleviate compassion fatigue.


SPIRIT trial: A phase III pragmatic trial of an advance care planning intervention in ESRD.
Advance care planning (ACP) is a central tenet of dialysis care, but the vast majority of dialysis patients report never engaging in ACP discussions with their care providers. Over the last decade, we have developed and iteratively tested SPIRIT (Sharing Patient's Illness Representation to Increase Trust), a theory-based, patient- and family-centered advance care planning intervention. SPIRIT is a six-step, two-session, face-to-face intervention to promote cognitive and emotional preparation for end-of-life decision making for patients with ESRD and their surrogates. In these explanatory trials, SPIRIT was delivered by trained research nurses. Findings consistently revealed that patients and surrogates in SPIRIT showed significant improvement in preparedness for end-of-life decision making, and surrogates in SPIRIT reported significantly improved post-bereavement psychological outcomes after the patient's death compared to a no treatment comparison condition. As a critical next step, we are conducting an effectiveness-implementation study. This study is a multicenter, clinic-level cluster randomized pragmatic trial to evaluate the effectiveness of SPIRIT delivered by dialysis care providers as part of routine care in free-standing outpatient dialysis clinics, compared to usual care plus delayed SPIRIT implementation. Simultaneously, we will evaluate the implementation of SPIRIT, including sustainability. We will recruit 400 dyads of patients at high risk of death in the next year and their surrogates from 30 dialysis clinics in four states. This trial of SPIRIT will generate novel, meaningful insights about improving ACP in dialysis care. ClinicalTrials.govNCT03138564, registered 05/01/2017.


Conserved Roles of CrRLK1L Receptor-Like Kinases in Cell Expansion and Reproduction from Algae to Angiosperms.
Receptor-like kinases (RLKs) are regulators of plant development through allowing cells to sense their extracellular environment. They facilitate detection of local endogenous signals, in addition to external biotic and abiotic stimuli. The Catharanthus roseus RLK1-like (CrRLK1L) protein kinase subfamily, which contains FERONIA, plays a central role in regulating fertilization and in cell expansion mechanisms such as cell elongation and tip growth, as well as having indirect links to plant-pathogen interactions. Several components of CrRLK1L signaling pathways have been identified, including an extracellular ligand, coreceptors, and downstream signaling elements. The presence and abundance of the CrRLK1L proteins in the plant kingdom suggest an origin within the Streptophyta lineage, with a notable increase in prevalence in the seeded land plants. Given the function of the sole CrRLK1L protein in a charophycean alga, the possibility of a conserved role in detection and/or regulation of cell wall integrity throughout the Strephtophytes is discussed. Orthologs of signaling pathway components are also present in extant representatives of non-vascular land plants and early vascular land plants including the liverwort Marchantia polymorpha, the moss Physcomitrella patens and the lycophyte Selaginella moellendorffii. Deciphering the roles in development of the CrRLK1L protein kinases in early diverging land plants will provide insights into their ancestral function, furthering our understanding of this diversified subfamily of receptors in higher plants.


Structure based prediction of binding affinity of human immunodeficiency virus-1 protease inhibitors.
A series of computations were performed to derive a strategy for the prediction of binding affinities of non-peptidic human immunodeficiency virus-1 (HIV-1) protease inhibitors. This paper describes the development of a 3D quantitative structure-activity relationship (3D-QSAR) methodology by using receptor information of HIV-1 protease. The docking and molecular dynamics simulations were performed on a model ligand/enzyme complex to optimize the variables involved in the generation of ligand/enzyme models. The protonation scheme of the active site aspartic acid residues of HIV-1 protease was derived from a computational study. The active site aspartate is monoprotonated with a proton placed on the OD1 atom of the ASP B25. This protocol of docking and molecular dynamics (MD) simulation was then used to derive the ligand-enzyme complexes of the molecules used in the present study. The molecular mechanics interaction descriptors were calculated from these ligand/enzyme models. A partial least squares (PLS) method was used to derive a linear correlation between the interaction descriptors and the biological activity. A good correlation was observed when the change in the energy of the ligand upon complex formation and the electrostatic contributions to the solvation energy of the ligand were included in the QSAR analysis. A highest cross-validated q2 value of 0.649 was observed. This model had a conventional r2 of 0.725, and when this model was used to predict the activity of the external test set, it produced a r2pred of 0.761. The total interaction energy was partitioned into interactions in different subsites and interactions with each of the amino acid residues of the enzyme. The PLS analysis using these descriptors helped to identify the important interactions which can be exploited for the design of HIV-1 protease inhibitors.


Mechanism of ganciclovir uptake by rabbit retina and human retinal pigmented epithelium cell line ARPE-19.
The objective of this study was to elucidate the mechanism of ganciclovir uptake by the rabbit retina and the human retinal pigmented epithelium cell line ARPE-19. [(3)H]Adenine, [(3)H]adenosine, [(3)H]thymidine, and [(3)H]ganciclovir were used to elucidate the mechanism of ganciclovir uptake by the ARPE-19 cell line and the isolated rabbit retinal tissue. Uptake studies using ARPE-19 cell line and isolated rabbit retina were carried out at 37 degrees C and 25 degrees C, respectively, for 5 min. Uptake of [(3)H]adenine by ARPE-19 cells decreased by 95% in the presence of unlabeled adenine. Other nucleobases such as guanine, thymine, and uracil and the nucleosides adenosine, guanosine, thymidine, uridine, and inosine also reduced uptake of [(3)H]adenine by the ARPE-19 cells. Although [(3)H]adenosine and [(3)H]thymidine uptake was inhibited by nucleosides, nucleobases did not demonstrate any inhibitory effect, indicating that nucleosides can only bind to the nucleobase transporter but are not translocated by it. Uptake of the nucleosides and nucleobases by the ARPE-19 cells was sodium and pH independent. [(3)H]adenosine and [(3)H]thymidine uptake by the ARPE-19 cells was inhibited by nanomolar quantities of nitrobenzylthioinosine. Uptake of [(3)H]adenine by the isolated rabbit retina was drastically reduced in the presence of unlabeled adenine. Unlabeled thymidine and guanosine, and removal of sodium from the uptake medium, inhibited uptake of [(3)H]thymidine by the rabbit retina. Nucleosides, nucleobases, and unlabeled ganciclovir did not exhibit any inhibitory effect on [(3)H]ganciclovir uptake by the isolated rabbit retina or ARPE-19 cells. Our results indicate that although the rabbit retina and the ARPE-19 cell line express nucleoside and nucleobase transporters, translocation of ganciclovir does not involve any carrier-mediated transport process. Rather, ganciclovir uptake by the rabbit retina and ARPE-19 cells is governed primarily by passive diffusion.


[Rhubarb decoction prevents intestinal bacterial translocation during necrotic pancreatitis].
This is a study on the efficacy and mechanism of rhubarb therapy for necrotizing pancreatitis in rats induce by intraductal infusion of 2% deoxycholate 0.4 ml/kg. The rats with such pancreatitis were orally fed with 10% rhubarb decoction 1.5 ml (treatment group n = 8) or normal saline 1.5 ml (control group n = 9) per 8 hours. Sham operated rats (sham group n = 8) were given intraductal infusion of normal saline 0.4 ml/kg. 48 hours after infusion, the rats were killed for studies of intestinal motility, serum endotoxin and amylase levels as well as bacterial cultures in messentary lymph nodes (MLN) and pancreas tissues. 5 rats died in the control group (5/9) and 1 died in the treatment group (1/8). Remarkable inhibition of gut motility was observed in control group, but gut motility was significantly improved by administration of rhubarb in treatment group. No rat died in the sham group and the rate therein were all free from endotoxemia or positive cultures. Endotoxin level of control group is much higher (61.36 +/- 28.30 pg/L) than that of treatment group (5.41 +/- 3.58 pg/L), (P < 0.001). Positive cultures were noted in most of MLN (4/4) and pancreas (4/4) in control group, but only 1 in MLN and 1 in pancreas were noted in treatment group. It is concluded that in the treatment of necrotic pancreatitis in rats rhubarb decoction is effective for promoting gut motility and preventing intestinal bacterial translocation.


Direction pathway analysis of large-scale proteomics data reveals novel features of the insulin action pathway.
With the advancement of high-throughput techniques, large-scale profiling of biological systems with multiple experimental perturbations is becoming more prevalent. Pathway analysis incorporates prior biological knowledge to analyze genes/proteins in groups in a biological context. However, the hypotheses under investigation are often confined to a 1D space (i.e. up, down, either or mixed regulation). Here, we develop direction pathway analysis (DPA), which can be applied to test hypothesis in a high-dimensional space for identifying pathways that display distinct responses across multiple perturbations. Our DPA approach allows for the identification of pathways that display distinct responses across multiple perturbations. To demonstrate the utility and effectiveness, we evaluated DPA under various simulated scenarios and applied it to study insulin action in adipocytes. A major action of insulin in adipocytes is to regulate the movement of proteins from the interior to the cell surface membrane. Quantitative mass spectrometry-based proteomics was used to study this process on a large-scale. The combined dataset comprises four separate treatments. By applying DPA, we identified that several insulin responsive pathways in the plasma membrane trafficking are only partially dependent on the insulin-regulated kinase Akt. We subsequently validated our findings through targeted analysis of key proteins from these pathways using immunoblotting and live cell microscopy. Our results demonstrate that DPA can be applied to dissect pathway networks testing diverse hypotheses and integrating multiple experimental perturbations. The R package 'directPA' is distributed from CRAN under GNU General Public License (GPL)-3 and can be downloaded from: http://cran.r-project.org/web/packages/directPA/index.html email@example.com Supplementary data are available at Bioinformatics online.


Studies on rat liver nuclear DNA damaged by chemical carcinogen (3'-Me DAB) and AP DNA endonuclease. II. Kinetic properties of AP DNA endonucleases in rat liver chromatin.
An experiment was designed to investigate the reaction mechanism of AP (apurinic or apyrimidinic) DNA endonucleases (APcI, APcII, APcIII) purified from rat liver chromatin. Sulfhydryl compounds (2-mercaptoethanol, dithiothreitol) brought about optimal activities of AP DNA endonucleases and N-ethylmaleimide or HgCl2 inhibited the enzyme activities, indicating the presence of sulfhydryl group at or near the active sites of the enzymes. Mg2+ was essential and 4mM of Mg2+ was sufficient for the optimal activities of AP DNA endonucleases. Km values of APcI, APcII and APcIII for the substrate (E. coli chromosomal AP DNA) were 0.53, 0.27 and 0.36 microM AP sites, respectively. AMP was the most potent inhibitor among adenine nucleotides tested and the inhibition was uncompetitive with respective to the substrate. The Ki values of APcI, APcII and APcIII were 0.35, 0.54 and 0.41mM, respectively. The degree of nick translation of AP DNAs nicked by APcI, APcII and APcIII with Klenow fragment in the presence and absence of T4 polynucleotide kinase or alkaline phosphatase were the same, suggesting that all 3 AP DNA endonucleases excise the phosphodiester bond of AP DNA strand to release 3-hydroxyl nucleotides and 5-phosphomonoester nucleotides.


Variant Angina is Associated with Myocarditis.
Vasospastic angina (VSA) is caused by severe diffuse or segmental coronary artery spasms. Patients with variant angina have poor clinical outcomes, although nitrates and calcium blockers help improve patient symptoms because there is no understanding of the etiology and causal treatment. The present study investigated whether VSA is associated with inflammation of the heart. A total of 109 patients with VSA diagnosed by the presence of recurrent angina pectoris, typical electrocardiography, and coronary angiography were recruited, and 61 normal participants and 61 patients with acute myocardial infarction (AMI) and coronary artery stenosis were recruited as controls. The plasma levels of 24 cytokines were measured using a magnetic Luminex assay, and endothelin-1 and histamine levels tested using enzyme-linked immunosorbent assay and mass-spectrometry, respectively, for all participants. Furthermore, four patients with VSA underwent 18-fluorine fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). The plasma levels of interleukin (IL)-12p70, IL-13, PDL-1, IL-10, IL-6, IL-15, macrophage inflammatory protein (MIP)-1α, and MIP-1β in patients with VSA were significantly higher than those in both normal controls and patients with AMI (p<0.001) but did not differ between normal controls and patients with AMI. 18F-FDG PET/CT showed that the left ventricle, coronary perivascular tissue volume, and coronary perivascular FDG uptake were significantly increased in all four patients. Our findings demonstrate that VSA patients have significantly elevated plasma cytokine levels and myocardial and pericoronary inflammation, suggesting that VSA is associated with myocarditis. This study provides novel insights into the etiology and treatment of VSA.


Geographical variation in residence and risk of multiple nonmelanoma skin cancers in US women and men.
Residence in high ultraviolet (UV) locations is associated with increased risk for incident nonmelanoma skin cancer (NMSC). However, the effect of geographic location on multiple NMSC development has not been well studied. We evaluated the association between state of residence at birth, age 15 and 30 and risk of multiple NMSCs among 80275 women and men. After adjusting for age, gender, hair color, number of sunburns, tanning ability, family history of melanoma and nevus count, the cumulative relative risks (RRs) of developing ≥1 NMSC for those consistently residing in medium- and high-UV index states were 1.20 (95% CI 1.14-1.27) and 1.42 (95% CI 1.32-1.53) respectively. We found that compared to individuals with one lifetime NMSC, the multivariate cumulative RRs of developing ≥2 NMSCs for those who stayed in medium- and high-UV index states at all three timepoints were 1.09 (95% CI 1.00-1.19) and 1.15 (95% CI 1.02-1.30) respectively. These results cannot account for migration during the interval period and seasonal changes in residence; further, as BCC is the predominant NMSC, the results may be BCC-driven. In conclusion, we found that consistent residence in medium- or high-UVR locations was significantly associated an incremental risk of ≥2 NMSCs later in life.


Early Brain Injury or Vasospasm? An Overview of Common Mechanisms.
Subarachnoid hemorrhage (SAH) following rupture of an intracranial is associated with high mortality and morbidity. The late deterioration of the patient's neurological status or late cognitive dysfunctions even after secure clipping or decent endovascular treatment which is defined as delayed ischemic neurological deficits recently has been attributed to vasospasm. Due to the failure of specific anti- vasospastic agents in clinical trials researchers focused to explore new pathological mechanisms to be responsible for the delayed deterioration of the patients suffering from SAH. Early brain injury (EBI), as a new term in the SAH research area has been the focus of scientist for the past couple of years. The goal of this study is to review the common mechanisms of early brain injury and vasospasm. The acute events following SAH, such as increased intracranial pressure and decreased cerebral blood flow, causing global cerebral ischemia initiate a cascade of pathological changes including inflammation, lipid peroxidation, cell death and blood brain barrier disruption. The more insight we gain into the EBI we realize that there are a bunch of common mechanisms between EBI and vasospasm. In the SAH management, a therapy targeting these early injuries may also reduce the later developing pathological neurological complications.


Word initial fricative production in children with cochlear implants and their normally hearing peers matched on lexicon size.
Fricative production is affected in children with cochlear implants (CI) as compared to age-matched normally hearing (NH) children. However, the phonological development of children with CI is rarely compared to that of NH peers matched on lexicon size. We compare the early word initial fricative development of 10 children with CI and 30 NH children matched on lexicon size and on chronological age. Children with CI are expected to differ from their NH peers when they are matched on chronological age. But, are lexical development and phonological development commensurate in children with CI as they have been shown to be in NH children? Results show that fricative production in children with CI deviates from that of age-matched NH peers. The differences between both groups disappear when they were matched on lexicon size. Thus, phonological development in children with CI is similar to that of their NH peers with comparable lexicon sizes.


Time series migration in Britain: the context for 1991 census analysis.
"An administrative register, the National Health Service Central Register (NHSCR), is used by the Census Office (OPCS) to produce counts of NHS patients re-registering in different Family Health Service Authorities (FHSAs) in England and Wales. These movement data can be used to establish how unique or typical the migration occurring in the year prior to the Census was in relation to that for the whole decade. This paper examines national, regional and local examples of the information that can be extracted from a database system called TIMMIG that provides access to an NHSCR migration time series and a parallel series of mid-year population estimates. In advance of the publication of Special Migration Statistics, a preliminary comparison is made between the levels of in-migration to FHSA areas recorded in the NHSCR and in the 1991 Census."


Human methamphetamine pharmacokinetics simulated in the rat: behavioral and neurochemical effects of a 72-h binge.
Bingeing is one pattern of high-dose methamphetamine (METH) abuse, which involves continuous drug taking over several days and can result in psychotic behaviors for which the brain pathology remains poorly defined. A corresponding animal model of this type of METH exposure may provide novel insights into the neurochemical and behavioral sequelae associated with this condition. Accordingly, to simulate the pharmacokinetic profile of a human METH binge exposure in rats, we used a computer-controlled, intravenous METH procedure (dynamic infusion, DI) to overcome species differences in METH pharmacokinetics and to replicate the human 12-h plasma METH half-life. Animals were treated over 13 weeks with escalating METH doses, using DI, and then exposed to a binge in which drug was administered every 3 h for 72 h. Throughout the binge, behavioral effects included unabated intense oral stereotypies in the absence of locomotion and in the absence of sleep. Decrements in regional brain dopamine, norepinephrine, and serotonin levels, measured at 1 and 10 h after the last injection of the binge, had, with the exception of caudate-putamen dopamine and frontal cortex serotonin, recovered by 48 h. At 10 h after the last injection of the binge, [(3)H]ligand binding to dopamine and vesicular monoamine transporters in caudate-putamen were reduced by 35 and 13%, respectively. In a separate METH binge-treated cohort, post-binge behavioral alterations were apparent in an attenuated locomotor response to a METH challenge infusion at 24 h after the last injection of the binge. Collectively, the changes we characterized during and after a METH binge suggest that for human beings under similar exposure conditions, multiple time-dependent neurochemical deficits contribute to their behavioral profiles.


Balancing Our Perceptions of the Efficacy of Success-Based Feedback Manipulations on Motor Learning.
We report two experiments evaluating the impact of success-related feedback on learning of a balance task. In Exp. 1, we studied the influence of lax and conservative outcome feedback, as well as large vs. small improvements in outcome feedback on balance learning. Despite impacts on competency, there were no between-group differences in actual performance or learning. Because no comparative information was provided in Exp. 1, we tested four further groups that either did or did not receive positive or negative comparative feedback (Exp. 2). Although the manipulations influenced competency and arousal, again, there was no impact on balance outcomes. These data cast doubt on the assertions made in the OPTIMAL theory that perceptions of success are moderators of motor learning.


[A case of pancreatic mucinous carcinoma which includes calcification].
A 60-year-old woman was pointed out a tumor, 2.6 cm in diameter, at the pancreas body, by screening ultrasonography examination. Jaundice and anemia were absent and no abdominal mass was palpable on physical examination. Enhanced CT revealed the tumor directly invaded to splenic vein, but lymph node metastases were not detected. ERCP showed a pancreatic duct was obstructed by the tumor, accompanied with dilatation of the peripheral pancreas duct. Because we cannot rule out the malignancy tumor, pancreatoduodenectomy and lymphadenectomy was done. The tumor was very hard and serosal invasion was suspicious in the operative findings. Histopathological study showed that the tumor was occupied with colloid differentiation, in which free mucinous epithelial malignant cells were floating. Then we diagnosed the tumor to be pancreatic mucinous carcinoma. Extra pancreatic extension such as vascular involvement was not proved microscopically. However, ten months after the resection, CT scan showed a recurrent tumor sized 4 cm diameter, at the middle abdominal cavity, which suspected to be disseminated diseases. Mucinous carcinoma occurs relatively rare in pancreas, of which the incidence is 1 .4% in pancreatic adenocarcinomas. We report herein the pancreatic mucinous carcinoma case with a calcificated region, which resulted in early recurrence with abdominal seeding.


The unorthodox SNAP50 zinc finger domain contributes to cooperative promoter recognition by human SNAPC.
Human small nuclear RNA gene transcription by RNA polymerases II and III depends upon promoter recognition by the SNAPC general transcription factor. DNA binding by SNAPC involves direct DNA contacts by the SNAP190 subunit in cooperation with SNAP50 and SNAP43. The data presented herein shows that SNAP50 plays an important role in DNA binding by SNAPC through its zinc finger domain. The SNAP50 zinc finger domain contains 15 cysteine and histidine residues configured in two potential zinc coordination arrangements. Individual alanine substitution of each cysteine and histidine residue demonstrated that eight sites are important for DNA binding by SNAPC. However, metal binding studies revealed that SNAPC contains a single zinc atom indicating that only one coordination site functions as a zinc finger. Of the eight residues critical for DNA binding, four cysteine residues were also essential for both U1 and U6 transcription by RNA polymerase II and III, respectively. Surprisingly, the remaining four residues, although critical for U1 transcription could support partial U6 transcription. DNA binding studies showed that defects in DNA binding by SNAPC alone could be suppressed through cooperative DNA binding with another member of the RNA polymerase III general transcription machinery, TFIIIB. These results suggest that these eight cysteine and histidine residues perform different functions during DNA binding with those residues involved in zinc coordination likely performing a dominant role in domain stabilization and the others involved in DNA binding. These data further define the unorthodox SNAP50 zinc finger region as an evolutionarily conserved DNA binding domain.


Ancient phylogenetic divergence of the enigmatic African rodent Zenkerella and the origin of anomalurid gliding.
The "scaly-tailed squirrels" of the rodent family Anomaluridae have a long evolutionary history in Africa, and are now represented by two gliding genera (Anomalurus and Idiurus) and a rare and obscure genus (Zenkerella) that has never been observed alive by mammalogists. Zenkerella shows no anatomical adaptations for gliding, but has traditionally been grouped with the glider Idiurus on the basis of craniodental similarities, implying that either the Zenkerella lineage lost its gliding adaptations, or that Anomalurus and Idiurus evolved theirs independently. Here we present the first nuclear and mitochondrial DNA sequences of Zenkerella, based on recently recovered whole-body specimens from Bioko Island (Equatorial Guinea), which show unambiguously that Zenkerella is the sister taxon of Anomalurus and Idiurus. These data indicate that gliding likely evolved only once within Anomaluridae, and that there were no subsequent evolutionary reversals. We combine this new molecular evidence with morphological data from living and extinct anomaluromorph rodents and estimate that the lineage leading to Zenkerella has been evolving independently in Africa since the early Eocene, approximately 49 million years ago. Recently discovered fossils further attest to the antiquity of the lineage leading to Zenkerella, which can now be recognized as a classic example of a "living fossil," about which we know remarkably little. The osteological markers of gliding are estimated to have evolved along the stem lineage of the Anomalurus-Idiurus clade by the early Oligocene, potentially indicating that this adaptation evolved in response to climatic perturbations at the Eocene-Oligocene boundary (∼34 million years ago).


Middle hepatic vein reconstruction in adult living donor liver transplantation: a randomized clinical trial.
In adult right lobe living donor liver transplantation (LDLT), venous drainage of the anterior sector is usually reconstructed on the bench to form a neo-middle hepatic vein (MHV). Reconstruction of the MHV for drainage of the anterior sector is crucial for optimal graft function. The conduits used for reconstruction include cryopreserved allografts, synthetic grafts, or the recipient portal vein. However, the ideal choice remains a matter of debate. This study compares the efficacy of the native recipient portal vein (RPV) with PTFE grafts for reconstruction of the neo-MHV. Patients in this equivalence-controlled, parallel-group trial were randomized to either RPV (62 patients) or PTFE (60 patients) for use in the reconstruction of the neo-MHV. Primary endpoint was neo-MHV patency at 14 days and 90 days. Secondary outcomes included 90-day mortality and post-transplant parameters as scored by predefined scoring systems. There was no statistically significant difference in the incidence of neo-MHV thrombosis at 14 days (RPV 6.5 per cent versus PTFE 10 per cent; P = 0.701) and 90 days (RPV 14.5 per cent versus PTFE 18.3 per cent; P = 0.745) between the two groups. Irrespective of the type of graft used for reconstruction, 90-day all-cause and sepsis-specific mortality was significantly higher among patients who developed neo-MHV thrombosis. Neo-MHV thrombosis and sepsis were identified as risk factors for mortality on Cox proportional hazards analysis. No harms or unintended side effects were observed in either group. In adult LDLT using modified right lobe graft, use of either PTFE or RPV for neo-MHV reconstruction resulted in similar early patency rates. Irrespective of the type of conduit used for reconstruction, neo-MHV thrombosis is a significant risk factor for mortality. CTRI/2018/11/016315 (www.ctri.nic.in).


Depletion of PCAT-1 in head and neck cancer cells inhibits tumor growth and induces apoptosis by modulating c-Myc-AKT1-p38 MAPK signalling pathways.
Head and neck squamous cell carcinoma (HNSCC) represents one of the most common malignancies worldwide with a high mortality rate mainly due to lack of early detection markers, frequent association with metastasis and aggressive phenotype. Recently, long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancers. The lncRNA prostate cancer-associated transcript 1 (PCAT-1) showed potential oncogenic roles in different cancers, however its role in HNSCC is not known. In this study, we evaluated the role of the PCAT-1 in HNSCC. The expression of PCAT-1 was measured by quantitative real-time PCR in 23 paired human HNSCC tissues and adjacent non-tumor tissue specimens. Cell proliferation after depleting PCAT-1 was determined. Effect of PCAT-1 depletion in HNSCC cell lines was determined by qRT-PCR and Western blot analyses. Finally, JHU029 HNSCC cells was implanted subcutaneously into athymic nude mice and therapeutic potential of PCAT-1 was investigated. Up-regulation of PCAT-1 in TCGA dataset of HNSCC was noted. We also observed increased expression of PCAT-1 in archived HNSCC patient samples as compared to adjacent non-tumor tissues. Knockdown of PCAT-1 significantly reduced cell proliferation in HNSCC cell lines. Mechanistic study revealed significant down regulation of c-Myc and AKT1 gene in both RNA and protein levels upon knockdown of PCAT-1. We observed that c-Myc and AKT1 positively correlate with PCAT-1 expression in HNSCC. Further, we observed activation of p38 MAPK and apoptosis signal-regulating kinase 1 upon knockdown of PCAT-1 which induces Caspase 9 and PARP mediated apoptosis. Targeted inhibition of PCAT-1 regresses tumor growth in nude mice. Together our data demonstrated an important role of the PCAT-1 in HNSCC and might serve as a target for HNSCC therapy.


[Genetic abnormality in 101 cases of plasma cell dyscrasias by FISH technology and cytogenetic examination].
To investigate several abnormal genes by the fluorescence in situ hybridization (FISH) in multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS) and reactive plasmacytosis (RP), and to increase the diagnosis and differential diagnosis levels for these common plasma diseases. The clinical manifestations, image and laboratory tests and the FISH detection were retrospectively analyzed in 61 cases of newly diagnosed MM, 20 cases of MGUS and 20 cases of RP from August, 2012 to February, 2015 in the Xiangya Hospital of Central South University. Fifty cases among 61 MM patients showed genetic abnormality by FISH technology. The total positive rate was 81.9%. Among them, 19 cases (31.1%) had 1q21 amplification, 18 cases (29.5%) lacked D13S319, 10 cases (16.4%) missed RB1, 10 cases (16.4%) had IGH translocation and 7 cases (11.4%) lacked p53 gene. The positive rate for two or more genes abnormal was 19.8% in 12 cases. However, in 20 cases of MGUS patients, the positive detection rate was 25%, including 4 cases (20%) of 1q21 augmentation and 2 cases (10%) of IGH translocation. There were not two or more abnormal genes in one case. While in RP cases, only 1 case of patients had D13S319 abnormal gene, and the positive rate was only 5%. There was significant difference (P<0.05) among the 3 groups. The positive detection rate is 81.9% in MM patients by FISH, which is significantly higher than that in patients with MGUS or RP. FISH technology can detect a variety of abnormal genes in MM. It is useful for the differential diagnosis and prognosis for MM, MGUS and RP.


Study on the Influence of Government Intervention on the Occupational Health and Safety (OHS) Services of Small- and Medium-Sized Enterprises (SMEs).
The OHS services of SMEs are still in their start-up stage in China. As such, there is an absence of mature market norms, which in turn makes it difficult to guarantee the quality of OHS services. The government, as the "night watchman" of the market, is supposed to not only involve itself in the regulation of OHS service quality, but also introduce and implement proper regulatory strategies. This paper employs a computational experiment approach to construct an experimental platform based on multiagent interactions. By simulating the OHS service transaction activities of SMEs, this paper takes the perspective of dynamic evolution. From this perspective, we probe into the optimal regulatory strategy covering the positive influence of government punishment, policy supports, and service quality ratings of the OHS services of SMEs. These strategies should be built on the foundation of proper punishment standard and intensity, proper support standard and intensity, and quality rating information disclosure.


Psychiatric emergency rates during the Christmas season in the years 1991 to 1997.
We compared the number of psychiatric admissions from the emergency room during the Christmas season, defined as the rate for the month of December, with those in other months. The psychiatric emergency rates were recorded for each month over six consecutive years, 1991 to 1997. The average number of emergency patients in none of the 12 months differed significantly from any of the remaining months (ANOVA, p > .05). Our data and those of other authors do not support the clinical lore that Christmas season is associated with higher rate of psychiatric emergencies.


Comparing regression methods for the two-stage clonal expansion model of carcinogenesis.
In the statistical analysis of cohort data with risk estimation models, both Poisson and individual likelihood regressions are widely used methods of parameter estimation. In this paper, their performance has been tested with the biologically motivated two-stage clonal expansion (TSCE) model of carcinogenesis. To exclude inevitable uncertainties of existing data, cohorts with simple individual exposure history have been created by Monte Carlo simulation. To generate some similar properties of atomic bomb survivors and radon-exposed mine workers, both acute and protracted exposure patterns have been generated. Then the capacity of the two regression methods has been compared to retrieve a priori known model parameters from the simulated cohort data. For simple models with smooth hazard functions, the parameter estimates from both methods come close to their true values. However, for models with strongly discontinuous functions which are generated by the cell mutation process of transformation, the Poisson regression method fails to produce reliable estimates. This behaviour is explained by the construction of class averages during data stratification. Thereby, some indispensable information on the individual exposure history was destroyed. It could not be repaired by countermeasures such as the refinement of Poisson classes or a more adequate choice of Poisson groups. Although this choice might still exist we were unable to discover it. In contrast to this, the individual likelihood regression technique was found to work reliably for all considered versions of the TSCE model.


Synthesis of quantum-sized ZnO nanoparticles in different medium and their application to NO2 sensors.
Quantum-sized ZnO nanoparticles were synthesized using zinc acetate dihydrate through a sol-gel process in different mediums: water, ethanol and methanol. Three types of modifiers: tetraethyl orthosilicate (TEOS), sodium dodecyl sulfate (SDS) and oleic acid (OA) were added to control the growth of the ZnO nanoparticles and inhibit Ostwald ripening. X-ray Diffraction (XRD) analyses revealed that ZnO have a hexagonal crystal structure, the estimated average crystallite sizes of modified ZnO are in the range of 4.5-10 nm, while the crystallite sizes of non-modified ZnO are large than 20 nm. X-ray photoelectron spectroscopy (XPS) analyses obtained the surface composition and chemical states of the products of ZnO. In this paper, the obtained quantum-sized ZnO nanoparticles as a novel sensing material were used to detect NO2 in environment. The sensing tests indicated that the ZnO based sensors not only have high response to NO2 but also exhibited high selectivity to CO and CH4 at low operating temperature of 290 degrees C.


ProteinChip clinical proteomics: computational challenges and solutions.
ProteinChip technology, a suite of analytical tools that includes retentate chromatography, on-chip protein characterization, and multivariate analysis, allows researchers to examine patterns ofprotein expression and modification. Based on the surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) approach, ProteinChip technology has been pioneered by researchers at Ciphergen Biosystems (Fremont, CA, USA), as well as by users of Ciphergen's commercial embodiment of this technology the ProteinChip Biomarker System. This report will begin with a background of the technology and describe its applications in clinical proteomics and will then conclude with a discussion of tools and strategies to mine the large amounts of data generated during the course of a typical clinical proteomics study.


1H-NMR assignments of the non-exchangeable protons of the consensus donor exon:intron junctioń d(CpApGpGpTpApApGpT).
The consensus donor exon:intron junction d(CpApGpGpTpApApGpT) has been synthesized by a modified phosphotriester method. The non-self-complementary nonamer has, in principle, only two G,C or four A,T points of self-recognition. The inference that it exists in the single strand form at 20 degrees C was confirmed by temperature variable 1H-NMR and NOE measurements. The proton assignments were secured using two-dimensional COSY which provided intra-nucleotide correlations, then NOE difference measurements as well as inversion recovery T1 experiments. Systematic procedures were developed for the assignment of the individual bases and their component protons based on the effects of molecular environment on chemical shifts. These latter procedures should be useful for the assignment of other random-coil single strand oligodeoxyribonucleotides.


'The body is difficult': reproductive navigation through sociality and corporeality in rural Burundi.
The route from family planning intentions to practices is not linear, it is contingent on different social factors including the preferences of individuals and couples, their gendered positions and bargaining power, the wider political, economic and social context, and also physical and bodily circumstances. We used qualitative data collected in rural Burundi between 2013 and 2016 to explore how these diverse factors influence reproductive navigation in a context framed by uncertainty and changing social norms. We describe representations of bodily (pre)dispositions for fertility and reproduction, such as the 'natural' capacity for birth spacing or the bodily capacity to use 'natural' (having a regular cycle) and 'modern' methods (not having negative side effects) that contribute collectively to an understanding of 'the body is difficult'. We found that despite these bodily constraints, women enact embodied agency to ensure livelihoods and social status, thus framing their reproductive intentions and practices. In the context of Burundi where corporeality is key to gendered social belonging, family planning programmes fail to respond to the needs and concerns of women and their embodied reproductive experiences.


Zika virus productively infects primary human placenta-specific macrophages.
The strong association of Zika virus infection with congenital defects has led to questions of how a flavivirus is capable of crossing the placental barrier to reach the fetal brain. Here, we demonstrate permissive Zika virus infection of primary human placental macrophages, commonly referred to as Hofbauer cells, and placental villous fibroblasts. We also demonstrate Zika virus infection of Hofbauer cells within the context of the tissue ex vivo using term placental villous explants. In addition to amplifying infectious virus within a usually inaccessible area, the putative migratory activities of Hofbauer cells may aid in dissemination of Zika virus to the fetal brain. Understanding the susceptibility of placenta-specific cell types will aid future work around and understanding of Zika virus-associated pregnancy complications.


Herbimycin A inhibits protein kinase C in vascular smooth muscle cells.
It has been observed that in growth arrested vascular smooth muscle cells herbimycin A treatment completely inhibits the activation of mitogen activated protein kinase induced by phorbol 12-myristate 13-acetate (a phorbol ester). Since herbimycin A is a tyrosine kinase inhibitor, this finding raised the possibility of protein kinase C inhibition or down regulation by this compound. Herbimycin A significantly inhibited phorbol myristate acetate-mediated protein kinase C activation as measured by in situ glycogen synthase (GS) peptide and neurogranin peptide phosphorylation in vascular smooth muscle cells. Basal protein kinase activity, i.e. kinase activity without phorbol ester treatment to vascular smooth muscle cells, was also decreased by the treatment of herbimycin A. These findings suggest that herbimycin A also inhibits protein kinase C in vascular smooth muscle cells.


Smart wheelchairs: A literature review.
Several studies have shown that both children and adults benefit substantially from access to a means of independent mobility. While the needs of many individuals with disabilities can be satisfied with traditional manual or powered wheelchairs, a segment of the disabled community finds it difficult or impossible to use wheelchairs independently. To accommodate this population, researchers have used technologies originally developed for mobile robots to create "smart wheelchairs." Smart wheelchairs have been the subject of research since the early 1980s and have been developed on four continents. This article presents a summary of the current state of the art and directions for future research.


[Association of haplotype formed on HLA-DRB1 and HLA-DQA1 alleles with outcomes of hepatitis B virus infection].
To assess the association of haplotype of HLA-DRB1 and HLA-DQA1 alleles with outcomes of hepatitis B virus infection in Han population of north China. Two hundred and seven chronic hepatitis B (HB) patients, two hundred and twelve chronic asymptomatic hepatitis B virus (HBV) carriers (HBV carrier) and one hundred and forty-eight self-limited HBV infection were investigated for HLA-DRB1 and HLA-DQA1 alleles by sequence specific-polymerase chain reaction (PCR-SSP). The frequency of DRB1*04-DQA1*0301 haplotype was 10.03% in self-limited HBV infection subjects, significantly higher than that in chronic HB patients (3.66%) (P=0.0005)ûthe frequency of DRB1*15/*16-DQA1*0102 haplotype was 6.80% in self-limited HBV infection subjects, significantly higher than 1.94% in chronic HB patients (P=0.0012) and 1.65% in asymptomatic HBV carriers (P=0.0004)ûwhile the frequency of DRB1*04-DQA1*0302 haplotype was 3.10% in chronic HB patients, higher than that in self-limited HBV infection subjects (0.39%) (P=0.0077). Individuals with different haplotypes composed of HLA-DRB1 and HLA-DQA1 might have different outcomes of HBV infection.


Real-world data on the use of insulin glargine 300 U/mL in Japanese patients with type 1 diabetes: twelve-month results from a post-marketing surveillance study (X-STAR study).
With limited real-world insulin glargine 300 U/mL (Gla-300) data among Japanese patients with type 1 diabetes mellitus (T1DM) available, the authors describe its effectiveness and safety in Japanese T1DM patients switching to Gla-300. X-STAR was a 12-month prospective, observational, post-marketing study in Japanese patients with diabetes mellitus from 2015 to 2018: insulin-experienced T1DM patients initiating Gla-300 were analyzed. Of 774 patients, mean (±standard deviation) HbA1c (%) and fasting plasma glucose (mg/dL) decreased from 8.27 ± 1.55 to 8.15 ± 1.35 (by -0.12 ± 1.30 [p = 0.013]) and 167.9 ± 92.6 to 153.9 ± 70.9 (by -13.9 ± 103.8 [p = 0.067]) from baseline to month 12, respectively. A total of 16.3% achieved HbA1c <7.0% at month 12. Gla-300 dose increased by 1.13 ± 3.18 U/day (0.02 ± 0.05 U/kg/day) (p < 0.001), with a + 0.22 ± 2.70 (p = 0.037) body-weight change (kg) from baseline 60.83 ± 12.81 to 12-month 61.06 ± 12.89. Adverse drug reactions (ADRs) and serious ADRs occurred in 9.82% and 0.78% of the patients, respectively. Hypoglycemia was the most common ADR (9.30%). In total, 88.9% adhered to Gla-300 administration schedules, whereas <40% adhered to exercise and dietary instructions, respectively. Gla-300 showed no unprecedented safety concerns for insulin-experienced T1DM patients in Japanese clinical settings. Our results provide insights into strategies for blunted Gla-300 up-titration dose, despite insufficient HbA1c control and lifestyle modification.


Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men.
Solute-free water diuretics (aquaretics) by antagonizing hydrosmotic vasopressin receptors (V2) may be useful in treating water-retaining diseases. The effects of intravenous administration of a newly developed nonpeptide, selective V2 antagonist, OPC-31260, at doses ranging from 0.017 to 1.0 mg/kg to groups of healthy, normally hydrated men were compared with those of 0.33 mg/kg furosemide and placebo. OPC-31260 increased the hypotonic urine volume dose dependently for the first 4 h, while furosemide induced sodium diuresis for 2 h. The absolute increase in the cumulative response in the urine to the highest doses of OPC-31260 was not significantly different from that to furosemide. The higher doses of OPC-31260 rapidly lowered urine osmolality for 2 h, particularly between minutes 15 and 45 (e.g., 1.0-mg/kg dose: 63 +/- 2 mOsm/kg in urine collected between minutes 30 and 45). In a marked hypotonic diuresis, mean free water clearance of the 4-h urine increased dose proportionally into the positive range, reaching 1.80 +/- 0.21 ml/min at 1.0 mg/kg. Whereas furosemide induced marked Na and K diuresis, OPC-31260 increased urinary Na excretion only slightly. At 4 h, 0.75 and 1.0 mg/kg of OPC-31260 almost doubled the plasma arginine vasopressin; and the higher doses increased plasma osmolality and plasma Na slightly, but did not alter plasma K, blood pressure, or heart rate. OPC-31260 thus safely induced a potent aquaretic effect in men.


Nanoencapsulated and microencapsulated enzymes in drug antidotal therapy.
A catalytic bioscavenger for the therapeutic and prophylactic defense against recognized chemical threat agents has been a long-standing objective of civilian and military research. Among the toxic agents, organophosphate molecules and cyanide have been widely studied. In order to overcome the limitations of traditional antidotal therapies, isolated, purified, recombinant enzymes with bacterial origin possessing fast catalytic activity were used in in vitro and in vivo experiments. However, the fast degradation, excretion and adverse immunologic reaction against enzymes limit their in vivo use. Development of biodegradable, nontoxic carrier systems, microparticles, and nanoparticles-offering advantageous pharmacokinetic parameters was suggested. Present work deals with the perspectives of carrier systems, such as resealed and annealed erythrocytes and sterically stabilized liposomes. Dendritic polymers and polymer-conjugated enzymes, being in the focus of extensive research efforts nowadays, are also discussed.


Cytokinin effects on growth of quiescent tobacco pith cells.
Excised pith tissue from Nicotiana glauca or the tumor-prone hybrid N. glauca x N. langsdorffii has no growth requirement for exogenous cytokinins. Addition of kinetin to cultures of these lines results in growth inhibition at a kinetin concentration 1000-fold lower than the optimal level for kinetin-requiring lines. Cytological comparison of the kinetin-inhibited 2N hybrid and glauca tissues with pith from the kinetin-requiring N. tabacum var. Wisconsin 38 suggests that the nature of the cytokinin action is similar in both situations and that the primary function of cytokinin, when it stimulates growth, may be to curtail cell expansion, thereby facilitating a balance of cell expansion and division requisite for maximal growth.


Trends in Mental Health Concerns Reported to Two Pediatric Mental Health Care Access Programs During the COVID-19 Pandemic.
Pediatric Mental Health Care Access (PMHCA) programs increase access to mental health care by providing training, consultation, and resource-referral support to primary care providers (PCPs). The authors compared trends in services provided by two PMHCA programs during the COVID-19 pandemic. Maryland and Mississippi PMHCA programs had 2,840 contacts with PCPs from January 2019 to March 2021. Descriptive trends on PMHCA program utilization, service type, clinical severity, diagnostic complexity, and PCP contact reasons were reported. Both programs observed significant increases in call volume during the COVID-19 pandemic compared with before COVID-19. Increases were observed in calls regarding patients with multiple diagnoses (Maryland, 20% to 37%; Mississippi, 0% to 11%) as well as patients with mood and anxiety symptoms. Changes in PMHCA program usage suggest that PCPs identified more complex mental health concerns, particularly regarding mood and anxiety, during the pandemic than before COVID-19. Trends underscore the importance of PMHCA programs in supporting PCPs with managing pediatric mental health concerns.


A Method of Information Protection for Collaborative Deep Learning under GAN Model Attack.
Deep learning is widely used in the medical field owing to its high accuracy in medical image classification and biological applications. However, under collaborative deep learning, there is a serious risk of information leakage based on the deep convolutional generation against the network's privacy protection method. Moreover, the risk of such information leakage is greater in the medical field. This paper proposes a deep convolution generative adversarial networks (DCGAN) based privacy protection method to protect the information of collaborative deep learning training and enhance its stability. The proposed method adopts encrypted transmission in the process of deep network parameter transmission. By setting the buried point to detect a generative adversarial network (GAN) attack in the network and adjusting the training parameters, training based on the GAN model attack is forced to be invalid, and the information is effectively protected.


Effects of long-term treatment with prazosin on left ventricular diastolic function in mild to moderate hypertension.
It is not well established if blood pressure control is associated with an improvement in diastolic function, whose impairment represents an early marker of cardiac involvement in systemic hypertension. The purpose of this study was to evaluate whether a prolonged treatment with an alpha 1-blocking agent can lead to a reversal of the abnormalities of left ventricular filling. Eleven never-treated patients with mild to moderate essential hypertension were examined before and after at least six months of treatment with prazosin. Cardiac function and left ventricular mass were measured by means of radionuclide ventriculography and echocardiography. Average blood pressure values significantly decreased during the treatment period: from 163.54 +/- 17.80 mm Hg to 146.81 +/- 13.14 mm Hg for systolic blood pressure and from 106.09 +/- 6.96 mm Hg to 92.90 +/- 8.93 mm Hg for diastolic blood pressure. All the indices of left ventricular mass showed a trend toward reduction, but the differences with respect to the baseline values did not reach statistical significance. Average value of ejection fraction was normal before treatment and did not change significantly after treatment. All indices of diastolic function were significantly lower than normal controls' values at the beginning of the study and tended to worsen at the end of the study. Our findings suggest that diastolic function is not consistently affected by the therapy with alpha 1-adrenoreceptor antagonists despite good blood pressure control.


Comorbidities in bipolar disorder: models and management.
Rates of conditions comorbid with bipolar disorder are very high, with anxiety disorders, impulse-control disorders, and drug and alcohol problems being the most distinctly over-represented conditions. Although the high rates of comorbid conditions may be overestimates--owing to measurement distortions in community surveys, and because definitions of comorbidity generally include antecedent and consequential conditions (not merely coterminous ones)--they are clinically distinctive. Clinical comorbidity can be explained by at least four different models, which each have clinical management implications. If the bipolar disorder and the comorbid conditions are deemed to be interdependent, two broad approaches are appropriate: hierarchical management strategies and sequential management strategies. Successful management of bipolar disorder often involves the development of a wellbeing plan that addresses comorbid issues iterative to the bipolar disorder.


Language development at 3 years in pre-term children of birth weight below 1000 g.
Language development at 3 years of pre-term children born below 1000 g birth weight was compared with full-term controls matched for social background. The pre-term group used less complex expressive language and showed lower receptive understanding, auditory memory and verbal reasoning. Language outcome was related to intraventricular haemorrhage but not to global indication of postnatal illness such as number of days on the ventilator. Average verbal intelligence in environmentally low risk, extremely low birth weight children is an insufficient indicator of complex language functioning.


Early risk stratification of unstable angina/non-Q myocardial infarction: biochemical markers of coronary thrombosis.
Coronary thrombosis is an important determinant of prognosis in patients with acute coronary syndromes (ACS). However, the identification of patients at high-risk for progression of coronary thrombosis is difficult partly because we currently lack clinically meaningful laboratory methods for its detection. The most promising approaches involve the measurement in plasma of markers of fibrin formation and degradation. Thrombin activity, as reflected by plasma or urine concentrations of fibrinopeptide A, is increased in patients with ACS and is associated with adverse outcome. However, the use of fibrinopeptide A as a marker of fibrin formation is limited by the very short half-life of the compound, by artifact due to sample acquisition, and by extremely long turnaround times. To overcome these limitations, measurement of soluble fibrin has been proposed. We have recently explored the prognostic value of a new fibrin-specific ELISA assay for soluble fibrin in patients with ACS and found that patients with the highest levels had a 2-fold increased risk of early and late cardiac events. Increases in plasma concentrations of cross-linked fibrin degradation products (XL-FDPs), which reflect increased fibrin turn-over, are a marker of risk for complications of myocardial infarction. However, until recently, assays for XL-FDPs lacked specificity, because they did not distinguish between fibrin and fibrinogen degradation products. Recently, fibrin-specific ELISAs have been described and a rapid whole blood assay for D-dimer has been developed. We recently validated the prognostic value of this whole blood agglutination assay in patients with ACS. These results suggest that: (1) The detection of significant activation of the coagulation and/or fibrinolytic system may be important for rapid risk stratification of patients with ACS; (2) patients with biochemical evidence of ongoing coronary thrombosis may particularly benefit from aggressive antithrombotic strategies; (3) sequential measurement of these markers may be useful to guide antithrombotic treatment during the unstable phase of coronary artery disease.


Metastasis to the renal hilum from malignant melanoma of the anterior trunk: an unusual finding.
A retroperitoneal metastasis from malignant melanoma is an uncommon event and mostly secondary to a primary lesion of the posterior trunk. We report on a 38-year-old patient with malignant melanoma of the anterior trunk who presented a symptomatic metastatic mass of the left renal hilum not originating from the retroperitoneal lymph nodes of the renal hilum, surrounding and infiltrating the renal pelvis, treated with left nephrectomy, complete mass excision and regional lymph node dissection. The patient later developed also brain metastases and is now undergoing immunotherapy.


Doxofylline Protects Gram-Negative Pathogens against Antibiotic-Mediated Killing.
Given the growing rate of Gram-negative bacterial infections, antibiotics are now frequently prescribed for various respiratory diseases. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities, but its influence on antibiotics remains poorly understood. Here, we first report the discovery of doxofylline-induced high minimum inhibitory concentrations of antibiotics. We also showed that doxofylline blocked antimicrobial-mediated killing for Gram-negative pathogens in vitro and in murine lung infection models in vivo. By combining efflux pump inhibition tests, gene expression analyses, and using the gene tolC knockout strain, we found that doxofylline positively regulated gene expression of the AcrAB-TolC efflux pump and attenuated the effect of doxofylline on antibacterial activities in ΔtolC mutants. Notably, doxofylline-mediated protection correlated with decreased reactive oxygen species (ROS) production. Collectively, our study indicates that doxofylline protects Gram-negative bacteria from antimicrobial lethality by regulating the AcrAB-TolC efflux pump in a TolC-dependent manner and suppressing antibiotic-induced ROS accumulation. These results suggest caution when using antibiotics alongside doxofylline in clinical treatment.


The rise in circulating gastrin with age is due to increases in gastric autoimmunity and Helicobacter pylori infection.
To assess the effect of increasing age on circulating gastrin, we surveyed serum gastrin, Helicobactor pylori seroantibody status and gastric autoimmunity in 366 hospitalized patients aged 15-90 years. Data were subjected to multivariate analysis, using logarithmic transformation to normalize the distribution of gastrin concentrations (presented as geometric means and 95% CIs). The frequency of H. pylori-positive antibody status increased with age from 28% in the second decade to > 70% beyond the fourth decade. Fasting gastrin concentrations rose significantly from 44 ng/l (41-48) in the second decade to 95 ng/l (67-131) by the eighth decade (p = 0.001) in the total group. Twenty-seven patients (6.8% of the total) tested positive for gastric auto-antibodies: 2% of patients in the second decade, rising to 15.9% in the eighth decade. These patients formed a distinct group with respect to circulating gastrin concentrations. Excluding these 27, fasting gastrin concentrations still rose significantly, from 44 ng/l (41-48) in the second decade, to 67 ng/l (50-89) in the eighth decade (p = 0.003) in the remaining 341 patients. Fasting gastrin concentrations were significantly higher in patients who were H. pylori-seropositive (59 ng/l, 54-64 vs. sero-negative 41 ng/l, 37-46) (p = 0.002), and there was no increase in circulating gastrin concentrations with increasing age in either the H. pylori-positive or the H. pylori-negative group. The increase in circulating fasting gastrin observed with increasing age is due to an increased incidence of gastric antibodies associated with auto-immune atrophic gastritis, and an increased incidence of H. pylori infection.


The potential reuse of biodegradable municipal solid wastes (MSW) as feedstocks in vermicomposting.
There is an urgent need globally to find alternative sustainable steps to treat municipal solid wastes (MSW) originated from mismanagement of urban wastes with increasing disposal cost. Furthermore, a conglomeration of ever-increasing population and consumerist lifestyle is contributing towards the generation of more MSW. In this context, vermicomposting offers excellent potential to promote safe, hygienic and sustainable management of biodegradable MSW. It has been demonstrated that, through vermicomposting, MSW such as city garbage, household and kitchen wastes, vegetable wastes, paper wastes, human faeces and others could be sustainably transformed into organic fertiliser or vermicompost that provides great benefits to agricultural soil and plants. Generally, earthworms are sensitive to their environment and require temperature, moisture content, pH and sometimes ventilation at proper levels for the optimum vermicomposting process. Apart from setting the optimum operational conditions for the vermicomposting process, other approaches such as pre-composting, inoculating micro-organisms into MSW and redesigning the conventional vermireactor could be introduced to further enhance the vermicomposting of MSW. Thus the present mini-review discusses the potential of introducing vermicomposting in MSW management, the benefits of vermicomposted MSW to plants, suggestions on how to enhance the vermicomposting of MSW as well as risk management in the vermicomposting of MSW.


Time course of cortical plasticity after facial nerve palsy: a single-case study.
Functional connectivity is defined as the temporal correlation between spatially remote neurophysiological events. This method has become particularly useful for studying neuroplasticity to detect changes in the collaboration of brain areas during cortical reorganization. In this article, the authors longitudinally studied voxel-based morphometry and resting state functional magnetic resonance imaging 10 times in 1 patient during the course of Bell palsy (idiopathic facial nerve palsy) up to complete clinical recovery. Morphometric analysis revealed a significant alteration in the face area of the primary motor cortex (M1) contralateral to the paretic face, with an initial increase in gray matter concentration. Functional connectivity analysis between the M1 and other parts of the facial motor network revealed acutely disrupted intrahemispheric connectivity but unaltered interhemispheric connectivity. The disrupted functional connectivity was most pronounced on the day of the onset of symptoms, with a subsequent return toward normal during the course of recovery. This time course was found to differ between the selected parts of the facial motor network. However, the increase in functional connectivity strength preceded clinical recovery in all areas and reached a stable level before the patient fully recovered. These results demonstrate that recovery from facial nerve palsy is complemented by cortical reorganization, with pronounced changes of functional connectivity that precede clinical recovery.