CSF rhinorrhoea after endonasal intervention to the skull base (CRANIAL): A multicentre prospective observational study.
Despite progress in endonasal skull-base neurosurgery, cerebrospinal fluid (CSF) rhinorrhoea remains common and significant. The CRANIAL study sought to determine 1) the scope of skull-base repair methods used, and 2) corresponding rates of postoperative CSF rhinorrhoea in the endonasal transsphenoidal approach (TSA) and the expanded endonasal approach (EEA) for skull-base tumors. A prospective observational cohort study of 30 centres performing endonasal skull-base neurosurgery in the UK and Ireland (representing 91% of adult units). Patients were identified for 6 months and followed up for 6 months. Data collection and analysis was guided by our published protocol and pilot studies. Descriptive statistics, univariate and multivariable logistic regression models were used for analysis. A total of 866 patients were included - 726 TSA (84%) and 140 EEA (16%). There was significant heterogeneity in repair protocols across centres. In TSA cases, nasal packing (519/726, 72%), tissue glues (474/726, 65%) and hemostatic agents (439/726, 61%) were the most common skull base repair techniques. Comparatively, pedicled flaps (90/140, 64%), CSF diversion (38/140, 27%), buttresses (17/140, 12%) and gasket sealing (11/140, 9%) were more commonly used in EEA cases. CSF rhinorrhoea (biochemically confirmed or requiring re-operation) occurred in 3.9% of TSA (28/726) and 7.1% of EEA (10/140) cases. A significant number of patients with CSF rhinorrhoea (15/38, 39%) occurred when no intraoperative CSF leak was reported. On multivariate analysis, there may be marginal benefits with using tissue glues in TSA (OR: 0.2, CI: 0.1-0.7, p<0.01), but no other technique reached significance. There was evidence that certain characteristics make CSF rhinorrhoea more likely - such as previous endonasal surgery and the presence of intraoperative CSF leak. There is a wide range of skull base repair techniques used across centres. Overall, CSF rhinorrhoea rates across the UK and Ireland are lower than generally reported in the literature. A large proportion of postoperative leaks occurred in the context of occult intraoperative CSF leaks, and decisions for universal sellar repairs should consider the risks and cost-effectiveness of repair strategies. Future work could include longer-term, higher-volume studies, such as a registry; and high-quality interventional studies.


Hypoxia alters steroidogenesis in female marine medaka through miRNAs regulation.
Hypoxia is a worldwide environmental problem in marine ecosystems, leading to serious declines in fishery production over large areas. Our previous studies demonstrated that hypoxia is an endocrine disruptor which can cause reproductive impairment through the regulation of miRNAs, suggesting the functional role of miRNAs in reproductive systems in response to hypoxia. In this study, we used small RNA sequencing to determine the change in miRNA profile in ovary of marine medaka Oryzias melastigma under hypoxic stress. A total of 509 miRNAs were found in the ovary of marine medaka, in which, 33 and 10 miRNAs were found to be statistically significant upregulated and downregulated under hypoxia, respectively. Bioinformatics analysis highlighted that a large number of hypoxia-suppressed miRNAs that target a variety of steroidogenic enzymes including steroidogenic acute regulatory protein, aromatase, and 17-alpha-monooxygenase. Also, estrogen receptor 2 and androgen receptor were found to be targeted by hypoxia-responsive miRNAs. For the first time, our results showed that hypoxia may upregulate specific steroidogenic enzymes and hormone receptors through actions of miRNA, and hence provide a novel mechanism for the observed female reproductive impairment caused by hypoxia.


[An analysis of the reasons for relaparotomy in the surgical clinic].
The results of surgical treatment of 4,078 patients who underwent operation in 1985-1989 were studied. Due to the occurrence of complications in the early postoperative period, 182 relaparotomies were carried out in 164 patients. The main indications for relaparotomies were advanced underlying disease, surgical errors (tactical, technical), changes of the patients' immune status. Early diagnosis, timely operation with the use of technically correct manipulations, and the application of a full complex of intensive therapy measures in the postoperative period are important in the prevention of complications.


ARNO3, a Sec7-domain guanine nucleotide exchange factor for ADP ribosylation factor 1, is involved in the control of Golgi structure and function.
Budding of transport vesicles in the Golgi apparatus requires the recruitment of coat proteins and is regulated by ADP ribosylation factor (ARF) 1. ARF1 activation is promoted by guanine nucleotide exchange factors (GEFs), which catalyze the transition to GTP-bound ARF1. We recently have identified a human protein, ARNO (ARF nucleotide-binding-site opener), as an ARF1-GEF that shares a conserved domain with the yeast Sec7 protein. We now describe a human Sec7 domain-containing GEF referred to as ARNO3. ARNO and ARNO3, as well as a third GEF called cytohesin-1, form a family of highly related proteins with identical structural organization that consists of a central Sec7 domain and a carboxy-terminal pleckstrin homology domain. We show that all three proteins act as ARF1 GEF in vitro, whereas they have no effect on ARF6, an ARF protein implicated in the early endocytic pathway. Substrate specificity of ARNO-like GEFs for ARF1 depends solely on the Sec7 domain. Overexpression of ARNO3 in mammalian cells results in (i) fragmentation of the Golgi apparatus, (ii) redistribution of Golgi resident proteins as well as the coat component beta-COP, and (iii) inhibition of SEAP transport (secreted form of alkaline phosphatase). In contrast, the distribution of endocytic markers is not affected. This study indicates that Sec7 domain-containing GEFs control intracellular membrane compartment structure and function through the regulation of specific ARF proteins in mammalian cells.


Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species.
Calcitonin gene-related peptide (CGRP) immunoreactivity was found throughout the entire spinal cord of man, marmoset, horse, pig, cat, guinea pig, mouse, rat, and frog. CGRP-immunoreactive fibers were most concentrated in the dorsal horn. In the ventral horn of some species large immunoreactive cells, tentatively characterized as motoneurons, were present. Pretreatment of rats with colchicine enhanced staining of these large cells but did not reveal CGRP-immunoreactive cell bodies in the dorsal horn. In the dorsal root ganglia, CGRP immunoreactivity was observed in most of the small and some of the intermediate sized cells. Substance P immunoreactivity, where present, was co-localized with CGRP to a proportion of the small cells. In the cat the ratio of substance P-immunoreactive to CGRP-immunoreactive ganglion cells was 1:2.7 (p less than 0.001). The concentration of CGRP-immunoreactive material in tissue extracts was determined by radioimmunoassay. In the dorsal horn of the rat spinal cord the levels of peptide were found to range from 225.7 +/- 30.0 pmol/gm of wet weight in the cervical region to 340.6 +/- 74.6 pmol/gm in the sacral spinal cord. In the rat ventral spinal cord, levels of 15.7 +/- 2.7 to 35.1 +/- 10.6 pmol/gm were found. The concentration in dorsal root ganglia of the lumbar region was 225.4 +/- 46.9 pmol/gm. Gel permeation chromatography of this extractable CGRP-like immunoreactivity revealed three distinct immunoreactive peaks, one eluting at the position of synthetic CGRP and the others, of smaller size, eluting later. In cats and rats, rhizotomy induced a marked loss of CGRP-immunoreactive fibers from the dorsal horn of the spinal cord. In the cat, unilateral lumbosacral dorsal rhizotomy resulted in a significant (p less than 0.05) reduction of extractable CGRP from the ipsilateral lumbar dorsal horn (5.6 +/- 1.2 pmol/gm of wet weight) compared to the contralateral side (105.0 +/- 36.0 pmol/gm of wet weight). We conclude that the major origin of CGRP in the dorsal spinal cord is extrinsic, from afferent fibers which are probably derived from cells in the dorsal root ganglia. The selective distribution of CGRP throughout sensory, motor, and autonomic areas of the spinal cord suggests many putative roles for this novel peptide.


[Ag15(N-triphos)4(Cl4)](NO3)3: a stable Ag-P superatom with eight electrons (N-triphos = tris((diphenylphosphino)methyl)amine).
A first and stable Ag-P superatom nanocluster [Ag15(N-triphos)4(Cl4)](NO3)3 (1) has been successfully synthesized and characterized. X-ray analysis shows that this Ag15 cluster has a hexacapped body-centered cubic (bcc) framework which is consolidated by four tripodal N-triphos ligands. The identity of 1 is confirmed by high resolution ESI-MS. Cluster 1 has an electronic and geometric shell closure structure with 8 free electrons, matching the stability idea of superatom theory for a nanocluster. DFT calculation of this Ag15 cluster reveals the superatom feature with a 1S21P6 configuration. The chelation of multidentate phosphines enhances the stability of this Ag15 cluster. The AgAg distances between the centered and the vertical Ag atoms of this bcc (Ag@Ag8) are in the range of 2.57-2.71 Å, and the distances between the face-capped and the vertical silver atoms are in the range of 2.84-2.92 Å, showing strong AgAg interactions within this cluster core. This superatom complex exhibits a relatively high thermal and photolytic stability.


The involvement of hepatic cytochrome P450s in the cytotoxicity of lapatinib.
Lapatinib, an oral tyrosine kinase inhibitor used as a first-line treatment for HER2-positive breast cancer, has been reported to be associated with hepatotoxicity; however, the underlying mechanisms remain unclear. In this study, we report that lapatinib causes cytotoxicity in multiple types of hepatic cells, including primary human hepatocytes, HepaRG cells, and HepG2 cells. A 24-h treatment with lapatinib induced cell cycle disturbances, apoptosis, and DNA damage, and decreased the protein levels of topoisomerase in HepG2 cells. We investigated the role of cytochrome P450 (CYP)-mediated metabolism in lapatinib-induced cytotoxicity using our previously established HepG2 cell lines, which express each of 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrate that lapatinib is metabolized by CYP1A1, 3A4, 3A5, and 3A7. Among these, lapatinib-induced cytotoxicity and DNA damage were attenuated in cells overexpressing CYP3A5 or 3A7. Additionally, we measured the production of three primary metabolites of lapatinib (O-dealkylated lapatinib, N-dealkylated lapatinib, and N-hydroxy lapatinib) in CYP1A1-, 3A4-, 3A5-, and 3A7-overexpressing HepG2 cells. We compared the cytotoxicity of lapatinib and its three metabolites in primary human hepatocytes, HepaRG cells, and HepG2 cells and demonstrate that N-dealkylated lapatinib is more toxic than the parent drug and the other metabolites. Taken together, our results indicate that lapatinib-induced cytotoxicity involves multiple mechanisms, such as apoptosis and DNA damage; that N-dealkylated lapatinib is a toxic metabolite contributing to the toxic effect of lapatinib; and that CYP3A5- and 3A7-mediated metabolism plays a role in attenuating the cytotoxicity of lapatinib.


Characterisation of the physical, chemical and mechanical properties of a radiopaque polyethylene.
Ultra-high molecular weight polyethylene has a low X-ray attenuation, hence, the performance of the polyethylene implants used for joint replacements cannot be directly investigated using X-ray-based imaging techniques. In this study, the X-ray attenuation of polyethylene was increased by diffusing an FDA-approved oil-based contrast agent (Lipiodol ultra fluid) into the surface of the samples, and the suitability of this novel radiopaque ultra-high molecular weight polyethylene for clinical applications was examined. Different levels of radiopacity were created by controlling the diffusion parameters, and the level of radiopacity was quantified from computed tomography scans and reported in Hounsfield units. The physical, chemical and tensile properties of the radiopaque ultra-high molecular weight polyethylene were examined and compared to untreated and thermally treated controls. The results of this study confirmed that for the samples treated at 115°C or less the diffusion of the contrast agent did not significantly alter the crystallinity (p = 0.7) or melting point (p = 0.4) of the polyethylene. Concomitantly, the tensile properties were not significantly different from the control samples (p > 0.05 for all properties). In conclusion, the radiopaque ultra-high molecular weight polyethylene treated for less than 18 h at a temperature of 115°C or below is a promising candidate for joint replacement applications as it can be identified in a standard X-ray while retaining the tensile properties of clinically used radiolucent ultra-high molecular weight polyethylene.


The presence of acyl-CoA hydrolase in rat brown-adipose-tissue peroxisomes.
The subcellular distribution of acyl-CoA hydrolase was studied in rat brown adipose tissue, with special emphasis on possible peroxisomal localization. Subcellular fractionation by sucrose-density-gradient centrifugation, followed by measurement of short-chain (propionyl-CoA) acyl-CoA hydrolase in the presence of NADH, resulted in two peaks of activity in the gradient: one peak corresponded to the distribution of cytochrome oxidase (mitochondrial marker enzyme), and another peak of activity coincided with the peroxisomal marker enzyme catalase. The distribution of the NADH-inhibited short-chain hydrolase activity fully resembled that of cytochrome oxidase. The substrate-specificity curve of the peroxisomal acyl-CoA hydrolase activity indicated the presence of a single enzyme exhibiting a broad substrate specificity, with maximal activity towards fatty acids with chain lengths of 3-12 carbon atoms. The mitochondrial acyl-CoA hydrolase substrate specificity, in contrast, indicated the presence of at least two acyl-CoA hydrolases (of short- and medium-chain-length specificity). The peroxisomal acyl-CoA hydrolase activity was inhibited by CoA at low (microM) concentrations and by ATP at high concentrations (greater than 0.8 mM). In contrast with the mitochondrial short-chain hydrolase, the peroxisomal acyl-CoA hydrolase activity was not inhibited by NADH.


Delayed presentation of manubriosternal dislocation after thoracolumbar spondylodesis in a polytrauma patient - a case report.
Manubriosternal dislocations are a rare entity and frequently associated with thoracic spine fractures and, in minority of cases, with cervical or thoracolumbar fractures. Our case represents a 38-year-old male who fell from a height resulting in multiple fractures, amongst others of the first lumbar vertebra. At primary survey and computed tomography scan no manubriosternal injury was apparent. After posterior stabilization of the thoracolumbar vertebrae a manubriosternal dislocation was identified and stabilized using plate-and-screw fixation. Clinical findings of a manubriosternal dislocation are not always obvious, allowing them to be missed at initial assessment. Manubriosternal dislocations can be missed at the initial investigation, even on cross-sectional imaging, and only become visible after spine stabilization because of the tight relationship between sternum and vertebrae in the thoracic cage. There is no unanimity in literature for surgical treatment of manubriosternal dislocations, although plate fixation is generally considered a safe and effective treatment option.


Structural basis of substrate selectivity of E. coli prolidase.
Prolidases, metalloproteases that catalyze the cleavage of Xaa-Pro dipeptides, are conserved enzymes found in prokaryotes and eukaryotes. In humans, prolidase is crucial for the recycling of collagen. To further characterize the essential elements of this enzyme, we utilized the Escherichia coli prolidase, PepQ, which shares striking similarity with eukaryotic prolidases. Through structural and bioinformatic insights, we have extended previous characterizations of the prolidase active site, uncovering a key component for substrate specificity. Here we report the structure of E. coli PepQ, solved at 2.0 Å resolution. The structure shows an antiparallel, dimeric protein, with each subunit containing N-terminal and C-terminal domains. The C-terminal domain is formed by the pita-bread fold typical for this family of metalloproteases, with two Mg(II) ions coordinated by five amino-acid ligands. Comparison of the E. coli PepQ structure and sequence with homologous structures and sequences from a diversity of organisms reveals distinctions between prolidases from Gram-positive eubacteria and archaea, and those from Gram-negative eubacteria, including the presence of loop regions in the E. coli protein that are conserved in eukaryotes. One such loop contains a completely conserved arginine near the catalytic site. This conserved arginine is predicted by docking simulations to interact with the C-terminus of the substrate dipeptide. Kinetic analysis using both a charge-neutralized substrate and a charge-reversed variant of PepQ support this conclusion, and allow for the designation of a new role for this key region of the enzyme active site.


Interaction of botulinum and tetanus toxins with the lipid bilayer surface.
The interaction of botulinum neurotoxins serotypes A, B and E (from Clostridium botulinum) and of tetanus neurotoxin (from Clostridium tetani) with the surface of liposomes made of different lipid compositions was studied by photolabelling with a radioiodinated photoactive phosphatidylethanolamine analogue [125I-dipalmitoyl (3,4-azidosalicylamido)phosphatidylethanolamine]. When the vesicles were made of negatively charged lipids (asolectin), each of these neurotoxic proteins was radioiodinated, thus providing evidence for their attachment to the membrane surface. The presence of gangliosides on liposome membranes enhanced fixation of the neurotoxic proteins to the lipid vesicle surface. Both the heavy and light chains of the clostridial neurotoxins were involved in the attachment to the lipid bilayer surface. Each of the toxins tested here attached poorly to liposomes made of zwitterionic lipids (egg phosphatidylcholine), even when polysialogangliosides were present. The data suggest that the binding of botulinum and tetanus neurotoxins to their target neuronal cells involves negatively charged lipids and polysialogangliosides on the cell membrane.


[Possibilities of eradicating the persistent HBsAg carrier state].
Five HBsAg carriers were examined by clinical, biochemical, radionuclide, immunologic and histomorphologic methods. Different variants of structural and functional relations were established. Attempts were made to eradicate the persistent virus carrierstate with the aid of the antiviral drug virasol, the immunomodulating drug levamisole, nonspecific (BCG vaccine) and specific (original corpuscular vaccine against hepatitis B) immunostimulants. No positive therapeutic effect was obtained. The difficulties and possibilities of a further study into the title problem with due regard for integration mechanisms of infection and prospects of the effective prophylaxis of virus transmission from the mother to the child at birth are discussed.


Short-term efficacy and safety of rituximab therapy in refractory systemic lupus erythematosus: results from the British Isles Lupus Assessment Group Biologics Register.
To describe the baseline characteristics of SLE patients requiring biologic therapy in the UK and to explore short term efficacy and infection rates associated with rituximab (RTX) use. Patients commencing biologic therapy for refractory SLE and who consented to join BILAG-BR were analysed. Baseline characteristics, disease activity (BILAG 2004/SLEDAI-2K) and rates of infection over follow-up were analysed. Response was defined as loss of all A and B BILAG scores to ⩽ 1 B score with no new A/B scores in other organ systems at 6 months. Two hundred and seventy SLE patients commenced biologic therapy from September 2010 to September 2015, most commonly RTX (n = 261). Two hundred and fifty (93%) patients were taking glucocorticoids at baseline at a median [interquartile range (IQR)] oral dose of 10 mg (5-20 mg) daily. Response rates at 6 months were available for 68% of patients. The median (IQR) BILAG score was 15 (10-23) at baseline and 3 (2-12) at 6 months (P < 0.0001). The median (IQR) SLEDAI-2K reduced from 8 (5-12) to 4 (0-7) (P < 0.001). Response was achieved in 49% of patients. There was also a reduction in glucocorticoid use to a median (IQR) dose of 7.5 mg (5-12 mg) at 6 months (P < 0.001). Serious infections occurred in 26 (10%) patients, being more frequent in the first 3 months post-RTX therapy. A higher proportion of early infections were non-respiratory (odds ratio = 1.98, 95% CI: 0.99, 3.9; P = 0.049). RTX is safe and is associated with improvement in disease activity in refractory SLE patients with concomitant reductions in glucocorticoid use. Early vigilance for infection post-infusion is important to further improve treatment risks and benefits.


'I forget myself': the case for the provision of culturally sensitive respite services for minority ethnic carers of older people.
The aim of the study was to investigate the need for, use of and preferences for respite services among minority ethnic carers of older people. It was anticipated that the similarities which these carers share in caring for a person from a minority group far outweight the differences arising from their particular ethnic origin. Interviews were conducted with 45 minority ethnic carers of older people in the Lothian region of Scotland. A detailed qualitative analysis of their need for respite services and preferences for service delivery was undertaken, the results of which have implications for other minority ethnic carers of older people in the United Kingdom. The findings suggest that many of these carers would be open to the use of respite services which would allow them a break from caring. Their need for respite services is evidenced by several factors including certain characteristics of those they look after and the lack of support from other members of the family. The low uptake of respite services by these carers may be accounted for by a general lack of awareness of the availability of these services as well as clear preferences for service delivery which are currently not being met. Existing policies in the United Kingdom provide a firm foundation for a pro-active approach which recognizes the particular isolation experienced by minority ethnic carers and addresses the current low uptake of services. Respite services which are currently available could also be made more appropriate to the needs of these carers by accommodating differences in linguistic ability, dietary needs, gender sensitivity, and other religious and cultural differences.


The use of herbal medicine in cancer-related anorexia/ cachexia treatment around the world.
Cancer-related cachexia, a condition in which the body is consumed by deranged carbohydrate, lipid and protein metabolism that is induced by inflammatory cytokines. Cachexia is associated with poor treatment outcome, fatigue and poor quality of life. Pharmacological intervention in the treatment and/or prevention of cachexia has been mainly aimed at the use of appetite enhancers to increase oral nutritional intake so far. Herbal remedies are part of traditional and folk healing methods with long histories of use. In this report, we have assessed which herbal approaches have had associated cancer cachexia case reports. Commonly used herbal medicines in western countries include essiac, iscador, pau d'arco tea, cannabinoids and so on. Some Kampo herbs and formulations are commonly used by cancer patients reduce the side effects and complications during the antitumor therapy. The relevant herbal medicines include ginseng, C. rhizome and radix astragali, and the related herbal remedies, such as TJ-48, TJ-41, PHY906 and Rikkunshito. However, there still have some adverse effects caused or amplified by herb and drug interactions that are difficult to separate. However, randomized effectiveness of herbal medicines shall be further identified in controlled clinical trials involving cancer patients with cachexia.


Involvement of Sodium Nitroprusside (SNP) in the Mechanism That Delays Stem Bending of Different Gerbera Cultivars.
Longevity of cut flowers of many gerbera cultivars (Gerbera jamesonii) is typically short because of stem bending; hence, stem bending that occurs during the early vase life period is a major problem in gerbera. Here, we investigated the effects of sodium nitroprusside (SNP) on the delay of stem bending in the gerbera cultivars, Alliance, Rosalin, and Bintang, by examining relative fresh weight, bacterial density in the vase solution, transcriptional analysis of a lignin biosynthesis gene, antioxidant activity, and xylem blockage. All three gerbera cultivars responded to SNP by delaying stem bending, compared to the controls; however, the responses were dose- and cultivar-dependent. Among the treatments, SNP at 20 mg L-1 was the best to delay stem bending in Alliance, while dosages of 10 and 5 mg L-1 were the best for Rosalin and Bintang, respectively. However, stem bending in Alliance and Rosalin was faster than in Bintang, indicating a discrepancy influenced by genotype. According to our analysis of the role of SNP in the delay of stem bending, the results revealed that SNP treatment inhibited bacterial growth and xylem blockage, enhanced expression levels of a lignin biosynthesis gene, and maintained antioxidant activities. Therefore, it is suggested that the cause of stem bending is associated with the above-mentioned parameters and SNP is involved in the mechanism that delays stem bending in the different gerbera cultivars.


[Biological properties of synthetic somatostatin].
Complex work on the assessment of biological properties of somatostatin synthesized according to a new original method was carried out. Its inhibitory action on the TTH, growth hormone and insulin secretion was demonstrated in vivo and in vitro. As a rule, somatostatin effect was expressed against the background of stimulated hormone secretion, although basal secretion inhibition was observed with respect to insulin, The inhibitory action of somatostatin on the hormonal secretion was direct, not mediated through any regulating factors.


MR-Guided Radiation Therapy With Concurrent Gemcitabine/Nab-Paclitaxel Chemotherapy in Inoperable Pancreatic Cancer: A TITE-CRM Phase I Trial.
Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. Magnetic resonance guided radiation therapy may safely permit radiation and chemotherapy dose escalation. We conducted a single-arm phase I study to determine the maximum tolerated dose of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC. Patients were treated with gemcitabine/nab-paclitaxel (1000/125 mg/m2) x 1c then concurrent gemcitabine/nab-paclitaxel and radiation. Gemcitabine/nab-paclitaxel and radiation doses were escalated per time-to-event continual reassessment method from 40 to 45 Gy 25 fxs with chemotherapy (600-800/75 mg/m2) to 60 to 67.5 Gy/15 fractions and concurrent gemcitabine/nab-paclitaxel (1000/100 mg/m2). The primary endpoint was maximum tolerated dose of radiation as defined by 60-day dose limiting toxicity (DLT). DLT was treatment-related G5, G4 hematologic, or G3 gastrointestinal requiring hospitalization >3 days. Secondary endpoints included resection rates, local progression free survival (LPFS), distant metastasis free survival (DMFS), and overall survival (OS). Thirty patients enrolled (March 2015-February 2019), with 26 evaluable patients (2 progressed before radiation, 1 was determined ineligible for radiation during planning, 1 withdrew consent). One DLT was observed. The DLT rate was 14.1% (3.3%-24.9%) with a maximum tolerated dose of gemcitabine/nab-paclitaxel (1000/100 mg/m2) and 67.5 Gy/15 fractions. At a median follow-up of 40.6 months for living patients the median OS was 14.5 months (95% confidence interval [CI], 10.9-28.2 months). The median OS for patients with Eastern Collaborative Oncology Group 0 and carbohydrate antigen 19-9 <90 were 34.1 (95% CI, 13.6-54.1) and 43.0 (95% CI, 8.0-not reached) months, respectively. Two-year LPFS and DMFS were 85% (95% CI, 63%-94%) and 57% (95% CI, 34%-73%), respectively. Full-dose gemcitabine/nab-paclitaxel with ablative magnetic resonance guided radiation therapy dosing is safe in patients with BR/LA-PDAC, with promising LPFS and DMFS.


[The effect of endoscopic sinus surgery on quality of life].
We assessed the effects of endoscopic sinus surgery on quality of life of patients with nasal polyposis or chronic sinusitis. Thirty patients (5 females, 25 males; mean age 36 years; range 17 to 58 years) who underwent endoscopic sinus surgery were prospectively evaluated. The diagnoses were nasal polyposis in 15 patients and chronic sinusitis in 15 patients. Primary and revision operations were performed in 23 patients and seven patients, respectively. The quality of life was evaluated before and six months after surgery with the use of the Chronic Sinusitis Survey (CSS), and Medical Outcomes Study Short Form-12 (SF-12). Prior to administration, the two questionnaires were translated and adapted to Turkish. Computed tomography (CT) findings were scored before and six months after surgery according to the Lund-Mackay system. The results of the surveys were compared with CT scores. The postoperative SF-12 and CSS scores of all the patients improved significantly. Computed tomography scores were not found in correlation with improvements in the SF-12 and CSS scores. Endoscopic sinus surgery results in significant improvement in the quality of life of patients with nasal polyposis and chronic sinusitis, which may not be reflected by CT scores.


Identification of genotoxic compounds using isogenic DNA repair deficient DT40 cell lines on a quantitative high throughput screening platform.
DNA repair pathways play a critical role in maintaining cellular homeostasis by repairing DNA damage induced by endogenous processes and xenobiotics, including environmental chemicals. Induction of DNA damage may lead to genomic instability, disruption of cellular homeostasis and potentially tumours. Isogenic chicken DT40 B-lymphocyte cell lines deficient in DNA repair pathways can be used to identify genotoxic compounds and aid in characterising the nature of the induced DNA damage. As part of the US Tox21 program, we previously optimised several different DT40 isogenic clones on a high-throughput screening platform and confirmed the utility of this approach for detecting genotoxicants by measuring differential cytotoxicity in wild-type and DNA repair-deficient clones following chemical exposure. In the study reported here, we screened the Tox21 10K compound library against two isogenic DNA repair-deficient DT40 cell lines (KU70 (-/-) /RAD54 (-/-) and REV3 (-/-) ) and the wild-type cell line using a cell viability assay that measures intracellular adenosine triphosphate levels. KU70 and RAD54 are genes associated with DNA double-strand break repair processes, and REV3 is associated with translesion DNA synthesis pathways. Active compounds identified in the primary screening included many well-known genotoxicants (e.g. adriamycin, melphalan) and several compounds previously untested for genotoxicity. A subset of compounds was further evaluated by assessing their ability to induce micronuclei and phosphorylated H2AX. Using this comprehensive approach, three compounds with previously undefined genotoxicity-2-oxiranemethanamine, AD-67 and tetraphenylolethane glycidyl ether-were identified as genotoxic. These results demonstrate the utility of this approach for identifying and prioritising compounds that may damage DNA.


Excess mortality in adults from Sao Paulo during the COVID-19 pandemic in 2020: analyses of all-cause and noncommunicable diseases mortality.
In this study, we estimated the excess mortality from all-causes of death and noncommunicable diseases (NCDs) in adults living in the state of São Paulo during the COVID-19 pandemic in 2020. Number of deaths were retrieved from the Mortality Information System before (2017-2019) and during (2020) the COVID-19 pandemic, considering the following underlying causes of death: Neoplasms; Diabetes Mellitus; Circulatory System Diseases, and Respiratory System Diseases. Standardized Mortality Ratio (SMR) were calculated by dividing the mortality rates in 2020 by average mortality rates in 2017-2019, according to sex, age group, geographic location (state, capital, and Regional Health Departments). In 2020, occurred 341,704 deaths in the state of São Paulo vs 290,679 deaths in 2017-2019, representing an 18% increase in all-cause mortality (SMR 1.18) or 51,025 excess deaths during the first year of COVID-19 pandemic. The excess mortality was higher in men (186,741 deaths in 2020 vs 156,371 deaths in 2017-2019; SMR 1.18; 30,370 excess deaths) compared to women (154,963 deaths in 2020 vs 134,308 deaths in 2017-2019; SMR 1.15; 20,655 excess deaths). Regarding NCDs mortality, we observed a reduction in cancer mortality (SMR 0.98; -1,354 deaths), diseases of the circulatory system (SMR 0.95; -4,277 deaths), and respiratory system (SMR 0.88; -1,945). We found a 26% increase in Diabetes Mellitus mortality (SMR 1.26; 2885 deaths) during the pandemic year. Our findings corroborate the need to create and strengthen policies aimed at the prevention and control of NCDs, in order to mitigate the impact of future infectious disease pandemics.


The 3Rs and animal welfare - conflict or the way forward?
The animal experiment is central to the 3R concept. In European law, animal experiments are classed according to their aims. In the German animal protection law, they are classed, e.g. as interventions and treatments for experimental purposes, for further education and training, or for the production, preparation, storage or multiplication of substances, products or organisms and for the fulfillment of legal requirements, and are thus regulated with varying strictness. In contrast, in Switzerland all such measures performed on live animals underlie the same approval requirements. For animal welfarists, the term "animal experiment" includes every intervention and every treatment which is associated with pain, fear and/or suffering and does not directly benefit the respective animal. In the animal experiment, the animal concerned usually suffers as a human would, independent of the experimental goal. Expecting an animal to suffer a treatment one would not want to undergo oneself cannot be in accord with an ethic of respect for fellow creatures. Animal welfarists aim to save animals such suffering. Consequently, they demand the immediate abolition of all animal experiments. From the perspective of those who allow animal experiments to be performed or who perform them themselves, the goal of the experiment is more important than the animal. Therefore, the following question is central to 3R research: "Can I reach my goal while causing the animal less suffering, using fewer animals or without using animals at all?" The starting point is that the ethical responsibility for man is valued higher than that for the animal. The aim is to protect humans from harm caused by substances and products or from unwanted side effects of medication, to understand diseases and to search for a cure or alleviation of these. When a scientist reaches his goals without using animals, the demand of animal welfarists to abolish the animal experiment is fulfilled. These aspects do of course not encompass all the differences and agreements in the positions of animal welfarists and those who support animal experiments. It is not without reason that the discussion around animal experiments is multifaceted and continues to be held intensely from all positions. The classic pattern of a discussion entails that the one side collects the arguments which illustrate that animal experiments lead to wrong results, cannot be transferred and finally stand more against than for the good of mankind. The latter statement is valid, because the wrong methods benefit from investment, thus preventing or hindering new, better research and application of knowledge. The other side uses, among others, the argument that the person performing the experiment knows the limits of the test procedure and can deal with them accordingly. For further defense of current and future animal experiments, scientists like to present their organ transplant patients, i.e. those who can only lead a life worth living thanks to continuous medication, and admonish that patients with Alzheimer's or Parkinson's disease or with cancer put their last hope into new medical insights which can only be gained with animal experiments. Animal welfarists argue against this, that the motivation for animal experiments does not always lie in the ethical responsibility for mankind, but also in pure gain of knowledge, titles and money. After all, they also claim that they are protecting man, animal and environment from diseases and want to help them. It is not about saving animals at any price, even including human life, as is commonly brought against them. But they are also not prepared to accept that without real necessity or at any hint of a dilemma, the decision always falls immediately against the animal. The animal experiment may no longer be the method of choice, both for ethical and also for scientific reasons. What does all of this have to do with 3R research? It is a fact that animal experiments are still the method of choice, the "gold standard". The official German statistics on animal experiments in 2001 (Governmental animal protection report, 2002) counts a total of 2.13 mill. experimental animals, with a tendency towards a further increase. The increase is ascribed to animal experiments especially in basic research, counting 926,294 animals. The other more than a million animals were used for research and development of products and equipment for human, dental or veterinary medicine (509,101), the production or quality control of products or equipment for human, dental or veterinary medicine (289,273), toxicological investigations or other safety tests (189,996), the diagnosis of diseases (26,508), education and training (39,625) and other purposes (145,764). Before this background, all activities which lead away from animal experiments or reduce the suffering caused in the remaining experimental animals must be judged as positive developments. 3R research leads to a reduction of animal experiments and animal suffering. At the same time, the earnest consideration of the 3Rs also leads to a critical and specific discussion of the animal experiment in question.


Appendicitis complicating pregnancy.
Thirty-four pregnant women with acute appendicitis presented at Parkland Memorial Hospital during a 15-year period. Abdominal pain, usually accompanied by nausea with or without vomiting, was the most common presenting symptom. Anorexia was less constant, and its occurrence decreased with advancing gestation. Physical findings usually included direct abdominal tenderness and, less often, rebound tenderness. Leukocytosis and/or a "left shift" were common laboratory findings, and the urinalysis was normal in most cases. Diagnosis was increasingly difficult as gestation progressed. This was reflected both by the increasing severity of the disease process found at surgery and by increasing fetal loss. If the diagnosis of appendicitis is suspected in the gravid patient, immediate surgical intervention is indicated to prevent the catastrophic complications associated with procrastination in diagnosis and treatment.


Recertification of psychiatrists: the time to act is now.
Because of the predictions of partial obsolescence for psychiatry as a profession and because of the increasing pressures of government, third-party payers, and a patient population that will no longer blindly follow physicians, psychiatrists must face the demands for professional accountability. The author suggests that to maintain high-quality care and continuing self-governance, psychiatrists must participate actively in self-assessment and continuing education programs.


The Trial-Ready Cohort for Preclinical/Prodromal Alzheimer's Disease (TRC-PAD) Project: An Overview.
The Trial-Ready Cohort for Preclinical/prodromal Alzheimer's Disease (TRC-PAD) project is a collaborative effort to establish an efficient mechanism for recruiting participants into very early stage Alzheimer's disease trials. Clinically normal and mildly symptomatic individuals are followed longitudinally in a web-based component called the Alzheimer's Prevention Trial Webstudy (APT Webstudy), with quarterly assessment of cognition and subjective concerns. The Webstudy data is used to predict the likelihood of brain amyloid elevation; individuals at relatively high risk are invited for in-person assessment in the TRC screeing phase, during which a cognitive battery is administered and Apolipoprotein E genotype is obtained followed by reassessment of risk of amyloid elevation. After an initial validation study, plasma amyloid peptide ratios will be included in this risk assessment. Based on this second risk calculation, individuals may have amyloid testing by PET scan or lumbar puncture, with those potentially eligible for trials followed in the TRC, while the rest are invited to remain in the APT Webstudy. To date, over 30,000 individuals have participated in the Webstudy; enrollment in the TRC is in its early stage.


Contribution of exoenzyme S to the virulence of Pseudomonas aeruginosa.
Exoenzyme S is an extracellular ADPR transferase produced by P. aeruginosa. Forms of this enzyme that have thus far been purified are not toxic, however, exoenzyme S clearly contributes to the virulence of strain 388. Thus, a Tn1 mutant deficient in exoenzyme S was found to be markedly less virulent than its exoenzyme S-producing parental strain in both a burned mouse infection model and a rat chronic lung infection model. Exoenzyme S does not appear to contribute to initial colonization of the rat lung or the burned mouse skin. Exoenzyme S does, however, appear to contribute to local tissue damage in the rat lung, and to dissemination of P. aeruginosa from the skin into the blood and distant organs of the burned mouse. Perhaps our most important observation is that specific antibody against exoenzyme S confers a high level of protection against subsequent infection of burned mice. While these results must be extended to include additional strains they are encouraging, and they underscore the relative importance of exoenzyme S in the pathogenesis of P. aeruginosa infections.


The diffusion of molecules in axonal plasma membranes: the sites of insertion of new membrane molecules and their distribution along the axon surface.
The neuronal cell surface consists of two domains, the somatodendritic and axonal plasma membranes. Each domain serves different functions, and has a different complement of membrane molecules. Since membrane molecules are able to diffuse in the plane of the plasma membrane lipid bilayer, with diffusion coefficients ranging from 10-8 cm 2 s-1 for lipids to 10-10 cm 2 s-1 for proteins, mechanisms must exist to prevent as intermixing of membrane molecules from each domain by diffusion. Presented here is a theoretical analysis of the distribution of axonal molecules in both growing and non-growing axons based on two models for the insertion of these molecules into the axonal membrane, namely insertion exclusively at the distal end of the axon, or insertion with equal probability all along the axon. In all cases, assuming that the molecules have a finite half-life in the axonal membrane, compositional differences between the axonal and somatodendritic membranes can be obtained that are similar to those observed in other polarized cells, even in the absence of a physical barrier to prevent the intermixing of membrane molecules. Moreover, our analyses demonstrate that the diffusion of membrane molecules in the plane of the axonal lipid bilayer is a sufficiently slow process to preclude the possibility that membrane molecules are inserted into axonal membranes at a site remote from their final location, and then move to their final locations for diffusion. Thus, in long axons, for membrane molecules that are localized all along the length of the axon, mechanisms must exist for their insertion in the axonal membrane at sites all along the axon, and not just at the distal end.


Barriers and facilitators for systematically registering adverse drug reactions in electronic health records: a qualitative study with Dutch healthcare professionals.
Systematically registering ADRs in electronic health records (EHRs) likely contribute to patient safety as it enables the exchange of drug safety data. Currently, ADRs registrations by healthcare professionals (HCPs) is suboptimal. This study aimed to identify barriers and facilitators perceived by HCPs to register ADRs systematically in EHRs. A qualitative study with individual interviews was conducted among specialist physicians and hospital pharmacists from 10 different Dutch hospitals. A semi-structured interview guide was used to identify experienced barriers and facilitators for systematically registering ADRs. Data was analyzed following thematic analysis. Themes within barriers and facilitators were aligned with the Capability-Opportunity-Motivation-Behavior (COM-B) framework. In total, 16 HCPs were interviewed. Identified barriers were: lack of knowledge to recognize ADRs, time constraints, inadequate IT system, lack of support, stuck in routine, and not recognizing the importance of registering ADRs. Identified facilitators were: enhanced knowledge and awareness of ADRs, functional IT systems, expanding accountability for registration, and motivation toward registering. Barriers and facilitators for registering spanned all aspects of the COM-B model and occurred in individual, social and environmental domains. Addressing these aspects could improve the registration of ADRs and may contribute to patient safety.


Late cretaceous precessional cycles in double time: a warm-Earth milankovitch response.
Late Cretaceous climatic cycles are reflected in lithological and magnetic variations in carbonate sediments from South Atlantic Deep-Sea Drilling Project site 516F at a paleolatitude of roughly 30 degrees S. Magnetic susceptibility cycles 20 to 60 centimeters in length appear to be controlled by the precession of the equinoxes. Cyclicity is particularly robust within a 24-meter interval in the lower Campanian, where overtone spectral peaks are observed as well as secondary susceptibility maxima within individual precession cycles. One model for this behavior is that sedimentation in the narrow Cretaceous South Atlantic was controlled by equatorial climate dynamics, with the precessional insolation signal rectified by the large land masses surrounding the ocean basin.


Theory of nonlinear elasticity, stress-induced relaxation, and dynamic yielding in dense fluids of hard nonspherical colloids.
We generalize the microscopic naïve mode coupling and nonlinear Langevin equation theories of the coupled translation-rotation dynamics of dense suspensions of uniaxial colloids to treat the effect of applied stress on shear elasticity, cooperative cage escape, structural relaxation, and dynamic and static yielding. The key concept is a stress-dependent dynamic free energy surface that quantifies the center-of-mass force and torque on a moving colloid. The consequences of variable particle aspect ratio and volume fraction, and the role of plastic versus double glasses, are established in the context of dense, glass-forming suspensions of hard-core dicolloids. For low aspect ratios, the theory provides a microscopic basis for the recently observed phenomenon of double yielding as a consequence of stress-driven sequential unlocking of caging constraints via reduction of the distinct entropic barriers associated with the rotational and translational degrees of freedom. The existence, and breadth in volume fraction, of the double yielding phenomena is predicted to generally depend on both the degree of particle anisotropy and experimental probing frequency, and as a consequence typically occurs only over a window of (high) volume fractions where there is strong decoupling of rotational and translational activated relaxation. At high enough concentrations, a return to single yielding is predicted. For large aspect ratio dicolloids, rotation and translation are always strongly coupled in the activated barrier hopping event, and hence for all stresses only a single yielding process is predicted.


Urethral injuries in Lagos.
Good results have been obtained following the treatment of incomplete urethral rupture while the results of complete urethral rupture treated in this hospital by the conventional method have been very poor. This poor result is comparable to those from other centers using similar methods. A review of various treatment methods was undertaken and reasons are given for advocating the method of initial suprapubic cystostomy, followed by delay urethroplasty.


Clinical nursing leaders', team members' and service managers' experiences of implementing evidence at a local level.
To describe the experiences of 14 clinical nursing leaders introducing a knowledge translation (KT) project into one metropolitan acute care hospital in South Australia. The study also explored team members' and service managers' experiences. KT strategies assume that local (nursing) clinical leaders have the capacity and capability to champion innovation combining positional leadership roles (ward leader) with a project lead role. There is limited evidence to support these assumptions. Semi-structured interviews of clinical nursing leaders and managers were undertaken at month 4 and 12 of the project. Data were also collected from the interdisciplinary team members (n = 28). Clinical nursing leaders identified risks and anxieties associated with taking on an additional leadership role, whereas managers acknowledged the multiple pressures on the system and the need for local level innovation. Team members generally reported positive experiences. With support, clinical nursing leaders can effectively embrace KT project leadership roles that complement their positional leadership roles. Clinical nursing leaders' experiences differed from nursing and medical managers' experiences. Managers need to be more attuned to the personal risks local leaders experience, providing support for leaders to experiment and innovate. Managers need to integrate local priorities with broader system wide agendas.


Similar frequencies of Pseudomonas aeruginosa isolates producing KPC and VIM carbapenemases in diverse genetic clones at tertiary-care hospitals in Medellín, Colombia.
Carbapenem-resistant Pseudomonas aeruginosa has become a serious health threat worldwide due to the limited options available for its treatment. Understanding its epidemiology contributes to the control of antibiotic resistance. The aim of this study was to describe the clinical and molecular characteristics of infections caused by carbapenem-resistant P. aeruginosa isolates in five tertiary-care hospitals in Medellín, Colombia. A cross-sectional study was conducted in five tertiary-care hospitals from June 2012 to March 2014. All hospitalized patients infected by carbapenem-resistant P. aeruginosa were included. Clinical information was obtained from medical records. Molecular analyses included PCR for detection of bla(VIM), bla(IMP), bla(NDM), bla(OXA-48), and bla(KPC) genes plus pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) for molecular typing. A total of 235 patients were enrolled: 91.1% of them were adults (n = 214), 88.1% (n = 207) had prior antibiotic use, and 14.9% (n = 35) had urinary tract infections. The bla(VIM-2) and bla(KPC-2) genes were detected in 13.6% (n = 32) and 11.5% (n = 27), respectively, of all isolates. Two isolates harbored both genes simultaneously. For KPC-producing isolates, PFGE revealed closely related strains within each hospital, and sequence types (STs) ST362 and ST235 and two new STs were found by MLST. With PFGE, VIM-producing isolates appeared highly diverse, and MLST revealed ST111 in four hospitals and five new STs. These results show that KPC-producing P. aeruginosa is currently disseminating rapidly and occurring at a frequency similar to that of VIM-producing P. aeruginosa isolates (approximately 1:1 ratio) in Medellín, Colombia. Diverse genetic backgrounds among resistant strains suggest an excessive antibiotic pressure resulting in the selection of resistant strains.


Reliability and validity of 2 single-item measures of psychosocial stress.
Practical limitations in epidemiologic research may necessitate use of only a few questions for assessing the complex phenomenon called "stress." The objective of this study was to evaluate the measurement characteristics of 2 single-item measures on the amount of stress and the ability to handle stress. We selected 218 adults age 50 to 76 years living in western Washington state from a large prospective cohort study of lifestyle factors and cancer risk to evaluate the 3-month test-retest reliability and intermethod reliability of the stress questions. To assess the latter, we compared 2 single-item measures on stress with 3 more fully validated multi-item instruments on perceived stress, daily hassles, and life events, which assessed the same underlying constructs as the single-item measures. The test-retest reliabilities for the single-item stress measures were good (kappa and intraclass correlations between 0.66 and 0.74). The intermethod reliabilities comparing the 2 single-item stress measures with 3 multi-item instruments were moderate (r = 0.31-0.46) and comparable to correlations observed among the 3 multi-item instruments (r = 0.25-0.47). The 2 single-item stress measures are reliable at measuring stress with validity similar to longer questionnaires. Single-item measures offer a practical instrument for assessing stress in large prospective epidemiologic studies that lack space for longer instruments.


Polysaccharides from Hemp Seed Protect against Cyclophosphamide-Induced Intestinal Oxidative Damage via Nrf2-Keap1 Signaling Pathway in Mice.
Hemp seed has been used as a traditional oriental medicine and health food in China for centuries. Polysaccharides from hemp seed (HSP) exhibit important properties of intestinal protection, but there are limited data on the specific underlying mechanism. The primary objective of this study was to investigate the protective effect of HSP on intestinal oxidative damage induced by cyclophosphamide (Cy) in mice. The results showed that pretreatment with HSP significantly increased the average daily gain, thymus index, spleen index, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity in serum and ileal homogenate and significantly reduced malondialdehyde (MDA) content in ileal homogenate. In addition, the expression levels of SOD, GSH-Px, Nrf2, heme oxidase-1 (HO-1), and quinoneoxidoreductase-1 (NQO1) mRNA in ileal homogenate were significantly increased. Western blot results showed that HSP significantly upregulated the expression of Nrf2 protein and downregulated the expression of Keap1 protein in the ileum. Collectively, our findings indicated that HSP had protective effects on intestinal oxidative damage induced by Cy in mice, and its mechanism might be related to the activation of Nrf2-Keap1 signaling pathway.


Association kinetics with coupled diffusion III. Ionic-strength dependence of the lac repressor-operator association.
The repressor-operator association is treated in a model where the repressor molecule can find its specific binding site, the operator, on a large DNA chain by performing a one-dimensional diffusion along the chain. The ionic-strength dependence is calculated by introducing a screened electrostatic potential around the DNA chain and coupling the free diffusion of the repressor in this potential to the proposed one-dimensional diffusion along the chain. The main influence on the association rate comes from the competitive binding of ions to the unspecific DNA sites. It is also demonstrated that during the time that the repressor is bound in a global sense, the diffusion along the chain will be made up of a strictly one-dimensional motion over fairly short distances, interspersed with many local dissociations during which the repressor in essence is free in solution.


Pseudocholinesterase Deficiency Considerations: A Case Study.
Pseudocholinesterase deficiency, sometimes called butyrylcholinesterase deficiency, is a rare disorder in which the neuromuscular blocking drugs succinylcholine and mivacurium cannot be metabolized properly in the blood plasma. This disorder can either be acquired as a result of certain comorbidities or it can be inherited genetically. Anesthesia providers must understand the pathophysiology of pseudocholinesterase deficiency and be prepared to safely and effectively manage patients who show signs and symptoms consistent with the disorder after the use of the indicated neuromuscular blocking drugs. This article summarizes the pharmacologic and physiologic data relevant to understanding the basic pathophysiology associated with pseudocholinesterase deficiency and illustrates a case study of a young woman suspected of having the disorder after a prolonged delay in emergence from general anesthesia.


[Characteristics of the human thermal state and environment in long-term space flight].
Summarized are data of many-year studies of thermal loading and thermal state of humans in different microclimates. Comparative analysis of various approaches to thermal monitoring of cosmonauts in space suits was performed with the conclusion about advantages of parotid thermometry. To set microclimate standards for long-term space flight, a complex index of the environment cooling potential (ECP) based on the use of an electrical dynamic catathermometer has been proposed. A correlation between ECP values and cosmonaut's thermal sensations was elicited. For the most part, the proposed recommendations have been verified or introduced in the space crew medical care system.


Relationship between meiotic behaviour and fertility in backcross-1 derivatives of the [(Gossypium hirsutum × G. thurberi)2 × G. longicalyx] trispecies hybrid.
Wild cotton species are an important source of desirable genes for genetic improvement of cultivated cotton Gossypium hirsutum Linnaeus, 1763. For the success of such an improvement, chromosome pairings and recombinations in hybrids are fundamental. The wild African species G. longicalyx Hutchinson & Lee, 1958 could be used as donor of the desirable trait of fiber fineness. Twelve BC1 plants obtained from the backcrossing of [(G. hirsutum × G. thurberi Todaro, 1877)2 × G. longicalyx] (AhDhD1F1, 2n = 4x = 52) trispecies hybrid (HTL) by G. hirsutum (cv. C2) (AhAhDhDh, 2n = 4x = 52) were investigated for meiotic behaviour and plant fertility. Their chromosome associations varied as follows: (2.5 to 11.5) I + (17 to 22) II + (0.31 to 1.93) III + (0.09 to 1.93) IV + (0 to 0.07) V + (0 to 0.14) VI. Their pollen fertility ranged from 4.67 to 32.10 %. Only four BC1 plants produced a few seeds through self-pollination. The remaining BC1 were totally self-sterile and usually presented the highest number of univalents. All BC1 materials produced BC2 seeds (0.44 to 6.50 seeds per backcross) with the number of seeds negatively correlated with the number of univalents (R2 = 0.45, P < 0.05). Most BC1 plants gave significantly finer fiber compared to the cultivated G. hirsutum. SSR markers showed a segregation of wild alleles among the backcross derivatives and Genomic in situ hybridization (GISH) revealed presence of entire chromosomes of G. longicalyx as well as recombinant chromosomes in the backcross derivatives. The significance and details of these results are presented and the prospects of successfully exploiting these plant materials are discussed.


[Nets of excitable elements. IX. Hebb nets].
It is shown that the mechanism of bond creation suggested by Hebb, acting in a neuron net without exterior effects arranges there a structure of a ring type. The activity of such a system has periodic component. Its period is close to the duration of trace processes in neuron nets. A hypothesis is suggested about a real object where this phenomenon may be observed.


[Scurvy after a suicide attempt by starvation].
A 29-year-old man was admitted to hospital, unconscious and with extensive bleedings in skin and muscles. For many weeks he had been practically starving himself with suicidal intent. Physical examination revealed signs of anaemia and gingivitis with hypertrophy of the tooth borders and bleeding gums, as well as bright blood on rectal examination. There were extensive ecchymoses and petechiae, especially in the legs. Some of the body hair was corkscrew-curly. Haemoglobin level was 7.2 g/dl, mean corpuscular volume 93 fl, reticulocyte count 29/1000. The Rumpel-Leede test was abnormal (60 petechiae/4 cm2), as were the vitamin C level (0.026 mg/dl whole blood) and the ascorbic acid tolerance test. As these findings indicated scurvy, vitamin C was administered, 1 g daily intravenously for 5 days, followed by 500 mg daily by mouth. Remarkable improvement was apparent as early as 72 hours after onset of treatment. The endogenous depression, the underlying cause of the suicide attempt, was treated with clomipramine. When the patient was discharged after 13 days his physical and mental state was much improved.


Cervical spondylotic myelopathy treated by anterior multilevel decompression and fusion. Follow-up report of 214 cases.
From 1974 to 1982, 214 patients were treated for cervical spondylotic myelopathy by anterior multilevel decompression and the Robinson anterior interbody fusion and followed for an average of three years and 11 months. Postoperative results were superior to those obtained previously using posterior decompression. The average patient age was 50.1 years (range, 30-75); there were 187 men and 27 women. Overall, the percent of patients with excellent and good results was 59.3%; with fair results, 29%, no change; 7.9%, and deterioration, 3.8%. Of the 111 patients who had the disease less than one year before treatment, 74% were categorized after surgery as excellent or good. In contrast, only 36% of the 66 patients who had the disease more than two years were rated excellent and good. Myelography is valuable in diagnosing and locating lesions. The average number of discs removed was 3.1 per patient. The number of cases with excellent and good results was the same whether or not union of the graft occurred. Reoperation was required in 12 patients, and a third operation was performed in three patients. Eventually, 93% of the patients were able to lead independent lives.


[Biological value of a soy-corn-wheat based noodle (macaroni) supplemented with lysine (author's transl)].
The biological value of a soy-corn-wheat based noodle (macaroni) prepared by the General Food Corporation was studied. The protein level of the noodle was of 20.5g%. Thirty-six Albino rats were used in this experimental. The animals were divided into sex groups of six animals each. The experimental groups were fed: a) cooked macaroni without lysine; and b) macaroni supplemented with increasing levels of L-lysine HCL. The control group received commercial casein. The protein level of the experimental diets was of 10g%. At the end of the fourth week of the experiment some rats showed a slight difference in the growth curve, specially the animals fed macaroni without lysine. However, statistical analysis did not show a significant difference. The protein efficiency ratio (PER) of the experimental groups was similar to that of the control group, but when the lysine level of the diets increased there was a corresponding increase in the PER. No significant difference was noted too. These results suggest that lysine do not improve the biological value of the noodle.


Bioflocculation: chemical free, pre-treatment technology for the desalination industry.
Rapid sand filtration (RSF), proceeded by chemical coagulation and flocculation, is a commonly used, effective pretreatment in the desalination industry. We designed and tested a novel, large pilot-scale, two-stage granular Rapid Bioflocculation Filter (RBF) based on a first-stage Bioflocculator (BF) unit followed by a mixed-media bed filter (MBF). The BF filter bed consisted of an extremely porous volcanic Tuff granular medium which provided an enlarged surface area for microbial development and biofilm proliferation. We compared the efficiency of the pilot RBF to that of a full-scale RSF, operating with upstream chemical coagulation, by measuring the removal from the same untreated seawater feed of key factors related to membrane clogging: SDI, turbidity, chlorophyll a (Chl a) and transparent exopolymer particles (TEP). After 2 weeks of operation, the Tuff grains were colonized extensively by coccoid bacteria that formed biofilm along the entire BF. With bacterial colonization and biofilm development, numerous aggregates of bacteria and some algal cells embedded in an amorphous organic matrix were formed on and within the Tuff grains. By 1-3 months, the biotic diversity within the Tuff filter bed had increased to include filamentous bacteria, cyanobacteria, fungi, protista and even crustaceans and marine worms. During and for ≈ 24 h after each cleaning cycle (carried out every 5 to 7 days by upward flushing with air and water), large numbers of floc-like particles, from ≈ 15 μm to ≈ 2 mm in size were observed in the filtrate of the BF unit. Microscopic examination of these flocs (stained with Alcian Blue and SYTO(R) 9) showed that they were aggregates of many smaller particles with associated bacteria and algae within a polysaccharide gel-like matrix. These biogenic flocs (bioflocs) were observed to form during normal operation of the RBF, accumulating as aggregates of inorganic and organic material on the Tuff surfaces. With each flush cleaning cycle, these bioflocs were released into the BF effluent but were retained by the second phase MBF unit. No flocs were seen in the MBF filtrate. Over a year-long study, both the pilot RBF and the full-scale RSF showed similar filtration efficiencies, measured as the percentage removal of Chl a, TEP, turbidity and SDI from the same seawater feed. These results indicate the potential of the bioflocculation approach with no chemical additives as an alternative to conventional RSF pretreatment for large SWRO facilities.


Does the "Hispanic paradox" occur in rheumatoid arthritis? Survival data from a multiethnic cohort.
Despite lower socioeconomic status (SES) and higher disease burden, Hispanics in the US paradoxically display equal or lower mortality on average than non-Hispanic whites. Our objective was to determine if the "Hispanic paradox" occurs among patients with rheumatoid arthritis (RA). In a cohort of 706 RA patients, we compared differences in RA severity and comorbidity between Hispanic and non-Hispanic white ethnic groups at baseline. Cox proportional hazards models were used to estimate and compare mortality risk between Hispanics and non-Hispanic whites. We studied 706 patients with RA, of whom 434 were Hispanic and 272 were non-Hispanic white. Hispanics had significantly lower SES, greater inflammation, as well as higher tender and swollen joint counts. Patients were observed for 6,639 patient-years, during which time 229 deaths occurred by the censoring date (rate 3.4 per 100 person-years; 95% confidence interval 3.0, 3.9). Age- and sex-adjusted mortality was not significantly different between the 2 ethnic groups (hazard ratio [HR] 0.96). After adjustment for comorbidities, RA severity, and level of acculturation, mortality among Hispanics was lower (HR 0.56, P = 0.004). Despite greater severity in most clinical manifestations and lower SES among Hispanics, paradoxically, their mortality was not increased. Further research is needed to understand the mechanisms underlying this survival paradox.


Inflammatory, anti-inflammatory and regulatory cytokines in relatively healthy lung tissue as an essential part of the local immune system.
The innate and adaptive immune systems in lungs are maintained not only by immune cells but also by non-immune tissue structures, locally providing wide intercellular communication networks and regulating the local tissue immune response. The aim of this study was to determine the appearance and distribution of inflammatory, anti-inflammatory and regulatory cytokines in relatively healthy lung tissue samples. We evaluated lung tissue specimens obtained from 49 patients aged 9-95 years in relatively healthy study subjects. Tissue samples were examined by hematoxylin and eosin staining. Interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-7 (IL-7), and interleukin-10 (IL-10) were detected by an immunohistochemistry (IMH) method. The number of positive structures was counted semiquantitatively by microscopy. Non-parametric tests were used to analyse the data. IL-1-positive cells were mostly found in the bronchial cartilage and alveolar epithelium. Immunoreactive lung macrophages were also found. The numbers of IL-4, IL-6, IL-7, and IL-10 containing cells were also found in the bronchial epithelium (in addition to those previously listed). The number of positive structures varied from occasional to moderate, but was graded higher in cartilage. Overall, fewer IL-1-positive cells and more IL-10-positive cells were found. Almost no positive structures for all examined cytokines were found in connective tissue and bronchial glands. Relatively healthy lung tissue exhibits anti-inflammatory response patterns. The cytokine distribution and appearance suggest persistent stimulation of cytokine expression in lung tissue and indicate the presence of local regulatory and modulating patterns. The pronounced cytokine distribution in bronchial cartilage suggests the involvement of a compensatory local immune response in the supporting tissue.


Community perception of school-based delivery of anthelmintics in Ghana and Tanzania.
This paper presents the results of an evaluation of community perception of two large-scale, government-run, school-based health programmes delivering anthelmintic drugs to primary school children, in Ghana (80 442 children in 577 schools) and Tanzania (110 000 children in 352 schools). Most teachers (96% in Ghana and 98% in Tanzania) were positive about their role in the programme, including administration of anthelmintic drugs, and parents and children fully accepted their taking on this role. The benefits of the programme were apparent to teachers, parents and children in terms of improved health and well-being of the children. Over 90% of parents in both Ghana and Tanzania indicated a willingness to pay for the continuation of drug treatment. The evaluation also highlighted areas that are critical to programme effectiveness, such as communication between schools and parents, the issue of collaboration between the health and education sectors, parents' perception of the importance of helminth infection as a serious and chronic health problem (compared with more acute and life threatening illnesses such as malaria), and who should pay for treatment of side-effects.


An analysis of intestinal transplant in the United States.
We performed a retrospective analysis of intestinal transplant patients from United States transplant centers using The Organ Procurement and Transplantation Network/United Network of Organ Sharing (OPTN/UNOS) registry. A total of 2164 intestinal transplants were performed in the United States between 1990 and the end of 2011 and were reported to UNOS. Gender, ethnicity, age at transplant, and original disease had little impact on intestinal allograft survival. We found that a shift in the type of transplant operation [intestine alone, intestine plus liver (I+L), or intestine plus liver and pancreas (I+L+P)] away from I+L, starting in 2005, led to better outcomes. Transplants including the stomach had significantly worse graft survival, and often were performed with the I+L+P method. Even though the outcomes of co-transplant of stomach methods, especially the I+L+P method were shown not to be favorable, in reality, the number of patients receiving the operation is still increasing. Despite the overall improvement in graft survival for intestinal transplants over the last 2 decades, within the 2 decades there is a different story. Graft survival after 2005 compared to seven years before 2005 has not improved. Going forward, there is still significant room for improvement in intestinal transplantation. Based on the improvements over the past 2 decades, there is hope that in the next 2 decades, intestinal transplant will reach the success of renal, cardiac, and liver transplantation.


Intermittent stimulation in the nucleus basalis of meynert improves sustained attention in rhesus monkeys.
Sustained attention is essential in important behaviors in daily life. Many neuropsychiatric disorders are characterized by a compromised ability to sustain attention, making this cognitive domain an important therapeutic target. In this study, we tested a novel method of improving sustained attention. Monkeys were engaged in a continuous performance task (CPT) while the nucleus basalis of Meynert (NB), the main source of cholinergic innervation of the neocortex, was stimulated. Intermittent NB stimulation improved the animals' performance by increasing the hit rate and decreasing the false alarm rate. Administration of the cholinesterase inhibitor donepezil or the muscarinic antagonist scopolamine alone impaired performance, whereas the nicotinic antagonist mecamylamine alone improved performance. Applying NB stimulation while mecamylamine or donepezil were administered impaired CPT performance. Methylphenidate, a monoaminergic psychostimulant, was applied in conjunction with intermittent stimulation as a negative control, as it does not directly modulate cholinergic output. Methylphenidate also improved performance, and it produced further improvement when combined with NB stimulation. The additive effect of the combination suggested NB stimulation altered behavior independently from methylphenidate effects. We conclude that basal forebrain projections contribute to sustained attention, and that intermittent NB stimulation is an effective way of improving performance.


Lessons from a gene regulatory network: echinoderm skeletogenesis provides insights into evolution, plasticity and morphogenesis.
Significant new insights have emerged from the analysis of a gene regulatory network (GRN) that underlies the development of the endoskeleton of the sea urchin embryo. Comparative studies have revealed ways in which this GRN has been modified (and conserved) during echinoderm evolution, and point to mechanisms associated with the evolution of a new cell lineage. The skeletogenic GRN has also recently been used to study the long-standing problem of developmental plasticity. Other recent findings have linked this transcriptional GRN to morphoregulatory proteins that control skeletal anatomy. These new studies highlight powerful new ways in which GRNs can be used to dissect development and the evolution of morphogenesis.


Serratia ficaria isolated from a human clinical specimen.
The first isolation of Serratia ficaria from a human source is reported. Investigation into the eating habits of the patient revealed the probable source as figs, which are one of the natural reservoirs of this organism. How this and other normally saprophytic Serratia species can be distinguished from Serratia marcescens is reviewed.


Willingness to Receive the Influenza A(H1N1) Vaccine and its Determinants among University Students during the 2009 Outbreak in Turkey.
The study aimed to determine the willingness to receive the Influenza A(H1N1) vaccine and its determinants in a large group of university students. This is a self-administered questionnairre based cross-sectional study. Students being educated at health and non-health faculties were invited to participate in this attitude survey. A total of 974 students were included in the study, of whom 51.3% (n=500) were in health related faculties. The rate of willingness to receive the Influenza A(H1N1) vaccine was 11.9 and 7.5% for health and non-health groups, respectively (p<0.05). For the health group, having been vaccined with seasonal influenza was a significant determinant of being willingness to receive the Influenza A(H1N1) vaccine (O.R [95% C.I.]), (O.R: 2.9 [1.5-5.6]) and to believe that the Influenza A(H1N1) vaccine prevents swine flu (O.R: 1.7 [1.09-2.8]). For the non-health group, the only determinant was to believe that Influenza A(H1N1) vaccine prevents from swine flu (O.R: 19.1 [5.7-64.1]) which found to be affected by confusing news in media. The public health professionals who will organize the efforts to improve the acceptability of Influenza A vaccines during influenza outbreaks should try to increase the vaccination rates of seasonal influenza. Information provided by the media should be organized in order not to cause fear and confusion, which was shown to decrease willingness and belief in the Influenza A(H1N1) vaccine.


Pyrimethamine inhibits rabies virus replication in vitro.
Rabies virus transmits from animals to humans and causes encephalitis. Every year more than 15 million people receive a post exposure prophylaxis (PEP) treatment that is highly effective in the prevention of rabies disease. However, when clinical symptoms appear, for example in people who did not receive PEP, rabies is almost invariably fatal. Due to the limited access to PEP in some target populations, mostly in Asia and in Africa, rabies causes at least 59,000 deaths a year. PEP is not effective after the onset of symptoms and attempts to develop a treatment for clinical rabies have been unsuccessful. After screening a library of 385 FDA-approved drugs, we found that pyrimethamine inhibits rabies infection in vitro through the inhibition of adenosine synthesis. In addition, this compound shows a synergistic interaction with ribavirin. Unfortunately, in rabies infected-mice, pyrimethamine showed no efficacy. One possible explanation may be that the antiviral effect is negated by the observed interference of pyrimethamine with the innate immune response.


Phenotypic changes in immune cell subsets reflect increased infarct volume in male vs. female mice.
Inflammatory responses in the brain after cerebral ischemia have been studied extensively in male mice, but not female mice, thus potentially giving a less-than-accurate view of gender associated pathological processes. In humans, cerebral infarcts are typically smaller in premenopausal females than in age-matched males. In the current study, we confirmed smaller infarcts in female vs. male mice after middle cerebral artery occlusion and 96 h of reperfusion. Moreover, we explored immunological alterations related to this difference and found that the percentage of CD4+ T lymphocytes was significantly higher in spleens in males than females, with increased expression of the activation markers, CD69 and CD44. In contrast, the percentage of CD8+ T lymphocytes was significantly higher in spleens of females than males, leading to the identification of a small but distinct population of IL-10-secreting CD8+CD122+ suppressor T cells that were also increased in females. Finally, we observed that males have a greater percentage of activated macrophages/microglia in the brain than females, as well as increased expression of the VLA-4 adhesion molecule in both brain and spleen. This new information suggesting gender-dependent immunological mechanisms in stroke implies that effective treatments for human stroke may also be gender specific.


[Prevalence of Staphylococcus aureus colonization in renal transplant patients].
to evaluate the prevalence of Staphylococcus aureus nasal colonization in renal transplant patients and to identify the related risk factors. Swabs were used to collect nasal samples from 160 patients who had undergone a transplant within the previous year at the Kidney and Hypertension Hospital. The 'National Committee for Clinical Laboratory Standards' norms were followed for the collection, isolation, identification and sensitivity measurements. There was a 9.4% (15) prevalence of Staphylococcus aureus nasal colonization, of which one (6.7%) was resistant to oxacillin. It was possible to identify as an associated risk factor a wait of more than one year for accessing dialysis prior to the transplant (p=0.029). Given the high morbidity and mortality rates that this microorganism causes in the target population, other studies should be carried out, and pre- and post-transplant screening should occur in order to develop strategies that improve the prevention and control of the spread of Staphylococcus aureus.


A Multi-Network Comparative Analysis of Transcriptome and Translatome Identifies Novel Hub Genes in Cardiac Remodeling.
Our understanding of the transition from physiological to pathological cardiac hypertrophy remains elusive and largely based on reductionist hypotheses. Here, we profiled the translatomes of 15 mouse hearts to provide a molecular blueprint of altered gene networks in early cardiac remodeling. Using co-expression analysis, we showed how sub-networks are orchestrated into functional modules associated with pathological phenotypes. We discovered unappreciated hub genes, many undocumented for their role in cardiac hypertrophy, and genes in the transcriptional network that were rewired in the translational network, and associated with semantically different subsets of enriched functional terms, such as Fam210a, a novel musculoskeletal modulator, or Psmd12, implicated in protein quality control. Using their correlation structure, we found that transcriptome networks are only partially reproducible at the translatome level, providing further evidence of post-transcriptional control at the level of translation. Our results provide novel insights into the complexity of the organization of in vivo cardiac regulatory networks.


The difference between acute and chronic pain.
Acute and chronic pain are different clinical entities. Acute pain is provoked by a specific disease or injury, serves a useful biologic purpose, is associated with skeletal muscle spasm and sympathetic nervous system activation, and is self-limited. Chronic pain, in contrast, may be considered a disease state. It is pain that outlasts the normal time of healing, if associated with a disease or injury. Chronic pain may arise from psychological states, serves no biologic purpose, and has no recognizable end-point. Both acute and chronic pain are an enormous problem in the United States, costing 650 million lost workdays and $65 billion a year. The therapy of acute pain is aimed at treating the underlying cause and interrupting the nociceptive signals. The therapy of chronic pain must rely on a multidisciplinary approach and should involve more than one therapeutic modality.


Management of oropharyngeal teratoma: Two case reports and a literature review.
Pharyngeal teratomas are very rare congenital tumours derived from pluripotent stem cells. Surgical resection is the main treatment to avoid breathing and feeding difficulties. This current case report describes two newborn infants with congenital oropharyngeal teratomas. In one of the infants, the tumour presented along with a cleft tongue and cleft palate. Prenatal diagnosis by ultrasonography did not identify the tumours because the masses were small and there was no polyhydramnios. Both cases were treated surgically and histological examination of the masses in both cases confirmed the diagnosis of a congenital epignathus. There were no complications such as infection, bleeding or residual recurrence following surgery. After 1-year follow-up, there was no recurrence of the epignathus in either case. Oropharyngeal teratoma is a very rare congenital tumour that may cause upper airway obstruction and feeding difficulties in the newborn, so it should be treated surgically in a timely manner.


Molecular Basis of Antigenic Drift in Serotype O Foot-and-Mouth Disease Viruses (2013-2018) from Southeast Asia.
Foot and mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals with serious economic consequences. FMD is endemic in Southeast Asia (SEA) and East Asia (EA) with the circulation of multiple serotypes, posing a threat to Australia and other FMD-free countries. Although vaccination is one of the most important control measures to prevent FMD outbreaks, the available vaccines may not be able to provide enough cross-protection against the FMD viruses (FMDVs) circulating in these countries due to the incursion of new lineages and sub-lineages as experienced in South Korea during 2010, a FMD-free country, when a new lineage of serotype O FMDV (Mya-98) spread to the country, resulting in devastating economic consequences. In this study, a total of 62 serotype O (2013-2018) viruses selected from SEA and EA countries were antigenically characterized by virus neutralization tests using three existing (O/HKN/6/83, O/IND/R2/75 and O/PanAsia-2) and one putative (O/MYA/2009) vaccine strains and full capsid sequencing. The Capsid sequence analysis revealed three topotypes, Cathay, SEA and Middle East-South Asia (ME-SA) of FMDVs circulating in the region. The vaccines used in this study showed a good match with the SEA and ME-SA viruses. However, none of the recently circulating Cathay topotype viruses were protected by any of the vaccine strains, including the existing Cathay topotype vaccine (O/HKN/6/83), indicating an antigenic drift and, also the urgency to monitor this topotype in the region and develop a new vaccine strain if necessary, although currently the presence of this topotype is mainly restricted to China, Hong Kong, Taiwan and Vietnam. Further, the capsid sequences of these viruses were analyzed that identified several capsid amino acid substitutions involving neutralizing antigenic sites 1, 2 and 5, which either individually or together could underpin the observed antigenic drift.


Properties of rat kidney glutaminase enzymes and their role in renal ammoniagenesis.
Rat kidney contains two distinct glutaminase activities; the mitochondrial phosphate-dependent glutaminase and a second glutaminase activity associated with the brush border membrane which is maleate-activated and phosphate-independent. It has recently been shown that the phosphate-independent glutaminase is a partial reaction of gamma-glutamyl transpeptidase and that maleate activates this enzyme by blocking transpeptidation. The gamma-glutamyl transpeptidase in other rat tissues is also affected by maleate. This enzyme has at least a 100-fold greater affinity for glutathione or for glutathione derivatives than for glutamine, suggesting that under physiological conditions glutathione is the preferred substrate. With either type of substrate, maleate affects the Vmax of the reaction but not the Km. These findings suggest that this enzyme probably contributes very little to renal ammoniagenesis. In contrast, the phosphate-dependent glutaminase, whose activity increases 20 to 30-fold in the proximal convoluted tubule cells in response to metabolic acidosis, probably contributes significantly to renal ammoniagenesis. We have purified the rat kidney phosphate-dependent glutaminase and compared the phosphate activation and the phosphate-induced dimerization of the Tris form of this enzyme. There is an excellent correlation between increased activity and extent of dimerization as phosphate concentration is increased. The molecular weights of the Tris form are 1600000 and 316000 in the absence and presence of -1 M NaPO4, respectively. At saturating concentration of phosphate, increasing concentrations of chloride ion similarly reverse both activation and dimerization. These observations suggest that only the dimer form of the Tris enzyme is active.


Two variants located in the upstream enhancer region of human UCP1 gene affect gene expression and are correlated with human longevity.
The brown fat specific UnCoupling Protein 1 (UCP1) is involved in thermogenesis, a process by which energy is dissipated as heat in response to cold stress and excess of caloric intake. Thermogenesis has potential implications for body mass control and cellular fat metabolism. In fact, in humans, the variability of the UCP1 gene is associated with obesity, fat gain and metabolism. Since regulation of metabolism is one of the key-pathways in lifespan extension, we tested the possible effects of UCP1 variability on survival. Two polymorphisms (A-3826G and C-3740A), falling in the upstream promoter region of UCP1, were analyzed in a sample of 910 subjects from southern Italy (475 women and 435 men; age range 40-109). By analyzing haplotype specific survival functions we found that the A-C haplotype favors survival in the elderly. Consistently, transfection experiments showed that the luciferase activity of the construct containing the A-C haplotype was significantly higher than that containing the G-A haplotype. Interestingly, the different UCP1 haplotypes responded differently to hormonal stimuli. The results we present suggest a correlation between the activity of UCP1 and human survival, indicating once again the intricacy of mechanisms involved in energy production, storage and consumption as the key to understanding human aging and longevity.


Kissing the cobra: Sexuality and high risk in a generalised epidemic-a case study of White university students.
This paper explores the social factors that may account for the way the HIV-AIDS epidemic is unfolding in a racially segmented and socially differentiated society. As a sexually transmitted infectious disease that particularly infects adolescents and decimates young adults, there is an urgent need to critically assess assumptions about the influence of culture and social relations on differences in patterns and the scale of infection across racial groups in South Africa. The point of departure is the recognition that while nationally there is a generalised epidemic of gigantic proportions, the epidemic among young White adults is still nascent. Through a qualitative exploration of White student perceptions of risk, sexual networking and practices in an HIV-AIDS environment, this small study hopes to shed light on some of the social and cultural issues surrounding the epidemic.


Distribution of pulmonary capillary transit times.
The length of time that blood remains in the pulmonary capillary is an important variable in gas exchange. We have investigated the distribution of capillary transit times in isolated rabbit lungs perfused with a bicarbonate-free buffer. The time course of gas exchange was monitored by enclosing the lungs in a plethysmograph. A bolus of buffer containing dissolved acetylene was injected into the perfusion system. Exchange of this inert gas occurred as soon as the bolus reached the capillary bed, thereby describing the input function into the bed. A separate bolus injection of bicarbonate solution resulted in production and excretion of CO2 as long as the bolus remained in the capillary bed. The rate of CO2 production was adjusted by partial inhibition of endothelial carbonic anhydrase. The distribution of capillary transit times was computed from a model of CO2 production in the capillary bed and the observed rates and volumes of acetylene and carbon dioxide excretion. The recovered distributions indicate that there is a fairly wide distribution of capillary transit times (relative dispersion, 0.45) around the mean value of 1.71 s (+/- 0.53 [SD]). Only 10% of capillary transit times are less than one half of mean transit time. It is likely that gas exchange reaches equilibrium in the capillary bed except possibly during strenuous exercise or exposure to high altitude or in disease.


Dimeric Structure of the Bacterial Extracellular Foldase PrsA.
Secretion of proteins into the membrane-cell wall space is essential for cell wall biosynthesis and pathogenicity in Gram-positive bacteria. Folding and maturation of many secreted proteins depend on a single extracellular foldase, the PrsA protein. PrsA is a 30-kDa protein, lipid anchored to the outer leaflet of the cell membrane. The crystal structure of Bacillus subtilis PrsA reveals a central catalytic parvulin-type prolyl isomerase domain, which is inserted into a larger composite NC domain formed by the N- and C-terminal regions. This domain architecture resembles, despite a lack of sequence conservation, both trigger factor, a ribosome-binding bacterial chaperone, and SurA, a periplasmic chaperone in Gram-negative bacteria. Two main structural differences are observed in that the N-terminal arm of PrsA is substantially shortened relative to the trigger factor and SurA and in that PrsA is found to dimerize in a unique fashion via its NC domain. Dimerization leads to a large, bowl-shaped crevice, which might be involved in vivo in protecting substrate proteins from aggregation. NMR experiments reveal a direct, dynamic interaction of both the parvulin and the NC domain with secretion propeptides, which have been implicated in substrate targeting to PrsA.


Cells in dengue virus infection in vivo.
Dengue has been recognized as one of the most important vector-borne emerging infectious diseases globally. Though dengue normally causes a self-limiting infection, some patients may develop a life-threatening illness, dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). The reason why DHF/DSS occurs in certain individuals is unclear. Studies in the endemic regions suggest that the preexisting antibodies are a risk factor for DHF/DSS. Viremia and thrombocytopenia are the key clinical features of dengue virus infection in patients. The amounts of virus circulating in patients are highly correlated with severe dengue disease, DHF/DSS. Also, the disturbance, mainly a transient depression, of hematological cells is a critical clinical finding in acute dengue patients. However, the cells responsible for the dengue viremia are unresolved in spite of the intensive efforts been made. Dengue virus appears to replicate and proliferate in many adapted cell lines, but these in vitro properties are extremely difficult to be reproduced in primary cells or in vivo. This paper summarizes reports on the permissive cells in vitro and in vivo and suggests a hematological cell lineage for dengue virus infection in vivo, with the hope that a new focus will shed light on further understanding of the complexities of dengue disease.


Can we learn anything from small trials?
In summary, then, we can learn three useful things from small clinical trials. First, we can learn when to challenge conventional but untested therapeutic wisdom. Second, because the patient number in any trial is the number of events, rather than the number of study patients, some small trials are so definitively positive that they are sufficient to identify the best therapy. And third, small trials, even when individually inconclusive, can serve as the basis for convincingly conclusive overviews and meta-analyses that carry, and deserve, greater credibility than a single large trial of similar size to their sum.


CO2 reduction or HCO2- oxidation? Solvent-dependent thermochemistry of a nickel hydride complex.
The hydricity (ΔGH-) of a newly synthesized nickel hydride was experimentally determined in acetonitrile (50.6 kcal mol-1), dimethyl sulfoxide (47.1 kcal mol-1), and water (22.8 kcal mol-1). The hydricity values indicate hydride transfer from [HNi(TMEPE)2][BF4] (TMEPE = 1,2-bis[di(methoxyethyl)phosphino]ethane) to CO2 is exergonic in water and endergonic in the organic solvents.


Pathway-specific protein domains are predictive for human diseases.
Protein domains are basic functional units of proteins. Many protein domains are pervasive among diverse biological processes, yet some are associated with specific pathways. Human complex diseases are generally viewed as pathway-level disorders. Therefore, we hypothesized that pathway-specific domains could be highly informative for human diseases. To test the hypothesis, we developed a network-based scoring scheme to quantify specificity of domain-pathway associations. We first generated domain profiles for human proteins, then constructed a co-pathway protein network based on the associations between domain profiles. Based on the score, we classified human protein domains into pathway-specific domains (PSDs) and non-specific domains (NSDs). We found that PSDs contained more pathogenic variants than NSDs. PSDs were also enriched for disease-associated mutations that disrupt protein-protein interactions (PPIs) and tend to have a moderate number of domain interactions. These results suggest that mutations in PSDs are likely to disrupt within-pathway PPIs, resulting in functional failure of pathways. Finally, we demonstrated the prediction capacity of PSDs for disease-associated genes with experimental validations in zebrafish. Taken together, the network-based quantitative method of modeling domain-pathway associations presented herein suggested underlying mechanisms of how protein domains associated with specific pathways influence mutational impacts on diseases via perturbations in within-pathway PPIs, and provided a novel genomic feature for interpreting genetic variants to facilitate the discovery of human disease genes.