Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts.
The down-regulation of multidrug resistance (mdr1) gene expression as detected by competitive reverse transcription-PCR and the antitumor activity of bryostatin 1 (Bryo1) are investigated in a newly established cell line from a patient with relapsed diffuse large cell lymphoma (DLCL). The cell line (WSU-DLCL2) grows in liquid culture and forms s.c. tumors in mice with severe combined immune deficiency. WSU-DLCL2 is a mature B-cell line (IgG lambda) that is negative for EBV nuclear antigen, expresses the multidrug resistance phenotype, and has t(14;18)(q32;q21) plus other chromosomal aberrations. Exposure of the WSU-DLCL2 cells to Bryo1 in culture reversed the multidrug resistance phenotype within 24 h. A functional assay revealed a 4-fold increase in [3H]vincristine accumulation in Bryo1-treated cells compared with control. Vincristine (VCR), doxorubicin, Bryo1, and 1-beta-D-arabinofuranosylcytosine showed no clinically significant activity when given alone to WSU-DLCL2-bearing severe combined immune deficiency mice. However, when given 24 h before each cytotoxic agent, Bryo1 substantially increased the antitumor activity of VCR but not 1-beta-D-arabinofuranosylcytosine. There was a statistically significant (P < 0.001) decrease in the expression of P-glycoprotein in WSU-DLCL2 tumors taken from Bryo1-treated animals compared with untreated controls. In vivo, a competitive reverse transcription-PCR assay revealed decreased mdr1 RNA expression 24 h after Bryo1 treatment. These findings taken together indicate that Bryo1-induced down-regulation of mdr1 might be one mechanism by which Bryo1 potentiates VCR activity. The sequential use of both agents resulted in clinically significant antitumor activity in this lymphoma model.


Classification Scheme for Incident Reports of Medication Errors.
This study aimed to develop a classification scheme for retrieving information from incident reports of medication errors. This 15-category classification scheme captures minimal medication-incident related information from incident reports and thus serves as an information model for automatic information retrieval solution. The automatic solution uses recent advances in artificial intelligence methods to learn from incident report resources and is promising to the prevention of adverse drug events and promotion of safety in medical care.


Fibromyalgia: the prototypical central sensitivity syndrome.
Fibromyalgia syndrome (FM), the most common central sensitivity syndrome (CSS) affecting over 5% of the population, is a disorder of chronic widespread pain accompanied by numerous other symptoms that causes significant functional impairment. The core FM symptom domains can be recalled using the FIBRO mnemonic and include Fatigue and Fog (cognitive dysfunction), Insomnia (difficulties with all aspects of sleep including initiation, maintenance and restorative), Blues (depression and anxiety), Rigidity (stiffness in muscles and joints) and Ow! (widespread pain and tenderness). While typically presenting in middle-aged women, FM can affect both sexes at any age. FM is a syndrome of abnormal central pain processing and increased central sensitivity caused by neurobiological changes that cause dysregulation of mechanisms that normally regulate pain sensation. There are currently three different methods for diagnosing FM; the 1990, 2010 and modified 2010 American College of Rheumatology (ACR) criteria. While disabling, FM symptoms can be managed with a regimen of pharmacologic and nonpharmacologic treatments. Medication types with benefit in treating FM include anticonvulsants, antidepressants, anti-inflammatories, muscle relaxers, tramadol, and stimulants. Beneficial nonpharmacologic therapies include aerobic and resistance exercise, stretching, cognitive behavioral therapy, and education. Effective management requires formulation of an individualized regimen since patients differ widely in symptoms and treatments they find beneficial. Such an individualized regimen should be based on a systematic assessment of problematic symptoms conducted at baseline and each follow-up with treatments modified over time. While challenging, FM symptoms can be effectively managed and patients can lead full, productive lives.


Deletion within the CYP17 gene together with insertion of foreign DNA is the cause of combined complete 17 alpha-hydroxylase/17,20-lyase deficiency in an Italian patient.
The molecular basis of 17 alpha-hydroxylase/17,20-lyase deficiency syndrome in a 14-yr-old 46,XY Italian patient was investigated by amplification, subcloning, and sequencing of specific exonic sequences from genomic DNA samples. A homozygous mutation, consisting of a 518-basepair (bp) deletion combined with a 469-bp insertion, was identified in the CYP17 gene of the patient. The deletion spans much of exon II, the whole intron 2, and a portion of exon III. A part (156 bp) of the inserted sequence shows 95.5% identity to the nuclear antigen-binding site on Marek disease virus DNA and sequences found in rearranged mitochondrial DNA of rat hepatoma cells. A similar degree of sequence identity (99%) was also found between the above sequences and part of the lac operon of E. coli. The inserted sequence is lacking the BamHI site in intron 2 of CYP17 and contains an in-frame stop codon (TAA). Thus, the mutated gene encodes a truncated nonfunctional steroid hydroxylase, giving rise to symptoms associated with complete combined 17 alpha-hydroxylase/17,20-lyase deficiency. The family history revealed that the patient is the child of a consanguineous marriage and has two genotypically and phenotypically female sisters also suffering from symptoms of the disease. Investigation of genomic DNA from these sisters revealed that in each case both CYP17 alleles contained the same mutation. On the other hand, the parents were found to be heterozygous for this mutation. The insertion could not be found in DNA from normal individuals or in the CYP17 gene of other Italian patients with the 17 alpha-hydroxylase deficiency syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)


Plasma glutathione levels are independently associated with gamma-glutamyltransferase activity in subjects with cardiovascular risk factors.
To investigate whether GGT (gamma-glutamyltransferase) is associated to specific redox patterns. GGT, total and reduced aminothiols and malondialdehyde, were measured in 150 subjects (83 males, 48 (39-56) years), with none, one or more risk factors. By univariable analysis GGT was positively associated with age (p =0.001), male gender (p <0.001), risk factor number (p <0.001), ACE-inhibitors (p =0.008), anti-platelet agents (p =0.029), atherothrombotic events (p =0.001), glucose (p =0.013), malondialdehyde (p =0.029), plasma total cysteine (p =0.046) and inversely associated with plasma total glutathione (p =0.001). By multivariable analysis only male gender (p <0.001), risk factor number (p <0.001) and glutathione (p <0.001) were independently associated with GGT activity. These findings suggest that an ongoing redox imbalance, in terms of decreased plasma glutathione, is associated with raised GGT activity in subjects with a greater risk factor burden.


Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis.
The safety and efficacy of taking low-molecular-weight heparin at home was previously demonstrated in a clinical trial in which patients with acute proximal deep vein thrombosis were randomized to receive either intravenous standard heparin in the hospital or subcutaneous low-molecular-weight heparin administered primarily at home. Treatment in the home has the potential to substantially reduce the cost to the health care system. To conduct an economic evaluation we prospectively collected data on resource use and health-related quality of life (Medical Outcomes Study Short-Form 36) on the 300 patients who formed the trial stratum presenting with proximal vein thrombosis as outpatients, of whom 151 received standard heparin and 149 received low-molecular-weight heparin. The primary viewpoint of the analysis was societal, and costs included health care costs, patient travel costs, and productivity costs as a result of time off work. Costs were assessed over a period of 3 months from randomization. Quality of life was assessed as the change in Short-Form 36 domain scores from baseline to day 7 for each treatment group. All costs are reported in 1997 Canadian dollars. There were 11 recurrent thromboembolic events and 1 bleed in the 151 patients who received standard heparin; the corresponding data for the 149 patients receiving low-molecular-weight heparin were 10 and 4, respectively. The mean cost per patient who received standard heparin was Can $5323 compared with Can $2278 for low-molecular-weight heparin, a total societal cost savings per patient using low-molecular-weight heparin of Can $3045 (95% confidence interval, Can $2012-$4050). There was no difference in quality of life between the 2 groups except for the domain of social functioning, where a greater improvement from baseline to day 7 was observed for the low-molecular-weight heparin group vs the standard heparin group (P =.005). For patients with acute proximal deep vein thrombosis, treatment at home with low-molecular-weight heparin is less costly than hospital-based treatment with standard heparin. The economic evidence in favor of outpatient treatment with low-molecular-weight heparin exhibits dominance; a situation of reduced cost is created with no compromise in clinical outcomes or patients' quality of life.


Decreased vasorelaxation induced by iloprost during acute inflammation in human internal mammary artery.
Cyclooxygenase-2 (COX-2) induction in human internal mammary arteries (IMA) under inflammatory conditions has been associated with attenuated norepinephrine (NE)-induced vasoconstriction. This effect was associated with increased prostaglandin (PG) E2 and prostacyclin (PGI2) releases. The present study was designed to assess the role of these PG and their receptors (EP and IP, respectively) on the vascular reactivity during acute inflammation. Isolated IMA were cultured in the absence (Control conditions) or presence (Inflammatory conditions) of both interleukin-1 beta (IL-1β) and lipopolysaccharide (LPS). The vasorelaxation and the increased content of cyclic adenosine monophosphate (cAMP) induced by iloprost, a PGI2 analogue, were significantly reduced under inflammatory conditions and restored in preparations cultured with the IP antagonist (CAY10441). Decreased cAMP levels under inflammatory conditions are due to at least increased phosphodiesterase (PDE) 4B expression. On the other hand, PGE2, thromboxane analogues and EP agonists-induced vasoconstrictions were not affected under inflammatory conditions. No vasorelaxation was observed with PGD2, PGE2 or the EP2/4 agonists in pre-contracted IMA. Finally, using RT-qPCR and immunohistochemistry, the COX-2, IP receptor and PGI2 synthase (PGIS) were detected. A significant increase of COX-2 and moderate increase of IP mRNA expression was observed under inflammatory conditions, whereas PGIS mRNA level was not affected. This study demonstrates that PGI2/IP receptor signalling and PGI2-induced relaxation are impaired in human IMA during acute inflammation, whereas the responses induced by other prostanoids are not affected. These results could explain some of the mechanisms of vascular dysfunction reported in inflammatory conditions.


Health and safety needs of older farmers: part II. Agricultural injuries.
A random sample (N = 87) of older Illinois farmers was surveyed to assess their experiences with traumatic injuries and the relationship between injury rate and age, type of farm activities, amount of stress, and hours of work per week. Farmers' knowledge of safety was assessed. Findings revealed that the number of hours worked, age, and type of farm activities were not significantly related to the number of injuries reported. However, self-reported stress, when stratified by age, was found to be related to injury among farmers aged 55 to 59 years. Also, scores on a farm safety quiz were found to be higher (less knowledge) among farmers who reported more injuries. Items in the safety quiz frequently missed by farmers included falls as a source of injury (29.2%), children being commonly injured on farms (19%), the cause of farmers' lung disease (46.9%), and animals as a cause of injury on farms (12.9%).


Cortical brain morphology in young, estrogen-naive, and adolescent, estrogen-treated girls with Turner syndrome.
Turner syndrome (TS) is a genetic condition that permits direct investigation of the complex interaction among genes, hormones, behavior, and brain development. Here, we used automated segmentation and surface-based morphometry to characterize the differences in brain morphology in children (n = 30) and adolescents (n = 16) with TS relative to age- and sex-matched control groups (n = 21 and 24, respectively). Our results show that individuals with TS, young and adolescent, present widespread reduction of gray matter volume, white matter volume and surface area (SA) over both parietal and occipital cortices bilaterally, as well as enlarged amygdala. In contrast to the young cohort, adolescents with TS showed significantly larger mean cortical thickness and significantly smaller total SA compared with healthy controls. Exploratory developmental analyses suggested aberrant regional brain maturation in the parahippocampal gyrus and orbitofrontal regions from childhood to adolescence in TS. These findings show the existence of abnormal brain morphology early in development in TS, but also suggest the presence of altered neurodevelopmental trajectories in some regions, which could potentially be the consequences of estrogen deficiency, both pre- and postnatally.


A practical approach to risk assessment to prevent coronary artery disease and its complications.
The recent focus on emerging cardiovascular risk factors, such as C-reactive protein, homocysteine, and small, dense low-density lipoprotein (LDL), may give the false impression that the current approach to the assessment of cardiovascular disease risk fails to identify a large section of the high-risk population. On the contrary, the new guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) propose classifying an enormous number of individuals, including people with any form of atherosclerotic disease, diabetes, and a combination of major risk factors, into the category of high risk (>20% likelihood of a major coronary event or stroke in 10 years). Considering the widespread prevalence of the metabolic syndrome-a high-risk condition characterized by mild hypertension, mild dyslipidemia, hyperglycemia, and visceral obesity-we may be faced with the challenge of implementing aggressive risk reduction therapies in as much as 30% of the adult US population. From the point of view of risk assessment, a practical approach is to follow the NCEP guidelines (ie, place patients with diabetes and those with atherosclerotic complications in the highest risk category), apply the Framingham calculation to determine risk in people with common risk factors, and initiate early intervention in people who have familial hypercholesterolemia (LDL cholesterol >200 mg/dL) or a family history of early cardiovascular disease. The emerging risk factors may be useful for further stratifying risk in individuals with intermediate risk and the presence of risk factors not included in the Framingham calculation.


Primary Anastomosis versus Ostomy after Colon Resection during Debulking of Ovarian Carcinomatosis: A NSQIP Analysis.
Ovarian carcinomatosis poses a dilemma for the surgeon. When resecting colon for tumor invasion, one must decide between diversion and primary anastomosis (PA). We examined the National Surgical Quality Improvement Program to determine whether PA associated with more complications than ostomy. The National Surgical Quality Improvement Program dataset was queried for patients with ovarian carcinomatosis between 2007 and 2012. Current Procedural Terminology codes were used to further identify patients undergoing colectomy with PA or ostomy. Logistic regression was used to evaluate 30-day morbidity and mortality. The 1013 ovarian carcinomatosis patients who underwent elective colon surgery were divided into primary repair (n = 453, 43.5%) or ostomy (n = 586, 56.5%) groups. Preoperative demographics were similar; however, ostomy patients had more severe preoperative laboratory derangements. The 30-day mortality and postoperative transfusion requirements were higher in the ostomy group. On multivariate analysis controlling for confounders, the differences were no longer significant. In conclusion, 30-day mortality and postoperative complications were increased in the ostomy group. Given the laboratory derangements in this group, this may reflect tendency to allocate ostomies to more ill patients. Primary repair in a selected population does not worsen outcomes. Prospective evaluation would help determine the impact of PA in the ovarian carcinomatosis population.


Nanoengineering ABO3 active sites from low-energy routes (TX100-stabilised water-in-oil microemulsions, surface segregation and surface complexation on colloidal AlOOH/sol-gel Al2O3 surfaces) for pollution control catalysis.
It is shown that water-in-oil microemulsions (m/e or μE) can produce BaCeO3 (BCO) and LaCoO3 (LCO) precursors. The nanoparticles (NPs) adsorb on AlOOH sols, in much the same way as Turkevich previously immobilised platinum group metal sols. BCO is active in CO and propane oxidation and NO removal under stoichiometric exhaust conditions, but LCO is a better oxidation catalyst. Activity was also seen when Ba,Ce and La,Co are inserted into/segregate at the surface of AlOOH/Al2O3. However, there is only formation of low levels of BCO, CAIO3 (CAO), LCO and LaAIO3 (LAO) perovskites, along with aluminates and separate oxides. The complexing of cations by AlOOH surface-held oxalate ions, albeit with different efficiencies, has also been explored. All three routes yield active catalysts with micro-domains of crystallinity; microemulsions produce the best defined perovskite NPs, but even those from surface segregation have higher turnover numbers than traditional Pt catalysts. Perovskite NPs may open up green chemistry for air pollution control that is consistent with a circular economy.


Psychometric properties of Addenbrooke's Cognitive Examination III (ACE-III): An item response theory approach.
The Addenbrooke's Cognitive Examination III is one of the most widely used tests to assess cognitive impairment. Although previous studies have shown adequate levels of diagnostic utility to detect severe impairment, it has not shown sensitivity to detect mild decline. The aim of this study was to evaluate the psychometric properties of Addenbrooke's Cognitive Examination III in a large sample of elderly people through Item Response Theory, due to the lack of studies using this approach. A cross-sectional study was conducted with 1164 people from the age of 60 upwards, of which 63 had a prior diagnosis of Alzheimer dementia. The results showed that, globally, the Addenbrooke's Cognitive Examination III possesses adequate psychometrics properties. Furthermore, the information function test shows that the subscales have different sensitivity to different levels of impairment. These results can contribute to determining patterns of cognitive deterioration for the adequate detection of different levels of dementia. An optimized version is suggested which may be an economic alternative in the applied field.


Synthesis and Biological Evaluation of Novel Thioether Pleuromutilin Derivatives.
To develop new pleuromutilin derivatives as veterinary antibiotic medicines, we designed and synthesized a series of new thioether pleuromutilin derivatives possessing acylthiazolyl moiety based on previously designed derivatives. The antibacterial properties of the prepared pleuromutilin derivatives were assessed in vitro by the broth dilution method against five kinds of bacteria and the mycoplasma Mycoplasma gallisepticum (MG). All of the tested compounds displayed moderate to good antibacterial activity to methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-sensitive Staphylococcus epidermidis (MSSE), methicillin-resistant S. aureus (MRSA), Streptococcus agalactiae (S. aga) and MG. However, the activity to Pyogeniccoccus (Pyogens) was generally poor. Compounds 13i and l showed potent antibacterial activity against MSSE and MRSA which are better than that of valnemulin. The structural modification for pleuromutilin affected the antibacterial activity. Amino substituents in the benzene ring can effectively improve activity. Compared with the analogue 13a that possesses unsubstitution benzoyl group, the nitro, methoxy, hydroxy and dichloro substituent contributed little to antibacterial activity. Increasing a methylene between benzene moiety and carbonyl group decreased the bioactivity of derivative. The analogues that obtained by the reaction of amino acids and intermediate 9 showed moderate activity.


Impact of tramadol and morphine abuse on the activities of acetylcholine esterase, Na+/K+-ATPase and related parameters in cerebral cortices of male adult rats.
To determine the effect of the most commonly abused drugs (tramadol and morphine), on acetylcholine esterase (AChE), Na+/K+-ATPase activities and related parameters, Na+ and K+ as biomarkers of neurotoxicity. Tramadol - as a weak μ opioid receptor agonist- and morphine - as opiate analgesic drugs, were chosen for the present study. Four series of experimental animals were conducted for either tramadol or morphine: control series; repeated single equal doses (therapeutic dose) series; cumulative increasing doses series and delay (withdrawal) series (96 hours withdrawal period after last administration), at time period intervals 7, 14 and 21 days. Acetylcholine esterase (AChE), Na+/K+-ATPase activities and related parameters, Na+ and K+ were measured in cerebral cortices of experimental rats. Acetylcholine esterase (AChE) activity in the brain cerebral cortex increased after the administration of therapeutic repeated doses of either tramadol (20 mg/kg b.w.) or morphine (4 mg/kg b.w.) in different groups. The daily intraperitoneal injection of cumulative increasing dose levels of either tramadol 20, 40 and 80 mg/kg or morphine 4, 8 and 12 mg/kg revealed a significant increase in the mean of acetylcholine esterase activities. The withdrawal groups of either tramadol or morphine showed significant decreases in their levels. Na+/K+ ATPase activity in the brain cerebral cortex of either repeated therapeutic doses of tramadol (20 mg/kg) or morphine repeated therapeutic doses (4 mg/kg) for 21 consecutive days at different intervals 7, 14 and 21 days, induced a significant decrease in the levels of Na+/K+-ATPase in all groups. Withdrawal groups showed a significant decrease in Na+/K+-ATPase level. Furthermore, the daily intraperitoneal injection of cumulative increasing dose levels of either tramadol (20, 40 and 80 mg/kg b.w.) or morphine (4, 8 and 12 mg/kg b.w.) induced significant decreases in Na+/K+-ATPase levels in all studied groups. Regarding Na+ and K+, concentrations of either repeated therapeutic doses or cumulative increasing doses at different time intervals, showed different fluctuations in their levels. The recorded data suggest that both drugs exert potent effects on AChE and Na+/K+-ATPase activities which could contribute to cerebral cortex malfunction including, memory deficits and the decline in cognitive function observed in chronic users.


Arsenolite: a quasi-hydrostatic solid pressure-transmitting medium.
This study reports the experimental characterization of the hydrostatic properties of arsenolite (As4O6), a molecular solid which is one of the softest minerals in the absence of hydrogen bonding. The high compressibility of arsenolite and its stability up to 15 GPa have been proved by x-ray diffraction measurements, and the progressive loss of hydrostaticity with increasing pressure up to 20 GPa has been monitored by ruby photoluminescence. Arsenolite has been found to exhibit hydrostatic behavior up to 2.5 GPa and a quasi-hydrostatic behavior up to 10 GPa at room temperature. This result opens the way to explore other molecular solids as possible quasi-hydrostatic pressure-transmitting media. The validity of arsenolite as an insulating, stable, non-penetrating and quasi-hydrostatic medium is explored by the study of the x-ray diffraction of zeolite ITQ-29 at high pressure.


Metabolic effects of antihypertensive therapy with a calcium antagonist.
The effect of diuretics to increase serum glucose, low-density lipoprotein cholesterol and triglycerides, as well as the adverse changes in triglycerides and high-density lipoprotein cholesterol produced by nonselective beta blockers, have been largely ignored in the treatment of hypertension. However, a number of trials have shown that reductions in serum lipids can alter cardiovascular mortality. Calcium antagonists have become major drugs in the treatment of hypertension, and some data suggest that calcium antagonists may increase serum glucose levels. Significantly less data on lipid effects have been published. Lipid and glucose effects were examined in an 8-week antihypertensive study using a sustained-release preparation of diltiazem titrated from 240 to 360 mg/day in a twice-daily regimen in a randomized, double-blind, placebo-controlled parallel trial in 96 patients. Average supine blood pressure at week 8 was 156/98 mm Hg, standing blood pressure with placebo 152/100 mm Hg, and with diltiazem 147/91 and 144/93 mm Hg. There were no statistically significant changes in serum lipids or glucose in the diltiazem or placebo group or between the groups. Mean values (mg/dl) at baseline and week 8 in the diltiazem group were, respectively, for cholesterol 215 and 218, high-density lipoprotein cholesterol 50 and 51, low-density lipoprotein cholesterol 128 and 133, triglycerides 169 and 175, and glucose 113 and 110. Thus, this large and placebo-controlled study shows that diltiazem is among the antihypertensives with no adverse long-term lipid or glucose effects.


Extracellular wildtype and mutant SOD1 induces ER-Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells.
Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ER-Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER-Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ER-Golgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS.


Primary immunodeficiency diseases in Norway.
This study represents the first national epidemiological survey of primary immunodeficiency diseases in Norway. Uniform questionnaires were sent out in April 1998 to all hospital departments considered relevant. As of February 1999, a total of 372 patients have been registered, of whom 69 patients are deceased. With a population of 4.45 million people, the total prevalence of primary immunodeficiency diseases in Norway February 1, 1999 is 6.82 per 100000 inhabitants. Distribution between the main immunodeficiency diagnoses is (a) antibody deficiencies 50.8%, (b) combined deficiencies included other immunodeficiency syndromes 12.4%, (c) complement deficiencies 21.0%, (d) phagocytic disorders 6.7%, (e) and immunodeficiency associated with other congenital diseases 9. 1%. Compared to previous reports from other European countries, there is a smaller proportion of antibody deficiencies due to few IgA deficiencies registered and a large proportion of complement deficiencies due to many patients with hereditary angioedema.


Replicating satellite RNA induces sequence-specific DNA methylation and truncated transcripts in plants.
Tobacco plants were transformed with a chimeric transgene comprising sequences encoding beta-glucuronidase (GUS) and the satellite RNA (satRNA) of cereal yellow dwarf luteovirus. When transgenic plants were infected with potato leafroll luteovirus (PLRV), which replicated the transgene-derived satRNA to a high level, the satellite sequence of the GUS:Sat transgene became densely methylated. Within the satellite region, all 86 cytosines in the upper strand and 73 of the 75 cytosines in the lower strand were either partially or fully methylated. In contrast, very low levels of DNA methylation were detected in the satellite sequence of the transgene in uninfected plants and in the flanking nonsatellite sequences in both infected and uninfected plants. Substantial amounts of truncated GUS:Sat RNA accumulated in the satRNA-replicating plants, and most of the molecules terminated at nucleotides within the first 60 bp of the satellite sequence. Whereas this RNA truncation was associated with high levels of satRNA replication, it appeared to be independent of the levels of DNA methylation in the satellite sequence, suggesting that it is not caused by methylation. All the sequenced GUS:Sat DNA molecules were hypermethylated in plants with replicating satRNA despite the phloem restriction of the helper PLRV. Also, small, sense and antisense approximately 22 nt RNAs, derived from the satRNA, were associated with the replicating satellite. These results suggest that the sequence-specific DNA methylation spread into cells in which no satRNA replication occurred and that this was mediated by the spread of unamplified satRNA and/or its associated 22 nt RNA molecules.


Distinguishing rat brainstem reticulospinal nuclei by their neuronal morphology. II. Pontine and mesencephalic nuclei.
The purpose of this study was to determine whether pontine and mesencephalic reticulospinal nuclei like those of the medulla, can be differentiated on the basis of neuronal morphology. Accordingly, neurons of the various pontine and mesencephalic brainstem reticulospinal nuclei (BRN) of adult albino or hooded rats were either backfilled with horseradish peroxidase (HRP) from spinal injections, stained with a Nissl method or impregnated with a Golgi-Kopsch variant. The results suggest that at least 13 BRN can be distinguished in the pons and mesencephalon of the rat on the basis of neuronal morphology. The dendritic arborizations (DA) of neurons in nucleus reticularis (NR) pedunculopontinus pars compacta (RPpc), NR pedunculopontinus pars dissipatus (RPpd), NR cuneiformis (RCf) and NR subcuneiformis (RScf) are radially symmetrical. The DA of neurons in NR pontis caudalis pars beta (RPoCb) and alpha (RPoCa), as well as those of NR subcoeruleus (RSc) and the A5 cell group, exhibit a pronounced dorsomedial to ventrolateral slant. The dendrites of locus coeruleus (LC) neurons slant from dorsolateral to ventromedial. The DA of NR pontis oralis pars medialis (RPoOm) neurons course medially, while those of NR pontis oralis pars lateralis (RPoOl) course laterally. The DA of Kolliker-Fuse neurons (KF) course horizontally. Finally, the DA of the nucleus raphe dorsalis (RaD) are either symmetrically multipolar or fusiform. The neurons of RPoCb, RPpc, KF and RCf project to the spinal cord with a strong ipsilateral predominance, while those of LC, RSc, RPoOm and RPpd project to the spinal cord with a weak ipsilateral predominance. The axons of A5, RPoOl and RaD neurons exhibit no lateral predominance in their spinal projections. Finally, RPoCa neurons, as well as neurons in RScf, project to the spinal cord with a strong contralateral predominance. The neurons of RPoCb, RPoCa, RPoOl, RPpd and RScf project to the spinal cord via the mlf and sulcomarginal fasciculus. The neurons of RSc, KF, RPoOm, RPpc and RCf project to the spinal cord via the lateral funiculus.


Role of Chronic Use of Tolvaptan in Patients with Heart Failure Undergoing Peritoneal Dialysis.
In the present study, we assessed the effect of chronic tolvaptan treatment and compared it with the effect of conventional treatment without tolvaptan. In addition, changes in cardiac load and body fluid composition were compared.The study enrolled 22 patients undergoing peritoneal dialysis who had been receiving tolvaptan for more than 1 year and 10 patients undergoing peritoneal dialysis who had been treated with conventional diuretics. Left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), and E/e' index were measured by echocardiography at baseline and after 12 months of tolvaptan treatment (or an equivalent period). Body composition was analyzed by bioimpedance monitoring (BIM).In the tolvaptan group, LVMI was significantly reduced after 12 months of treatment; in the conventional-treatment group, it was significantly increased. The measured LVEF did not change in the tolvaptan group, but it increased significantly in the conventional-treatment group. The E/e' index was not altered in either group; however, it was reduced in patients receiving tolvaptan whose initial E/e' was greater than 15. Although urine volume was not significantly increased in either group, renal creatinine clearance increased significantly in tolvaptan group; no change was observed in the conventional-treatment group. Renal and peritoneal Kt/V did not significantly change during the study. In both groups, β2-microglobulin was significantly and similarly increased. Extracellular water (ECW) and intracellular water (ICW) as determined by BIM were both reduced after 12 months of tolvaptan treatment. We observed a significant correlation between the ratio of ECW to total body water at the initiation of tolvaptan and the reduction in ECW after 12 months.Our results indicate that chronic tolvaptan treatment has a beneficial role in body fluid control without a reduction in cardiac and renal function. Volume control depends on an equal reduction in ECW and ICW, which can also have a benefit in avoiding hyponatremia.


Hereditary distal foreleg curvature in the rabbit. I. Manifestations and course of the bowing deformity: genetic studies.
An inwardly directed curvature of the distal segment of both forelegs of the rabbit has been described. The condition was detected at 2 to 3 weeks of age, developed rapidly, and reached its final and permanent stage at 2 to 3 months of age. Only the distal epiphysis of the ulna was primarily affected and this in the form of a massive chondrodystrophic lesion accompanied by a progressive curvature of the shaft. The curvature of the growing radius was a secondary effect due to the firm, immovable, anatomical connection of the ulna and radius. The positional changes of the wrist and paw were likewise effects secondary to the changed form of the ulna and radius. The bowing abnormality occurred only in certain families of pure bred Beveren, Belgian, French Silver, and Dutch rabbits and was found to be inherited. The mode of inheritance was on the basis of a single recessive unit factor (5).


Bipolar Disorder and Early Emotional Trauma: A Critical Literature Review on Indicators of Prevalence Rates and Clinical Outcomes.
After participating in this activity, learners should be better able to:• Evaluate the prevalence of early emotional trauma in patients with bipolar disorder (BD)• Assess the impact of these traumas on patients and on their development of BD OBJECTIVES: We performed a systematic literature review to (1) evaluate the prevalence of early emotional trauma (EET) in patients with bipolar disorder (BD) and the impact of these traumas on the development of the disorder, and (2) integrate the findings of our review with those previously reported by Fisher and Hosang, Daruy-Filho and colleagues, and Maniglio. The literature search was performed on PubMed, SciELO, and PsycINFO databases using the keywords bipolar disorder, early trauma, physical abuse, emotional abuse, sexual abuse, maltreatment, adversity, and neglect. Twenty-eight articles were selected and analyzed. Taken together, the articles described a high prevalence of EET in BD, consisting mainly of emotional neglect/abuse (approximately 40%), particularly when compared to healthy subjects. The review also identified substantial evidence regarding an association between the presence of EET, early disease onset, rapid cycling, comorbidity with anxiety/stress disorders, and cannabis use. The integration of the current findings with the identified studies reveals that (1) the methodological limitations noted by Daruy-Filho and colleagues have been largely resolved in more recent studies and (2) the presence of EET in patients with BD is associated with worse clinical outcomes, particularly early disease onset, presence of clinical or psychiatric comorbidities, suicide, and presence of psychotic episodes/symptoms. The review shows that patients with BD experience more traumatic situations than controls and that emotional trauma is the most frequent type of trauma in this group.


Can a heart failure-specific cardiac rehabilitation program decrease hospitalizations and improve outcomes in high-risk patients?
Heart failure is a common and costly condition, particularly in the elderly. A range of models of interventions have shown the capacity to decrease hospitalizations and improve health-related outcomes. Potentially, cardiac rehabilitation models can also improve outcomes. To assess the impact of a nurse-coordinated multidisciplinary, cardiac rehabilitation program to decrease hospitalizations, increase functional capacity, and meet the needs of patients with heart failure. In a randomized control trial, a total of 105 patients were recruited to the study. Patients in the intervention group received an individualized, multidisciplinary 12-week cardiac rehabilitation program, including an individualized exercise component tailored to functional ability and social circumstances. The control group received an information session provided by the cardiac rehabilitation coordinator and then follow-up care by either their cardiologist or general practitioner. This trial was stopped prematurely after the release of state-based guidelines and funding for heart failure programs. During the study period, patients in the intervention group were less likely to have been admitted to hospital for any cause (44 vs. 69%, P = 0.01) or after a major acute coronary event (24 vs. 55%, P = 0.001). Participants in the intervention group were more likely to be alive at 12 months, (93 vs. 79%; P = 0.03) (odds ratio = 3.85; 95% confidence interval=1.03-14.42; P = 0.0042). Quality of life scores improved at 3 months compared with baseline (intervention t = o/-4.37, P<0.0001; control t = /-3.52, P<0.01). Improvement was also seen in 6-min walk times at 3 months compared with baseline in the intervention group (t = 3.40; P = 0.01). This study shows that a multidisciplinary heart failure cardiac rehabilitation program, including an individualized exercise component, coordinated by a specialist heart failure nurse can substantially reduce both all-cause and cardiovascular readmission rates, improve functional status at 3 months and exercise tolerance.


Patients who survive 5 years or more with ALS in Olmsted County, 1925-2004.
A small proportion of patients with amyotrophic lateral sclerosis (ALS) survive more than 5 years. The frequency of 5-year or longer survival with ALS in a USA population is unknown but may provide a baseline for studies that employ survival as a primary endpoint of analysis. All persons diagnosed as having ALS in Olmsted County between 1925 and 2004 were studied for demographic and clinical features. Longer-term survivors were defined as patients who lived 5 years or longer, tracheostomy-free, following symptomatic onset. 94 patients (mean survival from symptomatic onset 2.95 years (95% CI 2.54 to 3.35), mean survival from diagnosis 1.89 years (95% CI 1.54 to 2.24)) were diagnosed as having ALS. Five-year or longer survivors accounted for 14% of the population of patients (95% CI 7.9% to 22.8%). The frequency of 5 year or longer survivors did not change over time. The mean survival of these individuals was 7.04 years (95% CI 6.14 to 7.94 years; range 5.11-9.35 years). They had a significantly longer mean time to diagnosis (1.77 years, 95% CI 0.95 to 2.58 years) as compared with survivors of less than 5 years (0.94 years, 95% CI 0.75 to 1.13 years) (p=0.02) but could not be reliably identified at the time of diagnosis by age, sex, clinical presentation or El Escorial category. Patients surviving more than 5 years following the symptomatic onset of ALS account for 14% of the total ALS population. This frequency has not changed over time. Patients with a survival of 5 years or longer are clinically similar to the total population ALS population in terms of age, gender, presentation and site of onset but have a longer time from symptomatic onset to diagnosis. GRANT NUMBER: NIH AR30582.


Stereoscopic surface interpolation supports lightness constancy.
The human visual system has a remarkable ability to construct surface representations from sparse stereoscopic, as well as texture and motion, information. In impoverished displays where few points are used to define regions in depth, the brain often interpolates depth estimates across intervening blank regions to create a compelling sense of a solid surface. The set of experiments described here examined stereoscopic interpolation using a novel technique based on lightness constancy. The effectiveness of this method is notable because it stands as the only technique to date that unequivocally examines the perception of interpolated surfaces, and not surfaces inferred subjectively from depth information in the stimulus. Further, these data support the growing evidence that a primary function of the stereoscopic system is to define three-dimensional surface structure.


Growth and Changing Characteristics of Pediatric Intensive Care 2001-2016.
We assessed the growth, distribution, and characteristics of pediatric intensive care in 2016. Hospitals with PICUs were identified from prior surveys, databases, online searching, and clinician networking. A structured web-based survey was distributed in 2016 and compared with responses in a 2001 survey. PICUs were defined as a separate unit, specifically for the treatment of children with life-threatening conditions. PICU hospitals contained greater than or equal to 1 PICU. Physician medical directors and nurse managers. None. PICU beds per pediatric population (< 18 yr), PICU bed distribution by state and region, and PICU characteristics and their relationship with PICU beds were measured. Between 2001 and 2016, the U.S. pediatric population grew 1.9% to greater than 73.6 million children, and PICU hospitals decreased 0.9% from 347 to 344 (58 closed, 55 opened). In contrast, PICU bed numbers increased 43% (4,135 to 5,908 beds); the median PICU beds per PICU hospital rose from 9 to 12 (interquartile range 8, 20 beds). PICU hospitals with greater than or equal to 15 beds in 2001 had significant bed growth by 2016, whereas PICU hospitals with less than 15 beds experienced little average growth. In 2016, there were eight PICU beds per 100,000 U.S. children (5.7 in 2001), with U.S. census region differences in bed availability (6.8 to 8.8 beds/100,000 children). Sixty-three PICU hospitals (18%) accounted for 47% of PICU beds. Specialized PICUs were available in 59 hospitals (17.2%), 48 were cardiac (129% growth). Academic affiliation, extracorporeal membrane oxygenation availability, and 24-hour in-hospital intensivist staffing increased with PICU beds per hospital. U.S. PICU bed growth exceeded pediatric population growth over 15 years with a relatively small percentage of PICU hospitals containing almost half of all PICU beds. PICU bed availability is variable across U.S. states and regions, potentially influencing access to care and emergency preparedness.


Plasma insulin response among Nauruans. Prediction of deterioration in glucose tolerance over 6 yr.
A longitudinal study of 266 randomly selected nondiabetic Nauruans [215 with normal tolerance and 51 with impaired glucose tolerance (IGT)] over 6 yr showed that deterioration in glucose tolerance status had occurred in 61 subjects. Of the subjects with initially normal tolerance, 34 (16%) progressed to IGT and 14 (6.5%) progressed to diabetes. Thirteen of the subjects with IGT (25%) progressed to diabetes. Subjects were examined in 1975 through 1976, and follow-up examinations were performed in 1982. After age, a high 2-h plasma insulin response to a glucose load was the factor most predictive of progression from normal tolerance to both diabetes (P less than .001) and IGT (P less than .01). Both a high 2-h glucose level and greater obesity independently predicted progression from IGT, and a diminished 2-h insulin response just failed to significantly improve the model (P less than .06). The negative parameter of the insulin response associated with deterioration from IGT differed significantly (P less than .01) from the positive-parameter estimate of the response associated with progression to diabetes from normal tolerance (P less than .01), implying a qualitative difference between these nondiabetic subgroups. The use of a glucose-insulin interaction term to predict progression to diabetes for all nondiabetic subjects confirmed this difference; this term's addition improved the model (P less than .01), and progression to diabetes was associated with a high insulin response for 2-h glucose less than 7.8 mM but a low response for 2-h glucose greater than 7.8 mM.


Adult rhinosinusitis: diagnosis and management.
Rhinosinusitis can be divided among four subtypes: acute, recurrent acute, subacute and chronic, based on patient history and a limited physical examination. In most instances, therapy is initiated based on this classification. Antibiotic therapy, supplemented by hydration and decongestants, is indicated for seven to 14 days in patients with acute, recurrent acute or subacute bacterial rhinosinusitis. For patients with chronic disease, the same treatment regimen is indicated for an additional four weeks or more, and a nasal steroid may also be prescribed if inhalant allergies are known or suspected. Nasal endoscopy and computed tomography of the sinuses are reserved for circumstances that include a failure to respond to therapy as expected, spread of infection outside the sinuses, a question of diagnosis and when surgery is being considered. Laboratory tests are infrequently necessary and are reserved for patients with suspected allergies, cystic fibrosis, immune deficiencies, mucociliary disorders and similar disease states. Findings on endoscopically guided microswab culture obtained from the middle meatus correlate 80 to 85 percent of the time with results from the more painful antral puncture technique and is performed in patients who fail to respond to the initial antibiotic selection. Surgery is indicated for extranasal spread of infection, evidence of mucocele or pyocele, fungal sinusitis or obstructive nasal polyposis, and is often performed in patients with recurrent or persistent infection not resolved by drug therapy.


Combined Bacteriophage and Antibiotic Treatment Prevents Pseudomonas aeruginosa Infection of Wild Type and cftr- Epithelial Cells.
With the increase of infections due to multidrug resistant bacterial pathogens and the shortage of antimicrobial molecules with novel targets, interest in bacteriophages as a therapeutic option has regained much attraction. Before the launch of future clinical trials, in vitro studies are required to better evaluate the efficacies and potential pitfalls of such therapies. Here we studied in an ex vivo human airway epithelial cell line model the efficacy of phage and ciprofloxacin alone and in combination to treat infection by Pseudomonas aeruginosa. The Calu-3 cell line and the isogenic CFTR knock down cell line (cftr-) infected apically with P. aeruginosa strain PAO1 showed a progressive reduction in transepithelial resistance during 24 h. Administration at 6 h p.i. of single phage, phage cocktails or ciprofloxacin alone prevented epithelial layer destruction at 24 h p.i. Bacterial regrowth, due to phage resistant mutants harboring mutations in LPS synthesis genes, occurred thereafter both in vitro and ex vivo. However, co-administration of two phages combined with ciprofloxacin efficiently prevented PAO1 regrowth and maintained epithelial cell integrity at 72 p.i. The phage/ciprofloxacin treatment did not induce an inflammatory response in the tested cell lines as determined by nanoString® gene expression analysis. We conclude that combination of phage and ciprofloxacin efficiently protects wild type and cftr- epithelial cells from infection by P. aeruginosa and emergence of phage resistant mutants without inducing an inflammatory response. Hence, phage-antibiotic combination should be a safe and promising anti-Pseudomonas therapy for future clinical trials potentially including cystic fibrosis patients.


[Neuroendocrine modulation of haloperidol-induced catalepsy].
Evidence has been accumulated implicating sex hormones as possible modulators of extrapyramidal motor function. In the present study we have investigated the effects of estrogens, progesterone, testosterone, prolactin and calcitonin on behavioral parameters related to nigro-striatal dopaminergic system, such as haloperidol-induced catalepsy in male rats. It was found that 7-days estradiol benzoate treatment (5 micrograms/rat/day) significantly increases haloperidol-induced catalepsy, suggesting a possible antidopaminergic activity of estrogens. On the other hand, prolactin facilitates nigro-striatal dopaminergic transmission. Interestingly, 7 day treatment with medroxy-acetate progesterone (MAP, 5 mg/Kg, i.p.) brings about a trend to a decrease in haloperidol-induced catalepsy, while no significantly effect was observed following acute MAP administration at the same dose. So, it is tempting to speculate that chronic progestinic treatment may result in an increase in dopaminergic tonus. Testosterone, acutely administered (5mg/kg.s.c.) induces changes similar to those observed following progesterone administration. Finally, also calcitonin is able to influence haloperidol-induced catalepsy by markedly increasing it.


Whole genome distribution and ethnic differentiation of copy number variation in Caucasian and Asian populations.
Although copy number variation (CNV) has recently received much attention as a form of structure variation within the human genome, knowledge is still inadequate on fundamental CNV characteristics such as occurrence rate, genomic distribution and ethnic differentiation. In the present study, we used the Affymetrix GeneChip(R) Mapping 500K Array to discover and characterize CNVs in the human genome and to study ethnic differences of CNVs between Caucasians and Asians. Three thousand and nineteen CNVs, including 2381 CNVs in autosomes and 638 CNVs in X chromosome, from 985 Caucasian and 692 Asian individuals were identified, with a mean length of 296 kb. Among these CNVs, 190 had frequencies greater than 1% in at least one ethnic group, and 109 showed significant ethnic differences in frequencies (p<0.01). After merging overlapping CNVs, 1135 copy number variation regions (CNVRs), covering approximately 439 Mb (14.3%) of the human genome, were obtained. Our findings of ethnic differentiation of CNVs, along with the newly constructed CNV genomic map, extend our knowledge on the structural variation in the human genome and may furnish a basis for understanding the genomic differentiation of complex traits across ethnic groups.


Spatial organization of RNA polymerase II transcription in the nucleus.
In eukaryotic cells, mRNA synthesis is carried out by large, multifunctional complexes that are also involved in coordinating transcription with other nuclear processes. This survey focuses on the distribution and structural arrangement of these complexes within the nucleus, in relationship with the discrete positioning of particular chromosomal loci. To better understand the link between the spatial organization of the nucleus and the regulation of gene expression, it is necessary to combine information from biochemical studies with results from microscopic observations of preserved nuclear structures. Recent experimental approaches have made this possible. The subnuclear locations of specific chromosome loci, RNA transcripts, RNA polymerases, and transcription and pre-mRNA-processing factors can now be observed with computer-assisted microscopy and specific molecular probes. The results indicate that RNA polymerase II (RNAPII) transcription takes place at discrete sites scattered throughout the nucleoplasm, and that these sites are also the locations of pre-mRNA processing. Transcribing polymerases appear to be grouped into clusters at each transcription site. Cell cycle-dependent zones of transcription and processing factors have been identified, and certain subnuclear domains appear specialized for expression or silencing of particular genes. The arrangement of transcription in the nucleus is dynamic and depends on its transcriptional activity, with the RNAPII itself playing a central role in marshalling the large complexes involved in gene expression.


Long-term occurrence of secondary compartment pelvic organ prolapse after open mesh sacrocolpopexy for symptomatic prolapse.
To report on the long-term occurrence of secondary compartment pelvic organ prolapse (POP) after open mesh sacrocolpopexy (MSC). A prospectively maintained, IRB-approved database of non-neurogenic women with symptomatic triple compartment POP who underwent open MSC between 1999 and 2011 and had a 1-year minimum follow-up was reviewed. Length of follow-up was categorized as: intermediate (1-3 yr), late (3-5 yr), and very late (>5 yr). Demographic data, history of POP repairs, exam with Baden-Walker grading, validated questionnaires (Urogenital Distress Inventory short form [UDI-6], QoL), and outcomes at each follow-up visit were recorded. Failure was defined by either secondary compartment prolapse recurrence (BW > 2) on examination at the last visit or re-operation for POP. Out of sixty-eight, sixty-one women met study criteria. Mean age was 66 ± 11, mean BMI 26.1 ± 4.5, mean parity 2.8 ± 1.4 and cohort was mostly Caucasian. --Eighty seven percent had prior hysterectomy and 72% had prior POP repair. Mean follow-up was 6.8 ± 3.9 years with over 75% in the late or very late categories. There were 4/61 (7%) clinical failures, 3 of which underwent surgical repair (2 anterior and 1 posterior compartment repair) at 2-12 year interval post-MSC. Mean changes between baseline and last visit UDI-6, QoL, and BW prolapse grade trended favorably. Following open MSC, the rate of secondary prolapse compartment failure was found low at very long-term follow-up.


Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells.
We report a Jak2V617F knockin mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild-type HSCs. In contrast, myeloid progenitor populations are expanded and skewed toward the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F-positive MPN.


Agarose Fluid Gels Formed by Shear Processing During Gelation for Suspended 3D Bioprinting.
The use of granular matrices to support parts during the bioprinting process was first reported by Bhattacharjee et al. in 2015, and since then, several approaches have been developed for the preparation and use of supporting gel beds in 3D bioprinting. This paper describes a process to manufacture microgel suspensions using agarose (known as fluid gels), wherein particle formation is governed by the application of shear during gelation. Such processing produces carefully defined microstructures, with subsequent material properties that impart distinct advantages as embedding print media, both chemically and mechanically. These include behaving as viscoelastic solid-like materials at zero shear, limiting long-range diffusion, and demonstrating the characteristic shear-thinning behavior of flocculated systems. On the removal of shear stress, however, fluid gels have the capacity to rapidly recover their elastic properties. This lack of hysteresis is directly linked to the defined microstructures previously alluded to; because of the processing, reactive, non-gelled polymer chains at the particle interface facilitate interparticle interactions-similar to a Velcro effect. This rapid recovery of elastic properties enables bioprinting high-resolution parts from low-viscosity biomaterials, as rapid reformation of the support bed traps the bioink in situ, maintaining its shape. Furthermore, an advantage of agarose fluid gels is the asymmetric gelling/melting transitions (gelation temperature of ~30 °C and melting temperature of ~90 °C). This thermal hysteresis of agarose makes it possible to print and culture the bioprinted part in situ without the supporting fluid gel melting. This protocol shows how to manufacture agarose fluid gels and demonstrates their use to support the production of a range of complex hydrogel parts within suspended-layer additive manufacture (SLAM).


Guanidinium Toxins and Their Interactions with Voltage-Gated Sodium Ion Channels.
Guanidinium toxins, such as saxitoxin (STX), tetrodotoxin (TTX) and their analogs, are naturally occurring alkaloids with divergent evolutionary origins and biogeographical distribution, but which share the common chemical feature of guanidinium moieties. These guanidinium groups confer high biological activity with high affinity and ion flux blockage capacity for voltage-gated sodium channels (NaV). Members of the STX group, known collectively as paralytic shellfish toxins (PSTs), are produced among three genera of marine dinoflagellates and about a dozen genera of primarily freshwater or brackish water cyanobacteria. In contrast, toxins of the TTX group occur mainly in macrozoa, particularly among puffer fish, several species of marine invertebrates and a few terrestrial amphibians. In the case of TTX and analogs, most evidence suggests that symbiotic bacteria are the origin of the toxins, although endogenous biosynthesis independent from bacteria has not been excluded. The evolutionary origin of the biosynthetic genes for STX and analogs in dinoflagellates and cyanobacteria remains elusive. These highly potent molecules have been the subject of intensive research since the latter half of the past century; first to study the mode of action of their toxigenicity, and later as tools to characterize the role and structure of NaV channels, and finally as therapeutics. Their pharmacological activities have provided encouragement for their use as therapeutants for ion channel-related pathologies, such as pain control. The functional role in aquatic and terrestrial ecosystems for both groups of toxins is unproven, although plausible mechanisms of ion channel regulation and chemical defense are often invoked. Molecular approaches and the development of improved detection methods will yield deeper understanding of their physiological and ecological roles. This knowledge will facilitate their further biotechnological exploitation and point the way towards development of pharmaceuticals and therapeutic applications.


The role of reverse transcriptase-polymerase chain reaction for staging patients with clinically localized prostate cancer.
Recent advances in molecular technology have been applied to the detection, staging, and prognosis of prostate cancer. The reverse transcriptase-polymerase chain reaction (RT-PCR) is an exquisitely sensitive tool that allows for the detection of minimal quantities of cells. The assay has been studied clinically to distinguish metastatic prostate cancer patients from controls, and to preoperatively stage prostatic carcinoma; it also has been studied as a marker for postoperative recurrences. We review our experience at Columbia University and reports in the literature from other institutions to date. In addition, we provide our most recent data correlating the "enhanced" RT-PCR for PSA assay of peripheral blood specimens with final pathologic stage in 300 radical prostatectomy patients.


Surface density of major outer membrane proteins in Salmonella typhimurium in different growth conditions.
The amount of major proteins per unit of surface area in the outer membrane (OM) of Salmonella typhimurium LT2 remained constant during steady-state growth in different media. Between growth rates of 2.40 doublings h-1 and 0.31 doublings h-1, the surface density of major OM proteins varied between 0.9 X 105 molecules per micrometer2, while surface area per cell more than halved. The accumulation of molecules of the major OM proteins was not affected by addition of cyclic AMP to the growth medium. When exponentially growing cells were subjected to shift-up transitions, cell dimensions began to increase after a lag period of 20 min. Accumulation of major OM proteins followed the same pattern as total protein; this created a transitory imbalance of major OM protein density in the shift from acetate minimal medium to LB medium, before the steady situation was reached. After shift-down transitions, cell dimensions began to decrease immediately, cells eventually becoming shorter than in steady-state conditions. No fluctuations in major OM protein density were observed during the shift-down, although final stable levels differed from those in steady-state conditions. All these results indicate that bacteria adapt the accumulation of major proteins into the OM according to the amount of surface. Thus, no large differences exist at different cell sizes, although transitions between media can lead to transitory or stable changes in the composition of the OM.


Amifostine prior to lethal irradiation prevents allogeneic bone marrow engraftment in mice.
We and others have demonstrated that the milieu created by ionizing radiation (IR) used for conditioning plays a major role in the development of acute graft-versus-host disease (aGVHD). We reasoned that antioxidants that could inhibit IR induction of inflammatory cytokines and/or apoptosis might reduce the incidence or severity of aGVHD. Therefore, BALB/c mice were treated with amifostine, n-acetyl cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC) prior to transplantation with allogeneic C57Bl/6 bone marrow and spleen cells. None of 30 amifostine-pretreated mice developed weight loss or other signs of aGVHD and they rejected their allogeneic transplants. However, pretreatment to groups of five mice each with molar equivalent doses of NAC or PDTC accelerated death, and lower doses did not prevent aGVHD. In vitro tests demonstrated that PDTC and NAC acted as pro-oxidants when incubated with isolated normal mouse lymphocytes, whereas amifostine and its active metabolite WR-1065 did not. The conclusion that amifostine protected immune function from IR in vivo was further supported by the fact that amifostine and WR-1065 preserved the response of radiated normal lymphocytes to respond to PHA and both stimulated growth of non-radiated, non-PHA-treated normal lymphocytes in vitro. Taken together, these data caution the use of amifostine in allogeneic transplantation.


Nitric Oxide Synthase Regulates Growth Coordination During Drosophila melanogaster Imaginal Disc Regeneration.
Mechanisms that coordinate growth during development are essential for producing animals with proper organ proportion. Here we describe a pathway through which tissues communicate to coordinate growth. During Drosophila melanogaster larval development, damage to imaginal discs activates a regeneration checkpoint through expression of Dilp8. This both produces a delay in developmental timing and slows the growth of undamaged tissues, coordinating regeneration of the damaged tissue with developmental progression and overall growth. Here we demonstrate that Dilp8-dependent growth coordination between regenerating and undamaged tissues, but not developmental delay, requires the activity of nitric oxide synthase (NOS) in the prothoracic gland. NOS limits the growth of undamaged tissues by reducing ecdysone biosynthesis, a requirement for imaginal disc growth during both the regenerative checkpoint and normal development. Therefore, NOS activity in the prothoracic gland coordinates tissue growth through regulation of endocrine signals.


Robust control for nonlinear motor-mechanism coupling system using wavelet neural network.
A robust controlled toggle mechanism, which is driven by a permanent magnet (PM) synchronous servo motor is studied in this paper. First, based on the principle of computed torque control, a position controller is developed for the motor-mechanism coupling system. Moreover, to relax the requirement of the lumped uncertainty in the design of a computed torque controller, a wavelet neural network (WNN) uncertainty observer is utilized to adapt the lumped uncertainty online. Furthermore, based on the Lyapunov stability a robust control system, which combines the computed torque controller, the WNN uncertainty observer and a compensated controller is proposed to control the position of the motor-mechanism coupling system. The computed torque controller with WNN uncertainty observer is the main tracking controller, and the compensated controller is designed to compensate the minimum approximation error of the uncertainty observer. Finally, simulated and experimental results due to a periodic sinusoidal command show that the dynamic behaviors of the proposed robust control system are robust with regard to parametric variations and external disturbances.


A randomized controlled trial of interventions to promote cervical cancer screening among Chinese women in North America.
North American Chinese women have lower levels of Papanicolaou (Pap) testing than other population subgroups. We conducted a randomized controlled trial to evaluate the effectiveness of two alternative cervical cancer screening interventions for Chinese women living in North America. Four hundred and eighty-two Pap testing underutilizers were identified from community-based surveys of Chinese women conducted in Seattle, Washington, and Vancouver, British Columbia. These women were randomly assigned to one of two experimental arms or control status. Several Chinese-language materials were used in both experimental arms: an education-entertainment video, a motivational pamphlet, an educational brochure, and a fact sheet. Women in the first experimental group (outreach worker intervention) received the materials, as well as tailored counseling and logistic assistance, during home visits by trilingual, bicultural outreach workers. Those in the second experimental group (direct mail intervention) received the materials by mail. The control group received usual care. Follow-up surveys were completed 6 months after randomization to ascertain participants' Pap testing behavior. All statistical tests were two-sided. A total of 402 women responded to the follow-up survey (83% response rate). Of these women, 50 (39%) of the 129 women in the outreach group, 35 (25%) of the 139 women in the direct mail group, and 20 (15%) of the 134 women in the control group reported Pap testing in the interval between randomization and follow-up data collection (P<.001 for outreach worker versus control, P =.03 for direct mail versus control, and P =.02 for outreach worker versus direct mail). Intervention effects were greater in Vancouver than in Seattle. Culturally and linguistically appropriate interventions may improve Pap testing levels among Chinese women in North America.


Outcome of patients who develop acute leukemia or myelodysplasia as a second malignancy after solid tumors treated surgically or with strategies that include chemotherapy and/or radiation.
Evaluation of therapeutic outcomes and risk factors was undertaken for patients with primary solid tumors (PST) developing acute leukemia or myelodysplasia (MDS) as a second malignancy. In all, 131 consecutive patients presenting to a single institution with leukemia or MDS after treatment for PST with surgery or chemotherapy/radiotherapy were examined. Management of the secondary acute leukemia and MDS consisted either of intensive therapy including allogeneic blood and marrow transplants or supportive measures. The time from diagnosis of PST to development of acute leukemia or MDS, the cytogenetic profile of patients, and their survival were similar irrespective of PST therapy with surgery alone or strategies involving chemotherapy and/or radiation. The median survival of all 131 patients was 10.5 months with a 5-year survival of 15.6%. Induction therapy and/or transplantation resulted in a median survival of 13.6 months and a 5-year survival of 26.6% compared with 6.5 months and 2% with supportive measures. Subset analysis of transplant recipients revealed a median survival of 17.6 months and a 37.9% 5-year survival. Despite a significantly lower recurrence rate the survival of transplant recipients was not improved secondary to a higher treatment-related mortality (TRM) rate. Patients developing acute leukemia or MDS after PST demonstrated similar cytogenetic profiles and clinical outcomes independent of the type of treatment. Survival was significantly better for patients able to undergo intensive therapy compared with supportive measures. The low recurrence rate for allograft recipients was consistent with a potent antileukemic effect that may translate into a survival benefit if TRM could be reduced.


Capsule 13C-urea breath test for the diagnosis of Helicobacter pylori infection.
To compare the accuracy of capsule 13C-urea breath test (UBT) with conventional invasive methods for the diagnosis of Helicobacter pylori infection. One hundred patients received CLO test, histological examination, culture and 100- or 50-mg capsule UBT for the diagnosis of H pylori infection. H pylori infection was defined as those with positive culture or positive results from both histology and CLO test. Both the sensitivity and specificity of the 100-mg capsule UBT (n = 50) were 100%. The sensitivity and specificity of the 50-mg capsule UBT (n = 50) were 96.4 and 100%, respectively. Taken together, the accuracy of capsule UBT (n = 100) was higher than that of CLO test, histology and culture (100% vs 92%, 91% and 89%, respectively; P = 0.035, 0.018 and 0.005, respectively). Our data showed that the optimal timing of sampling for 100- and 50-mg capsule UBT was 15-30 and 6-15 min, respectively. Capsule UBT has a higher accuracy compared with biopsy-based tests. It is an ideal method for the diagnosis of H pylori infection.


Screening for Abdominal Aortic Aneurysms and Risk Factors in 65-Year-Old Men in Oslo, Norway.
To investigate the prevalence of and risk factors for abdominal aortic aneurysm (AAA) in 65-year-old men in Oslo, Norway. From May 2011, until September 2019, the annual population of 65-year-old men living in Oslo were invited to an ultrasonographic screening of the abdominal aorta. Candidates received a one-time invitation by mail, including a questionnaire on possible risk factors and comorbidities. Abdominal aortic outer-to-outer diameter and ankle-brachial index were measured by the screening team. Participants were allocated into three groups: non-, sub- and aneurysmal aorta. Written information on recommended follow-up regime was given to participants with an aortic diameter ≥25 mm. Univariate and multivariate analyses of potential risk factors were performed, in addition to descriptive analyses and significance testing. In total, 19,328 were invited, 13,215 men were screened, of which 12,822 accepted inclusion in the study. Aortic diameter was registered for 12,810 participants and 330 men had aortic diameter ≥30 mm, giving a prevalence of AAA of 2.6% (95% confidence interval (CI) 2.31-2.86). We identified 4 independent risk factors for AAA: smoking (OR = 3.64, 95% CI 2.90-4.58), hypertension (OR = 1.87, 95% CI 1.49-2.35), BMI >30 (OR = 1.02, 95% CI 1.00-1.03), and diabetes mellitus (OR = 0.52, 95% CI 0.35-0.79), the latter showing an inverse association with AAA growth. A subgroup of 862 men with aortic diameters 25-29 mm had a significantly higher prevalence of BMI >25, smoking and family history of AAA, compared to participants with aortic diameter <25 mm. Among the participants in this study, the prevalence of abdominal aortic aneurysms was 2.6%. Participants with AAA more frequently reported cardiovascular risk factors, and less frequently diabetes mellitus.


Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period.
It is urgent to understand the future of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) transmission. We used estimates of seasonality, immunity, and cross-immunity for human coronavirus OC43 (HCoV-OC43) and HCoV-HKU1 using time-series data from the United States to inform a model of SARS-CoV-2 transmission. We projected that recurrent wintertime outbreaks of SARS-CoV-2 will probably occur after the initial, most severe pandemic wave. Absent other interventions, a key metric for the success of social distancing is whether critical care capacities are exceeded. To avoid this, prolonged or intermittent social distancing may be necessary into 2022. Additional interventions, including expanded critical care capacity and an effective therapeutic, would improve the success of intermittent distancing and hasten the acquisition of herd immunity. Longitudinal serological studies are urgently needed to determine the extent and duration of immunity to SARS-CoV-2. Even in the event of apparent elimination, SARS-CoV-2 surveillance should be maintained because a resurgence in contagion could be possible as late as 2024.


Porphyromonas gingivalis Stimulates Bone Resorption by Enhancing RANKL (Receptor Activator of NF-κB Ligand) through Activation of Toll-like Receptor 2 in Osteoblasts.
Periodontitis has been associated with rheumatoid arthritis. In experimental arthritis, concomitant periodontitis caused by oral infection with Porphyromonas gingivalis enhances articular bone loss. The aim of this study was to investigate how lipopolysaccharide (LPS) from P. gingivalis stimulates bone resorption. The effects by LPS P. gingivalis and four other TLR2 ligands on bone resorption, osteoclast formation, and gene expression in wild type and Tlr2-deficient mice were assessed in ex vivo cultures of mouse parietal bones and in an in vivo model in which TLR2 agonists were injected subcutaneously over the skull bones. LPS P. gingivalis stimulated mineral release and matrix degradation in the parietal bone organ cultures by increasing differentiation and formation of mature osteoclasts, a response dependent on increased RANKL (receptor activator of NF-κB ligand). LPS P. gingivalis stimulated RANKL in parietal osteoblasts dependent on the presence of TLR2 and through a MyD88 and NF-κB-mediated mechanism. Similarly, the TLR2 agonists HKLM, FSL1, Pam2, and Pam3 stimulated RANKL in osteoblasts and parietal bone resorption. LPS P. gingivalis and Pam2 robustly enhanced osteoclast formation in periosteal/endosteal cell cultures by increasing RANKL. LPS P. gingivalis and Pam2 also up-regulated RANKL and osteoclastic genes in vivo, resulting in an increased number of periosteal osteoclasts and immense bone loss in wild type mice but not in Tlr2-deficient mice. These data demonstrate that LPS P. gingivalis stimulates periosteal osteoclast formation and bone resorption by stimulating RANKL in osteoblasts via TLR2. This effect might be important for periodontal bone loss and for the enhanced bone loss seen in rheumatoid arthritis patients with concomitant periodontal disease.


Health Care Payments in Vietnam: Patients' Quagmire of Caring for Health versus Economic Destitution.
In the last three decades many developing and middle-income nations' health care systems have been financed via out-of-pocket payments by individuals. User fees charges, however, may not be the best approach or thenmost equitable approach to finance and/or reform health services in developing nations. This study investigates the status of Vietnam's current health system as a result of implementing user fees policies. A recent mandate by the government to increase the universal cover to 100% attempts to tackle inadequate insurance cover, one of the four major factors contributing to the high and increasing probability of destitution for Vietnamese patients (the other three being: non-residency, long stay in hospital, and high cost of treatment). Empirical results however suggest that this may be catastrophic for low-income earners: if insurance cover reimbursement decreases below 50% of actual health expenditures, the probability of Vietnamese falling into destitution will rise further. Our findings provide policy implications and directions to improve Vietnam's health care system, in particular by ensuring the utilization of health services and financial protection for the people.


Abnormal cortical network activation in human amnesia: A high-resolution evoked potential study.
Little is known about how human amnesia affects the activation of cortical networks during memory processing. In this study, we recorded high-density evoked potentials in 12 healthy control subjects and 11 amnesic patients with various types of brain damage affecting the medial temporal lobes, diencephalic structures, or both. Subjects performed a continuous recognition task composed of meaningful designs. Using whole-scalp spatiotemporal mapping techniques, we found that, during the first 200 ms following picture presentation, map configuration of amnesics and controls were indistinguishable. Beyond this period, processing significantly differed. Between 200 and 350 ms, amnesic patients expressed different topographical maps than controls in response to new and repeated pictures. From 350 to 550 ms, healthy subjects showed modulation of the same maps in response to new and repeated items. In amnesics, by contrast, presentation of repeated items induced different maps, indicating distinct cortical processing of new and old information. The study indicates that cortical mechanisms underlying memory formation and re-activation in amnesia fundamentally differ from normal memory processing.


Decreased Nesfatin-1 Level in Overweight Depressed Patients.
Nesfatin-1 (NF-1) is a parameter that has been shown to have an important potential in the modulation of the emotional state such as depression. The study focused to investigate the relationship between the plasma NF-1 level and depression. Seventy-three patients who have a major depressive disorder (MDD) and 71 healthy individuals participated in the study. Plasma NF-1 was analyzed by Enzyme Linked Immunosorbent Assay (ELISA) and compared according to the groups. The mean NF-1 was lower in the patients with MDD than being in the healthy (p:0.019). Plasma NF-1 level was statistically significantly lower in the overweight MDD than in the non-overweight MDD (p:0.024). We observed a negative correlation between plasma NF-1 level and age (r:-0.178, p:0.033), BMI (r:-0.212, p:0.011), HAM-D scores (r:-0.185, p:0.026). However, there was no correlation for smoking status in both groups (r:0.095, p:0.259). This study demonstrated the relationship between plasma NF-1 level and MDD as well as overweight. Therefore, NF-1 might be related to certain nervous system pathologies as well as adipose tissue in the body.


Stereotypical Questions: How Stereotypes About Conversation Partners Are Reflected in Question Formulations.
In conversations, activated stereotypes about conversation partners can influence communicative behaviors. We investigate whether and how stereotypes about categorized conversation partners shape topic choice and the types of questions asked. In three experiments, participants imagined having a conversation. Gender or age stereotypes of the conversation partner were manipulated by means of a picture. Results show a higher likelihood of addressing conversation and question topics consistent with stereotypic expectancies about conversation partners. Moreover, stereotypes were reflected in subtle variations in question formulations. When questions address stereotype-consistent topics, they are likelier formulated with high-frequency adverbs and positive valence, while questions addressing stereotype-inconsistent topics more likely contain low-frequency adverbs and negative valence. In addition, Experiment 4 suggests that recipients are sensitive to detect that questions reflect stereotypes about themselves, which can influence the evaluation of the conversation and partner. We discuss the consequences of biased question asking for interpersonal conversation and stereotype maintenance.


Comparison between clinical significance of serum proinflammatory protein interleukin-6 and classic tumor markers total PSA, free PSA and free/total PSA prior to prostate biopsy.
The aim of the study was to clarify whether serum levels of proinflammatory cytokine interleukin-6 (IL-6) could be a useful marker in prostate diseases. Serum IL-6 was determined prior to prostate biopsy procedure in 82 patients with prostate adenocarcinoma (PCa), 25 patients with benign prostatic hyperplasia (BPH), 24 patients with high-grade prostatic intraepithelial neoplasia (PIN) and 17 patients with chronic prostatitis. Serum IL-6 levels were compared with total PSA (tPSA), free PSA (fPSA) and the free/total ratio (f/tPSA) serum levels. Statistically significant difference was not found in serum IL-6 levels among the four groups (p = 0.088). However, the patients with poorly differentiated PCa with Gleason score (GS) 4 + 3 = 7 and > 7 had significantly higher serum IL-6 levels than the patients with moderately differentiated PCa with GS 3 + 4 = 7 and < 7 (p = 0.007). The findings suggest that serum IL-6 level might be a potentially useful marker for poorly differentiated PCa.


Experimental in vitro transmission of Babesia sp. (EU1) by Ixodes ricinus.
Babesia sp. (EU1), first characterized in 2003, has been implicated in human cases of babesiosis in Italy, Austria and Germany. It has been identified in roe deer and in its suspected tick vector, Ixodes ricinus, in several European countries. The aim of the present study was to validate the competence of I. ricinus as a vector of Babesia sp. (EU1) via experimental infections. For this purpose, a parasite strain isolated from roe deer was cloned in sheep erythrocytes. After experimental infections, parasite DNA was successfully amplified by PCR in both eggs and larvae originating from infected I. ricinus females and in the salivary glands of females exposed to Babesia sp. (EU1) as nymphs. We also demonstrate that infected females were able to transmit parasite DNA during a new blood meal. Together with previous epidemiological studies, these results validate I. ricinus as a competent vector for Babesia sp. (EU1).


Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses.
Diagnosis of pancreatic tumors can be problematic. This study aimed to determine the performance of endoscopic ultrasound-guided fine needle aspiration biopsy (EUS FNA) in pancreatic malignancy when prior biopsies performed by CT guidance or ERCP were negative. A total of 185 patients with known or suspected pancreatic masses were prospectively evaluated with EUS FNA. Before EUS FNA, all patients were evaluated with abdominal CT (61 with CT-guided biopsy) and 91 with ERCP (41 had brushings or biopsy). EUS had greater sensitivity than CT in detecting a mass (99% vs 57%, p < 0.0001). In 58 patients with negative CT-guided biopsies, EUS FNA had 90% sensitivity for malignancy, 50% specificity for benign disease and 84% accuracy. Similarly, in 36 patients with negative ERCP tissue sampling, results for EUS FNA were 94%, 67% and 92%, respectively. Complications were mild and infrequent (0.5%). EUS FNA of pancreatic masses safely and accurately diagnoses pancreatic malignancy when prior biopsy techniques have been unsuccessful.


Acromegaly: the disease, its impact on patients, and managing the burden of long-term treatment.
Acromegaly is a rare disease most often caused by the prolonged secretion of excess growth hormone from a pituitary adenoma. The disease is associated with multiple significant comorbidities and increased mortality. The delay to diagnosis is often long. This may be because of low disease awareness among health care professionals, the insidious onset of differentiating features, and because patients are likely to present with complaints typical of other conditions more frequently seen in primary care. Early identification of acromegaly facilitates prompt treatment initiation and may minimize the permanent effects of excess growth hormone. The primary treatment for many patients will be pituitary surgery, although not all patients will be eligible for surgery or achieve a surgical cure. If biochemical control is not achieved following surgery, other treatment options include medical therapy and radiation therapy. Improved biochemical control may only alleviate rather than reverse the associated comorbidities. Thus, lifelong monitoring of patient health is needed, with particular attention to the management of cardiovascular risk factors. It is additionally important to consider the impact of both disease and treatment on patients' quality of life and minimize that impact where possible, but particularly for chronic therapies. For the majority of patients, chronic therapy is likely to include somatostatin analog injections. In some circumstances, it may be possible to extend the dosing interval of the analog once good biochemical control is achieved. Additional convenience may be gained from the possibility of self-/partner administration of treatment or administration of treatment by a health care professional at home. Overall, it is clear that the care of patients with acromegaly requires a highly coordinated approach involving numerous specialties (eg, endocrinology, surgery, cardiology). Further, patients' needs must be at the core of management and every effort must be made to improve health care experiences and minimize treatment burdens.


Dietary tangeretin improved antibiotic-associated diarrhea in mice by enhancing the intestinal barrier function, regulating the gut microbiota, and metabolic homeostasis.
Antibiotic-associated diarrhea is mediated by antibiotic treatment and is usually caused by the disruption of the intestinal barrier, gut microbiota, and metabolic balance. To identify a dietary strategy that can mitigate the side effects of antibiotics, this study investigated the effect of tangeretin on antibiotic-associated diarrhea in C57BL/6 mice. The results revealed that dietary tangeretin significantly ameliorated symptoms of antibiotic-associated diarrhea, as evidenced by the decreased diarrhea status scores, the reduced fecal water content, the decreased caecum/body weight ratio, and the alleviated colonic tissue damage. Dietary tangeretin also exhibited a protective effect on the intestinal barrier function by upregulating the mRNA and protein expression of claudin-1 and ZO-1. Furthermore, analysis of the gut microbiota using 16S rRNA gene sequencing indicated that dietary tangeretin modulated the gut microbiota of mice with antibiotic-associated diarrhea via increasing the gut microbiota diversity and the abundance of beneficial bacteria, e.g., Lactobacillaceae and Ruminococcaceae, and decreasing the abundance of harmful bacteria, e.g., Enterococcus and Terrisporobacter. Additionally, dietary tangeretin restored the levels of short-chain fatty acids and modulated metabolic pathways by enriching purine metabolism, bile acid metabolism, ABC transporters, and choline metabolism in cancer. Collectively, these findings provide a solid scientific basis for the rational use of tangeretin as a preventive and therapeutic agent for antibiotic-associated diarrhea.


Glucanase-producing organisms in human dental plaques.
Selective media were used to isolate a wide range of bacteria from sixty human dental plaques. Glucanase activities of the isolates were determined on dextran- and starch-containing media. All sixty samples of dental plaque yielded some colonies showing amylolytic and dextranolytic activities. The glucanase-producing organisms comprised 20% of the isolates. Of these 38% were Gram-positive rods, 27% Gram-positive cocci, 28% Gram-negative rods and 7% were Gram-negative cocci. The cultural groups most commonly represented among the glucanase-producing isolates were Actinomycetaceae, streptococci, haemophili and Gram-negative anaerobes. Species prominent among these isolates included Streptococcus sanguis, Streptococcus mitior, Actinomyces naeslundii, Actinomyces viscosus, Bacterionema matruchotii, Bifidobacterium sp. and Bacteroides sp. No isolates capable of degrading starch or dextran were identified as Streptococcus milleri, Rothia dentocariosa or Fusobacterium sp. This study has shown that a wide range of bacterial species commonly isolated from human dental plaques exhibit both amylolytic and dextranolytic activities. In order to understand glucan metabolism in human dental plaques further investigation of these catabolic activities is necessary.


Disseminated intravascular coagulopathy in the first 24 hours after trauma: the association between ISTH score and anatomopathologic evidence.
Recent studies questioned "classical" concepts in trauma care, including whether disseminated intravascular coagulation (DIC) occurs in trauma. The knowledge on trauma DIC is limited to few studies built on diagnosing DIC with laboratory-based scores. This study explores whether DIC diagnosed by the well-established ISTH (International Society for Thrombosis and Hemostasis) score is corroborated by anatomopathologic findings. Prospective observational cohort study of severely injured (ISS ≥ 16) patients. DIC was diagnosed by the ISTH score throughout the first 24 hours after trauma. All organs surgically removed within 24 hours of trauma were reviewed by two independent pathologists. All autopsy reports were reviewed. Of 423 patients enrolled, ∼11% had "overt DIC" and 85% had "suggestive of non-overt DIC" scores throughout the 24 hours after trauma. "Overt DIC" patients had higher mortality and worse bleeding, receiving more blood and plasma transfusions. One hundred and sixteen patients underwent surgery within 24 hours of trauma, and all 40 excised organs were reviewed by two pathologists. Twenty-seven autopsies reports were reviewed. No anatomopathologic evidence of DIC was identified in the first 24 hours, even after additional histochemical staining. d-dimer was universally elevated after trauma. Common DIC features: platelet count, fibrinogen, clotting time, and factor VIII drop were mostly absent. d-dimer has a disproportional participation in trauma DIC scores. Within 24 hours of trauma, most severely injured patients have DIC scores "suggestive for" or of "overt DIC" but no anatomopathologic evidence of DIC. Considering pathologic findings as the gold standard diagnosis, then DIC is exceptionally uncommon and the ISTH score should not be used for trauma.


Strategies for increasing high-quality intervention research in Aboriginal and Torres Strait Islander health: views of leading researchers.
To identify policy strategies that are perceived by researchers active in Aboriginal and Torres Strait Islander health as effective in increasing the amount of high-quality intervention research undertaken in this field. A cross-sectional study using a web-based survey was emailed to researchers based in clinical, public health and other academic institutions. Researchers who had published more than once in Aboriginal health between 1 January 2005 and 1 August 2009, based on a MEDLINE search. Participants selected and weighted 17 strategies that were, in their opinion, important for increasing the amount of high-quality intervention research being conducted in Aboriginal health. We invited 157 researchers to complete the survey, and received 74 completed surveys. The most highly weighted strategies were: for research funding bodies to give funding priority to intervention research proposals that target Aboriginal populations (median weighted score,15%); for peak bodies representing Aboriginal communities to clearly specify intervention research priorities in a national Aboriginal health research agenda (median weighted score, 10%); for research funding bodies to fund research to develop reliable measures of health for Aboriginal people (median weighted score, 9.5%); for health care organisations to participate more in intervention research targeting Aboriginal populations (median, 8.5%); and for research review panels to accept intervention research designs other than the randomised controlled trial (median weighted score, 8%). Researchers who are active in Aboriginal health research perceive that improvements in funding mechanisms, priority setting and research systems are required to increase the amount of high-quality intervention research being conducted in this field. A national intervention research agenda that encourages multidisciplinary research teams and community partnerships may offer a solution.


Natriuresis induced by arginine vasopressin infusion in sheep.
The aim of this study was to investigate whether arginine vasopressin (AVP) is natriuretic in sheep at plasma concentrations comparable to those induced by water deprivation. AVP was infused intravenously at 0.1, 0.2, and 0.5 microgram/h for 24-48 h in sheep allowed free access to water. Infusion of AVP at 0.1 microgram/h did not alter renal Na output, whereas infusion of AVP at both 0.2 and 0.5 microgram/h significantly increased daily output of Na in urine. Significant natriuresis did not occur until 3.5 h after the start of AVP infusion at 0.2 microgram/h. Plasma AVP levels induced by these infusions were 9.8 +/- 1.6 (0.1 microgram/h AVP), 21.9 +/- 7.7 (0.2 microgram/h AVP), and 32.5 +/- 9.0 pg/ml (0.5 microgram/h AVP) after 24 h. These concentrations are within the range found in sheep deprived of water for 3 days. Hypophysectomy abolished increases in plasma AVP concentration but not natriuresis in response to water deprivation. This suggests that increased plasma AVP concentration does not play an essential role in the mechanisms subserving dehydration-induced natriuresis.


Mid-Term Outcomes of Cementless Total Hip Arthroplasty in Adult Patients with Childhood Hip Infection.
BACKGROUND Patients with hip joint infections in childhood often have many aftereffects of different degrees, regardless of the kind of treatment or natural course. Total hip arthroplasty is currently the most effective treatment for sequelae of childhood hip septic or tuberculous infection. This is a mid-term follow-up study of treatment results of patients who had undergone total hip arthroplasty (THA) with cementless prostheses. MATERIAL AND METHODS We retrospectively analyzed and followed 45 patients (45 hips) who underwent THA with cementless prostheses between 2010 and 2017. There were 45 patients, including 17 men and 28 women. The average age of the patients was 46 years (range, 18-67 years). All hip infections occurred in early childhood or adolescence, and the mean interval between initial infection and THA was 38.2 years (range, 15-60 years). The mean follow-up was 6.1 years (range, 2.7-9.5 years). RESULTS Two patients underwent revision surgery because of loosening of the prosthesis, and 1 patient underwent revision surgery because of a new infection with no relationship with childhood infection during the follow-up. The average Harris hip scores significantly increased from 43.1 to 86.4 (P<0.01), and the average visual analog scale significantly increased from 4.6 to 1.7 (P<0.01). The hip dysfunction and osteoarthritis outcome scores were also significantly changed (P<0.01) at the final follow-up. There were 2 cases of transient sciatic nerve palsy and intraoperative periprosthetic fractures in 3 cases. During follow-up, single revision was performed after 6 years of primary arthroplasty because of aseptic loosening in 2 cases and prosthesis infection in 1 case, which was not related to childhood pathogens. CONCLUSIONS THA for patients with sequelae of hip joint infection has a satisfactory effect that can effectively relieve joint pain and improve hip function. The recurrence rate of infection after either pyogenic infection or tuberculous is very low. The mid-term outcomes of THA in this setting were satisfactory, with high prosthesis survivorship and hip function scores.