How Working Memory and Reinforcement Learning Are Intertwined: A Cognitive, Neural, and Computational Perspective.
Reinforcement learning and working memory are two core processes of human cognition and are often considered cognitively, neuroscientifically, and algorithmically distinct. Here, we show that the brain networks that support them actually overlap significantly and that they are less distinct cognitive processes than often assumed. We review literature demonstrating the benefits of considering each process to explain properties of the other and highlight recent work investigating their more complex interactions. We discuss how future research in both computational and cognitive sciences can benefit from one another, suggesting that a key missing piece for artificial agents to learn to behave with more human-like efficiency is taking working memory's role in learning seriously. This review highlights the risks of neglecting the interplay between different processes when studying human behavior (in particular when considering individual differences). We emphasize the importance of investigating these dynamics to build a comprehensive understanding of human cognition.


Simultaneous confidence intervals for an extended Koch-Röhmel design in three-arm non-inferiority trials.
Three-arm 'gold-standard' non-inferiority trials are recommended for indications where only unstable reference treatments are available and the use of a placebo group can be justified ethically. For such trials, several study designs have been suggested that use the placebo group for testing 'assay sensitivity', that is, the ability of the trial to replicate efficacy. Should the reference fail in the given trial, then non-inferiority could also be shown with an ineffective experimental treatment and hence becomes useless. In this article, we extend the so-called Koch-Röhmel design where a proof of efficacy for the experimental treatment is required in order to qualify for the non-inferiority test. While the efficacy of the experimental treatment is an indication of assay sensitivity, it does not guarantee that the reference is sufficiently efficient to let the non-inferiority claim be meaningful. It has, therefore, been suggested to adaptively test the non-inferiority only if the reference demonstrates superiority to placebo and otherwise to test δ-superiority of the experimental treatment over placebo, where δ is chosen in such a way that it provides proof of non-inferiority with regard to the reference's historical effect. In this article, we extend the previous work by complementing its adaptive test with compatible simultaneous confidence intervals. Confidence intervals are commonly used and suggested by regulatory guidelines for non-inferiority trials. We show how to adopt different approaches to simultaneous confidence intervals from the literature to the setting of three-arm non-inferiority trials and compare these methods in a simulation study. Finally, we apply these methods to a real clinical trial example.


RuO2-ReO3 composite nanofibers for efficient electrocatalytic responses.
We present a facile synthetic route to ruthenium dioxide (RuO2)-rhenium oxide (ReO3) electrospun composite nanofibers and their electrocatalytic responses for capacitance and H2O2 sensing. The contents of rhenium oxide of electrospun ruthenium dioxide (RuO2) were carefully controlled by an electrospinning process with the preparation of the precursor solutions followed by the thermal annealing process in air. The electrochemical applications of RuO2-ReO3 electrospun composite nanofibers were then investigated by modifying these materials on the surface of glassy carbon (GC) electrodes, RuO2-ReO3(n)/GC (n = 0.0, 0.07, 0.11, and 0.13), where n denotes the relative atomic ratio of Re to the sum of Ru and Re. Specific capacitance and H2O2 reduction sensitivity were remarkably enhanced depending on the amount of ReO3 increased. Among the four compositions of RuO2-ReO3(n), RuO2-ReO3(0.11)/GC showed the highest performances, i.e., a 20.9-fold higher specific capacitance (205 F g(-1) at a potential scan rate (v) of 10 mV s(-1); a capacity loss of 19% from v = 10 to 2000 mV s(-1)) and a 7.6-fold higher H2O2 reduction sensitivity (668 μA mM(-1) cm(-2), normalized by GC disk area), respectively, compared to only RuO2/GC.


[Possibilities of recanalization of cicatricial strictures of esophagus].
Long-term results of recanalization of the esophagus by orthograde bouginage through the guide and by endoprosthesis post-burn strictures were evaluated in 105 patients. The application of these methods enabled in 81% of patients to achieve steadfast restoration of esophageal continuity, sufficient enough for adequate feeding. Orthograde bouginage of the esophagus through the guide showed to be effective in 45.5% patients with strictures up to 100 mm length and over 6 mm in diameter, the end of the bouge being not more than 1.5 kg. Endoprosthetic procedure provided to achieve restoration of esophageal continuity in 95% of patients.


Catabolism of alpha-ketoglutarate by a sucA mutant of Bradyrhizobium japonicum: evidence for an alternative tricarboxylic acid cycle.
A complete tricarboxylic acid (TCA) cycle is generally considered necessary for energy production from the dicarboxylic acid substrates malate, succinate, and fumarate. However, a Bradyrhizobium japonicum sucA mutant that is missing alpha-ketoglutarate dehydrogenase is able to grow on malate as its sole source of carbon. This mutant also fixes nitrogen in symbiosis with soybean, where dicarboxylic acids are its principal carbon substrate. Using a flow chamber system to make direct measurements of oxygen consumption and ammonium excretion, we confirmed that bacteroids formed by the sucA mutant displayed wild-type rates of respiration and nitrogen fixation. Despite the absence of alpha-ketoglutarate dehydrogenase activity, whole cells of the mutant were able to decarboxylate alpha-[U-(14)C]ketoglutarate and [U-(14)C]glutamate at rates similar to those of wild-type B. japonicum, indicating that there was an alternative route for alpha-ketoglutarate catabolism. Because cell extracts from B. japonicum decarboxylated [U-(14)C]glutamate very slowly, the gamma-aminobutyrate shunt is unlikely to be the pathway responsible for alpha-ketoglutarate catabolism in the mutant. In contrast, cell extracts from both the wild type and mutant showed a coenzyme A (CoA)-independent alpha-ketoglutarate decarboxylation activity. This activity was independent of pyridine nucleotides and was stimulated by thiamine PP(i). Thin-layer chromatography showed that the product of alpha-ketoglutarate decarboxylation was succinic semialdehyde. The CoA-independent alpha-ketoglutarate decarboxylase, along with succinate semialdehyde dehydrogenase, may form an alternative pathway for alpha-ketoglutarate catabolism, and this pathway may enhance TCA cycle function during symbiotic nitrogen fixation.


Etiology of developmental hip dysplasia or dislocation: review article.
There is no consensus in the literature regarding the impact of several, so-called, etiological factors in the appearance of developmental dysplasia or dislocation of the hip (DDH). Furthermore, the mechanism explaining the appearance of a dislocated or subluxated hip in the perinatal period is not well defined. The latter explains, as well, the different terms used to describe the same clinical entity. Terms like congenital dislocation of the hip (CDH), developmental dysplasia/dislocation of the hip or teratological dislocation of the hip are usually applied for the description of the same condition. Constitutional and mechanical disorders are accused of encouraging the evolution of an antenatal or neonatal hip towards instability, subluxation or even dislocation. An understanding of the predisposing factors as well as the natural history is essential in order to prevent and/or treat them effectively as well as to decide on the most appropriate nomenclature. A review of the multiple published theories affirms that the determining predisposing factors for hip dislocation or subluxation are mechanical and are associated with intra-uterine posture in full hip flexion, adduction and external femoral rotation together with abnormal pressure on the greater trochanter tending to expel the femoral head in a supero-posterior direction relative to the acetabulum. The role of genetic factors is secondary, but present, and can influence the natural history of a patient if the primary mechanical and postural factors are not inhibited.


Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice.
Among chronically ill populations, affective disorders remain underdiagnosed and undertreated. A high degree of comorbidity exists between diabetes and affective disorders, particularly depression and anxiety. The mechanisms underlying stress-induced affective dysregulation are likely distinct from that induced by diabetes. A direct comparison between stress- and hyperglycemia-induced affective dysregulation could provide insight into distinct mechanistic targets for depression/anxiety associated with these different conditions. To this end, the present study used male C57BL/6J mice to compare the independent and combined behavioral and neuroinflammatory effects of two models: (1) unpredictable chronic mild stress and (2) pharmacologically induced hyperglycemia. Streptozotocin-induced hyperglycemia was associated with a set of behavioral changes reflective of the neurovegetative symptoms of depression (i.e., reduced open field activity, reduced grooming, increase immobility in the forced swim task, and decreased marble burying), increased hippocampal Bdnf and Tnf expression, and elevations in frontal cortex Il1b expression. Our chronic stress protocol produced alterations in anxiety-like behavior and decreased frontal cortex Il1b expression. While the combination of chronic stress and hyperglycemia produced limited additive effects, their combination exacerbated total symptom burden. Overall, the data indicate that stress and hyperglycemia induce different symptom profiles via distinct mechanisms.


DDT: A NEW HYPOTHESIS OF ITS MODE OF ACTION.
It is suggested that DDT and perhaps other chlorinated hydrocarbon insecticides owe their activity to the formation of a charge-transfer complex with a component of the nerve axon, with consequent disturbance of function. Experimental evidence is provided for the formation of two complexes with components of cockroach nerve; the complexes have been partially purified. Their formation is accompanied by an absorption in the 245- to 270-millimicron range.


Interferon production by Epstein-Barr virus in human mononuclear leukocytes.
Interferon (IFN) production following exposure to Epstein-Barr virus (EBV) was studied in primary human mononuclear leukocytes. When the leukocytes were exposed to EBV (strain B95-8 or P3HR-1) the IFN level reached a maximum 24 h after exposure to the virus, and a gradual decrease followed. A linear relationship was obtained between the input dose of EBV and the IFN titre. The IFN inducibility of leukocytes did not correlate with the EBV infectibility. IFN was also induced by u.v.-inactivated EBV and heat-inactivated EBV, but not by neutralized virus. IFN inducibility varied among adult donors, but there was no significant difference between EBV-seropositive and -seronegative groups. The response of cord blood leukocytes, however, was lower than that of the cells from adults. The activity of all IFN samples in this study was stable to acid and heat and exclusively neutralized by anti-human IFN-alpha. B cells, T cells and NK cells all produced IFN in response to EBV, but monocytes did not.


The product of the US10 gene of herpes simplex virus type 1 is a capsid/tegument-associated phosphoprotein which copurifies with the nuclear matrix.
We have identified the herpes simplex virus type 1 (HSV-1) US10 gene product using rabbit polyclonal antisera raised against a recombinant 6xHis-US10 fusion protein expressed in Escherichia coli. The antiserum reacted specifically with 34 and 36 kDa proteins in HSV-1 KOS-infected cells as shown by Western blotting and immunoprecipitation experiments. The 36 kDa protein was immunoprecipitated with the US10 antiserum from 32P-labelled lysates of Vero cells infected with HSV-1 KOS, demonstrating that the US10 protein was phosphorylated. Indirect immunofluorescence studies localized the US10 protein mainly to nuclei as large discrete particles at later times post-infection (p.i.), and nuclear fractionation studies revealed that the protein was tightly associated with the nuclear matrix. Moreover, analysis of isolated intracellular capsids showed that both phosphorylated and unphosphorylated forms of the US10 product were also associated with the capsid/tegument. These results indicate that the US10 gene of HSV-1 encodes a capsid/tegument-associated phosphoprotein which copurifies with the nuclear matrix.


Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma.
The role of immunotherapy in cancer is now well-established, and therapeutic options such as checkpoint inhibitors are increasingly being approved in many cancers such as non-small cell lung cancer (NSCLC). Malignant pleural mesothelioma (MPM) is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Evidence from clinical trials of checkpoint inhibitors in this rare disease, suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. While the majority of studies currently focus on the established checkpoint inhibitors (CTLA4 and PD1/PDL1), there are many other potential checkpoints that could also be targeted. In this review I provide a synopsis of current clinical trials of immunotherapies in MPM, explore potential candidate new avenues that may become future targets for immunotherapy and discuss aspects of immunotherapy that may affect the clinical outcomes of such therapies in this cancer. The current situation regarding checkpoint inhibitors in the management of MPM whilst encouraging, despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Additional studies are therefore required to further delineate and improve our understanding of both checkpoint inhibitors and the immune system in MPM. Moreover, many new potential checkpoints have yet to be studied for their therapeutic potential in MPM. All these plus the existing checkpoint inhibitors will require the development of new biomarkers for patient stratification, response and also for predicting or monitoring the emergence of resistance to these agents in MPM patients. Other potential therapeutic avenues such CAR-T therapy or treatments like oncolytic viruses or agents that target the interferon pathway designed to recruit more immune cells to the tumor also hold great promise in this hard to treat cancer.


Molecular identification, phylogenetic status, and geographic distribution of Culicoides oxystoma (Diptera: Ceratopogonidae) in Israel.
Culicoides oxystoma (Diptera: Ceratopogonidae) is an important vector species, reported mainly from Asia, with high potential to transmit viral diseases affecting livestock. In Japan, many arboviruses have been isolated from C. oxystoma, suggesting it as a key player in the epidemiology of several Culicoides-borne diseases. Over the years, C. oxystoma has also been reported in the Middle East region, including Israel. In this region, however, C. oxystoma cannot be easily distinguished morphologically from its sibling species included in the Culicoides schultzei complex. We therefore used genomic data for species identification and phylogeny resolution. Phylogenetic analyses based on internal transcribed spacer 1 (ITS-1) of ribosomal DNA and the mitochondrial gene encoding cytochrome oxidase subunit I (COI) showed that C. oxystoma from Israel is closely related to C. oxystoma from Japan. Using differential probing PCR, we showed that C. oxystoma is distributed all over the country, especially in Mediterranean climate regions. Culicoides oxystoma is less common or even absent in arid regions, while the other genetic cluster of C. schultzei complex was found only in the east of the country (mostly arid and semiarid regions). The molecular finding of C. oxystoma in wide geographical regions, together with its high proportion in the general Culicoides population and its vectoring potential, imply that it may be an important vector species in the Middle East.


[Evaluation of antibiotic sensitivity of pathogenic vibrios of various species].
The recent increase of the number of antimicrobials and isolation of antibiotic resistant strains from humans and environmental objects is indicative of the necessity of further investigation of antibiotic susceptibility of the representatives of the genus Vibrio pathogenic for man to provide rational therapy of the diseases due to them. Susceptibility of 160 strains of pathogenic vibrios of 9 species to 11 antibiotics and chemotherapeutic drugs was assayed by the method of serial dilutions in agar media. The isolates were shown to be highly susceptible to chloramphenicol, doxycycline, cefotaxime, nalidixic acid and ciprofloxacin which made it possible to consider them as the drugs of choice in the treatment of the diseases caused by the microorganisms. A tendency to form polyantibiotic resistant strains within every species of tested pathogenic vibrios was observed. It conditioned the prospects of further profound study of the phenomenon with the analysis of the genetic determination of antibiotic resistance markers in pathogenic vibrios.


Buspirone induced acute and chronic changes of neural activation in the periaqueductal gray of rats.
5-HT(1A) modulation within the midbrain periaqueductal gray (PAG) is closely associated with anxiety- or panic-like behavior. Several findings have demonstrated that the properties of buspirone (a 5-HT(1A) partial agonist) would function as either anxiolytic or panicolytic in both clinical and laboratory animal research. In this study, we have investigated the neuronal activity occurring within the different regions of the PAG induced by buspirone treatment. Twenty-eight albino Wistar rats (350-400 g) were injected with either acute or chronic saline/buspirone (each, n=7), respectively. Our results show that buspirone treatment reduced locomotor activity, body weight and fecal boli, particularly in the chronic buspirone group. Two-way ANOVA revealed a significant decrease of c-Fos-immunoreactive (ir) cells expression in all regions of the rostral PAG after both acute and chronic buspirone (acute buspirone (AB) and chronic buspirone (CB), respectively) treatment. However, no effects on c-Fos-ir were detected in the caudal lateral periaqueductal gray (lPAG) and ventrolateral periaqueductal gray (vlPAG) in both the AB and CB groups, and in the dorsolateral periaqueductal gray (dlPAG) of the CB group. Interestingly, c-Fos-ir cells in the dorsomedial periaqueductal gray (dmPAG) column were reduced consistently in both the rostral and caudal PAG in both AB and CB groups. Besides, in all regions the number of c-Fos-ir cells was higher in the AB than in the CB group with exception of the rostral lPAG. In conclusion, the main anxiolytic effect of buspirone was specifically localized in all regions of the rostral PAG and in the caudal dmPAG. However, the caudal dlPAG, lPAG and vlPAG were found to be ineffective to buspirone treatment, probably due to their distinctive function in mediating higher level of anxiety in defensive behavior. This indicates that the longitudinal anatomical structure of the PAG possesses a different level of receptor sensitivity of 5-HT(1A) in the pathophysiology of anxiety and panic disorder.


The role of traditional Chinese medicines in osteogenesis and angiogenesis.
The article aims to review various Traditional Chinese Medicines (TCMs) with both osteogenic and angiogenic effects, alone and in combination, and to consider whether these TCMs promote osteogenesis via angiogenesis and vascular endothelial growth factor (VEGF). Each of the TCMs involving in osteogenesis was searched through PubMed and CBMdisc using its Latin name and English name, and keywords such as 'osteogenesis', 'bone', 'osteoblast', 'angiogenesis', 'VEGF' were used. A total of 241 articles were screened from PubMed and CBMdisc. The articles were only chosen if they discussed the relationship of the TCMs with bone formation and/or angiogenesis. Twenty-seven articles were chosen, of which 16 were in English and 11 were in Chinese with English abstract. As a result, the TCMs (Danshen or Salvia miltiorrhiza Bunge, Danggui or Angelica sinensis, Astragalus membranaceus Bunge or Huangqi, and Ge Gan or Puerarin radix) that have a relationship with both osteogenesis and angiogenesis were screened out. It is found that the aforementioned TCMs enhance angiogenesis and osteogenesis. They show a positive effect on bone formation, and the possible mechanisms may be related to their ability to promote angiogenesis via an effect on substances such as VEGF.


The year in cardiothoracic and vascular anesthesia: selected highlights from 2013.
This article reviewed selected research highlights of 2013 that pertain to the specialty of cardiothoracic and vascular anesthesia. The first major theme is the commemoration of the sixtieth anniversary of the first successful cardiac surgical procedure with cardiopulmonary bypass conducted by Dr Gibbon. This major milestone revolutionized the practice of cardiovascular surgery and invigorated a paradigm of mechanical platforms for contemporary perioperative cardiovascular practice. Dr Kolff was also a leading contributor in this area because of his important contributions to the refinement of cardiopulmonary bypass and mechanical ventricular assistance. The second major theme is the diffusion of echocardiography throughout perioperative practice. There are now guidelines and training pathways to guide its generalization into everyday practice. The third major theme is the paradigm shift in perioperative fluid management. Recent large randomized trials suggest that fluids are drugs that require a precise prescription with respect to type, dose, and duration. The final theme is patient safety in the cardiac perioperative environment. A recent expert scientific statement has focused attention on this issue because most perioperative errors are preventable. It is likely that clinical research in this area will blossom because this is a major opportunity for improvement in our specialty. The patient care processes identified in these research highlights will further improve perioperative outcomes for our patients.


Hydrogeochemistry of groundwater in coastal wetlands: implications for coastal conservation in Scotland.
Groundwater in a shallow coastal aquifer in north east Scotland was monitored over the hydrological year October 1996-September 1997. Groundwater flow from inland areas sustained freshwater conditions in a dune-wetland complex of conservation importance. In particular, seasonal flooding of the coastal wetlands due to water table rise provided important roosting and breeding habitats for waterfowl. Hydrogeochemical analysis revealed that groundwater in the shallow sand aquifer was circum-neutral, and non-saline, despite being within 50 m of the sea and only 1 m above the mean high water mark. Calcium and HCO3 were the dominant cation and anion respectively, reflecting weathering processes in the aquifer. Use of the geochemical code NETPATH indicated that calcite weathering in shell fragments within the sand was the primary source of Ca and alkalinity generation. The concentrations of Na and Cl were also important, though these can be explained primarily by atmospheric inputs from precipitation. In detail, the spatial and temporal variation in groundwater chemistry was remarkably complex for what intuitively appeared a simple aquifer system. Temporal variations in groundwater chemistry mainly related to the seasonal event of groundwater recharge. Thus, the main period of rising groundwater levels resulted in a marked dilution of solutes in the aquifer, implying that water storage greatly increased in a relatively short period. A period of several weeks appeared to be required for dissolution processes to proceed to equilibrium. Spatial variation in groundwater chemistry appears to relate to the spatial distribution of geochemical processes in different hydrogeological units. Sulphate reduction, alkalinity generation and Fe precipitation appear to be locally important processes. The chemistry of groundwater maintains the wetland habitat by providing freshwater conditions that allow populations of various plant species to flourish. The potentially large recharge catchments of coastal wetlands, together with increasing pressures in the coastal zone, dictate that pollution can threaten the integrity of hydrochemical processes and requires careful monitoring if freshwater wetlands are to maintain their conservation importance.


Useful sample handlings for reversed phase high performance liquid chromatography in emergency toxicology.
Some physicochemical treatments of biological samples, before being injected into a liquid chromatograph, are discussed. The advantages of dilution, liquid and solid extraction are compared referring mainly to unpublished results. Assays of antiepileptic drugs, caffeine, theophylline, tricyclic antidepressants, valproic acid, and meprobamate are used to demonstrate the importance of sample handlings in toxicological analyses in which reversed phase high performance liquid chromatographies are applied.


The Influence of Supportive Oncodermatology Interventions on Patient Quality of Life: A Cross-Sectional Survey.
Dermatologic adverse events (dAEs) secondary to anticancer treatments reduce patients' quality of life (QOL) and result in interruptions in anticancer therapy. Determine if a comprehensive supportive oncodermatology program improves patients' QOL scoring. This was a cross-sectional survey of adult cancer patients enrolled in the George Washington University Supportive Oncodermatology Clinic. All patients were above age 18 years and received dermatologic care between May 1, 2017 and November 1, 2019. Fifty-five patents meeting inclusion criteria were invited to complete an online survey with questions adapted from the Dermatology Life Quality Index (DLQI) and Patient Satisfaction Questionnaire (PSQ-18). Survey initiation rate was 61.8% (34/55) and completion rate 88.2% (30/34). Average QOL score prior to treatment was 6.5 (moderate effect on QOL) and 3.8 (small effect) afterwards (P=0.0005; 95% CI -3.9 to -1.). Average satisfaction score was 4.15 ± 0.7 (satisfied). Impact on treatment adherence earned the lowest score (3.67, neutral to satisfied). Recall bias Conclusion: Enrollment was significantly associated with improved QOL. Dermatologic care also resulted in overall satisfied patient outcomes, although many patients were unsure if these dermatologic interventions aided in anticancer treatment adherence, highlighting the need for evidence-based management strategies for dAEs. J Drugs Dermatol. 2020;19(5):  doi:10.36849/JDD.2020.5040.


Management of postoperative junctional ectopic tachycardia in pediatric patients: a survey of 30 centers in Germany, Austria, and Switzerland.
Postoperative junctional ectopic tachycardia (JET) is a frequent complication after pediatric cardiac surgery. Current recommendations on how and when to treat JET are inconsistent. We evaluated the management strategies of postoperative JET in German-speaking countries. We sent an online survey to 30 centers of pediatric cardiology that perform surgery for congenital heart defects in Germany (24), Austria (4), and Switzerland (2). The survey asked 18 questions about how and in what treatment sequence postoperative JET was managed. All 30 centers completed the survey (100% return rate). There was general agreement that the management of JET is based on administration of antiarrhythmic drugs, body surface cooling, and temporary pacing. Many centers presented treatment algorithms based on published literature, all centers named amiodarone as the first drug of choice. Significant disagreement was found concerning the timing and sequential order of additional therapeutic measures and particularly about the dosing of amiodarone and the role of R-wave synchronized atrial pacing. This survey reveals that from center to center, the treatment of postoperative JET may vary substantially. Future work should focus on those treatment modalities where a high rate of variation is found. Such studies may be of value to achieve commonly adopted treatment recommendations. What is known: • Treatment of postoperative junctional ectopic tachycardia is predominantly based on administration of antiarrhythmic drugs, therapeutic cooling, and temporary pacing. • Amiodarone is the antiarrhythmic drug of choice in this context. What is new: • Dosing and duration of administration of amiodarone differ relevantly from center to center. • The sequential order of drug administration, therapeutic cooling, and pacing is not consistent.


Regulation of protein phosphorylation and motility of sperm by cyclic adenosine monophosphate and calcium.
Motility and protein phosphorylation have been measured under identical experimental conditions in ejaculated dog sperm lysed with low concentrations of Triton X-100 and reactivated with [gamma-32P]ATP. Cyclic AMP stimulates motility and protein phosphorylation while calcium inhibits motility and the overall incorporation of phosphate into endogenous proteins. Analysis of 32P-labeled sperm proteins on 1- and 2-dimensional polyacrylamide gels demonstrates that an enhanced phosphorylation of a defined number of specific proteins is associated with cAMP-stimulated motility. A major axonemal proteins, namely tubulin, has been tentatively identified as a phosphoprotein subject to regulation by cAMP. The phosphorylation of tubulin is almost completely dependent upon cAMP and is not affected by microM calcium. On the other hand, the cAMP-dependent stimulated phosphorylation of the other sperm proteins still occurs, but in most instances at a reduced rate in the presence of calcium. Two high molecular weight (Mr) phosphoproteins (350,000 and 260,000 daltons) whose phosphorylation states are modified by cAMP and calcium also were identified. It is suggested that 1 or both these proteins may be high Mr subunits of dynein. The phosphorylation of 1 of these proteins is stimulated by cAMP, but not affected by calcium; the other is stimulated by cAMP and inhibited by calcium. Three major cAMP-independent phosphoproteins of Mr 98,000, 43,000 and 26,000 have been identified. The phosphorylation of the 98,000 Mr protein is markedly reduced by micromolar calcium and not restored by cAMP. Using anticalmodulin drugs to inhibit motility, we suggest that the inhibitory effects of calcium on flagellar motility may be mediated in part by calmodulin. We conclude that the regulation of flagellar motility in cAMP and calcium includes mechanisms involving the control of the phosphorylation state of sperm proteins, some of which may be axonemal components.


[Hashimoto's disease with pregnancy].
That normal pregnancy, PIH and Hashimoto's were all closely related with human immunology has been reported by many authors. Six pregnant women with Hasimoto's were studied. Among them four were complicated with PIH, and one with postpartum transient hypothyroidism. MCHA and TGHA were slightly decreased in 2 cases during pregnancy and one congenital hypothyroidism happened among 6 neonates. Our data indicates that pregnancy and Hashimoto's can affect each other.


Effect of walking speed on lower extremity joint loading in graded ramp walking.
Lower extremity joint loading during walking is strongly affected by the steepness of the slope and might cause pain and injuries in lower extremity joint structures. One feasible measure to reduce joint loading is the reduction of walking speed. Positive effects have been shown for level walking, but not for graded walking or hiking conditions. The aim of the study was to quantify the effect of walking speed (separated into the two components, step length and cadence) on the joint power of the hip, knee and ankle and to determine the knee joint forces in uphill and downhill walking. Ten participants walked up and down a ramp with step lengths of 0.46, 0.575 and 0.69 m and cadences of 80, 100 and 120 steps per minute. The ramp was equipped with a force platform and the locomotion was filmed with a 60 Hz video camera. Loading of the lower extremity joints was determined using inverse dynamics. A two-dimensional knee model was used to calculate forces in the knee structures during the stance phase. Walking speed affected lower extremity joint loading substantially and significantly. Change of step length caused much greater loading changes for all joints compared with change of cadence; the effects were more distinct in downhill than in uphill walking. The results indicate that lower extremity joint loading can be effectively controlled by varying step length and cadence during graded uphill and downhill walking. Hikers can avoid or reduce pain and injuries by reducing walking speed, particularly in downhill walking.


Down-regulation of ET(B) receptor, but not ET(A) receptor, in congestive lung secondary to heart failure. Are marked increases in circulating endothelin-1 partly attributable to decreases in lung ET(B) receptor-mediated clearance of endothelin-1?
Receptors for endothelin (ET)-1, a potent vasoconstrictor peptide, have two isoforms, i.e. ET(A) receptors and ET(B) receptors. We previously reported that an ET(A) receptor antagonist greatly ameliorated pulmonary hypertension due to congestive heart failure (CHF) in rats. In the present study of rats with pulmonary congestion secondary to CHF, we determined not only ET(A) receptor mRNA expression but also ET(B) receptor mRNA expression in the congestive lung because lung ET(B) receptors are reported to be important for the clearance of circulating ET-1. We also measured lung ET-1 and circulating ET-1 levels. The expression of ET(B) receptor mRNA in the lung was significantly lower in rats with CHF than in age-matched control rats, while the expression of ET(A) receptor mRNA did not differ between the two groups. The protein level of ET(B) receptor, determined by Western blot, in the lung was lower in the rats with CHF than in the control rats, while the protein level of ET(A) receptor did not differ between the two groups. The lung ET-1 level and plasma ET-1 level were significantly higher in the rats with CHF than in the controls by 1.4-fold and 5.3-fold, respectively. Thus, in the rats with CHF, ET-1 was increased to a much greater extent in plasma than in the lung. The present findings suggest that selective down-regulation of ET(B) receptor, but not ET(A) receptor, occurs in the congestive lung. Since lung ET(B) receptors play a role in the clearance of circulating ET-1, we propose that down-regulation of lung ET(B) receptors partly contributes to marked increases in circulating ET-1 and that increased ET-1 in the circulating plasma as well as in the lung is involved in the progression of pulmonary hypertension in CHF.


Limitations of a contemporary prostate biopsy: the blind march forward.
In an attempt to reduce morbidity, focal targeted therapies and active surveillance have become increasingly popular treatment choices for localized prostate cancer. However, these modalities rely heavily on accurate and reliable tumor localization information provided by a prostate biopsy. Evidence that our contemporary biopsy techniques can do little more than detect some prostate cancers is notably lacking. What is meant by the accuracy and reliability of a prostate biopsy and why they are such important concepts to focal therapy and active surveillance are discussed.


Routine plasma anti-Xa monitoring is required for low-molecular-weight heparins.
Low-molecular-weight heparins are anticoagulants used in the treatment of thrombosis. They have effectiveness and safety profiles similar to those of unfractionated heparin but are considered an attractive alternative because of their predictable pharmacokinetic characteristics. In this article, we demonstrate the need for therapeutic monitoring of low-molecular-weight heparins by addressing evidence arising from the literature and from modelling and simulation. First, treatment targets for unfractionated heparin and enoxaparin sodium were identified. Then, 10 000 virtual patients were simulated and the rate of treatment success was calculated. Treatment success was found to be similar between the two drugs (48% with unfractionated heparin and 54% with enoxaparin sodium). These results are consistent with empirical evidence from the literature and reflect the inadequacy of current dosing strategies in achieving desired biomarker targets. These results, along with recent advances in Bayesian forecasting techniques, support the need for routine monitoring and dose individualization of enoxaparin sodium in order to improve treatment success.


HcpR of Porphyromonas gingivalis is required for growth under nitrosative stress and survival within host cells.
Although the Gram-negative, anaerobic periodontopathogen Porphyromonas gingivalis must withstand nitrosative stress, which is particularly high in the oral cavity, the mechanisms allowing for protection against such stress are not known in this organism. In this study, microarray analysis of P. gingivalis transcriptional response to nitrite and nitric oxide showed drastic upregulation of the PG0893 gene coding for hybrid cluster protein (Hcp), which is a putative hydroxylamine reductase. Although regulation of hcp has been shown to be OxyR dependent in Escherichia coli, here we show that in P. gingivalis its expression is dependent on the Fnr-like regulator designated HcpR. Growth of the isogenic mutant V2807, containing an ermF-ermAM insertion within the hcpR (PG1053) gene, was significantly reduced in the presence of nitrite (P < 0.002) and nitric oxide-generating nitrosoglutathione (GSNO) (P < 0.001), compared to that of the wild-type W83 strain. Furthermore, the upregulation of PG0893 (hcp) was abrogated in V2807 exposed to nitrosative stress. In addition, recombinant HcpR bound DNA containing the hcp promoter sequence, and the binding was hemin dependent. Finally, V2807 was not able to survive with host cells, demonstrating that HcpR plays an important role in P. gingivalis virulence. This work gives insight into the molecular mechanisms of protection against nitrosative stress in P. gingivalis and shows that the regulatory mechanisms differ from those in E. coli.


Navigated percutaneous lumbosacral interbody fusion: a feasibility study.
Advances in surgical navigation have opened new possibilities for lumbosacral interbody fusion procedures. We have designed a novel navigated surgical method, Navigated Percutaneous Lumbosacral Interbody Fusion (NPLSIF), that enables lumbosacral discectomy and bone grafting to be performed percutaneously and safely. To prove that NPLSIF is feasible from an anatomical perspective, it was simulated on 3D models of the lumbosacral spine created using CT data from 60 patients. Feasibility would be verified if both the working corridor and the S1 pedicle screw could be accommodated in the sacral ala without overlapping and without penetrating either the spinal canal or the anterior or upper sacral wall. In addition, the discectomy that could be achieved using NPLSIF was evaluated, and a surgical experiment was performed using a plastic torso model. The 3D modeling and surgical simulation were successfully completed in all cases. The feasibility of the NPLSIF approach was verified in every case, i.e., both the working corridor and the S1 pedicle screw were accommodated in the sacral ala without overlapping and without penetrating either the spinal canal or the anterior or upper sacral wall. The mean ratio of the area of discectomy that could be achieved by NPLSIF to the total area of the lumbosacral disc was 0.721 ± 0.065 (range: 0.57-0.894), 0.956 ± 0.045 (range: 0.8-1.0) and 0.945 ± 0.058 (range: 0.813-1.0) in the axial, coronal and sagittal planes, respectively. NPLSIF was also successfully executed on the plastic torso model. Preoperative planning on the navigation workstation took 5 minutes and each intraoperative CT scan took 30 seconds. Locating the entry point of the working corridor according to the preoperative plan took 3 minutes. Postoperative CT images and direct viewing of the plastic model revealed no penetration of the spinal canal or sacral wall. The feasibility of Navigated Percutaneous Lumbosacral Interbody Fusion (NPLSIF) was verified from an anatomical perspective. We also demonstrated that an adequate discectomy can be achieved using the procedure. Cadaveric experiments and clinical trials are needed to further evaluate the efficacy and efficiency of NPLSIF.


Photometry at Cerro Tololo, Chile: Effects of Mount Agung Eruption.
Extinction effects of the volcanic dust injected into the stratosphere by the violent eruption of Mount Agung, Bali, 17 March 1963, were studied. Visual extinction coefficients were measured photoelectrically for 153 nights during the period from March 1963 to September 1964. The data indicate that the dust is now widely dispersed and that its effects may persist for several more years. A study of the wavelength dependence of the extinction shows that the dust is a neutral scattering agent. The total global amount of airborne volcanic material is crudely estimated at 10(12) grams as of September 1964.


Simple calibration of a phase-based 3D imaging system based on uneven fringe projection.
Phase-based fringe projection metrology systems have been widely used to obtain the shape of 3D objects. One vital step is calibration, which defines the relationship between the phase and depth data. Existing calibration methods are complicated because of the dependence of the relationship on the pixel position. In this Letter, a simple calibration procedure is introduced based on an uneven fringe projection technique, in which the relationship between phase and depth becomes independent of the pixel position and can be represented by a single polynomial function for all pixels. Therefore, given a set of discrete points with a known phase and depth in the measuring volume, the coefficient set of the polynomial function can be determined. A white plate having discrete markers with known separation is used to calibrate the 3D imaging system. Experimental results demonstrate that the proposed calibration method is simple to apply and can build up an accurate relationship between phase and depth data.


[Protective effects of adenovirus-mediated hepatocyte growth factor on injury of rat cortex neurons].
To investigate the protective effects of adenovirus-mediated hepatocyte growth factor (Ad-HGF) on injury of rat cortex neurons induced by in vitro serum-free culture. Flow cytometry was used to assay the transfection rate of rat cortex neurons infected by adenovirus-mediated green fluorescent protein(Ad-GFP) at different multiplicity of infection (MOI) to find out the best MOI in experiment. ELISA was used to elucidate the expression patterns of cortex neuron. Neutral red stain and PI-Hoechst 33342 double stain were used to compare the viability of cortex neurons, which were cultured in serum-free medium for 6 h, 12 h, 24 h and 48 h respectively, among the Ad-HGF transfected group, the Ad-GFP transfected group and the control group. It was found that when MOI was 50 PFU per cell, a transfection rate as high as 99.3% was maintained and Ad-HGF was able to express in cortex neurons effectively and persistently. In addition, the death rate and apoptotic rate of cortex neurons (infected 2 hours after seeding) cultured in serum-free medium for 12 h in Ad-HGF transfected group was significantly lower than that in both the Ad-GFP group and the control group (P < 0.05). Ad-HGF plays a protective role against in vitro serum-free culture induced injury on rat cortex neurons infected 2 hours after seeding. Though its effects on rat cortex neurons infected 5 days after seeding are not so remarkable, Ad-HGF also has the potential to protect cortex neurons from serum-free culture induced injury.


Investigating the Influence of Glycerol on the Utilization of Glucose in Yarrowia lipolytica Using RNA-Seq-Based Transcriptomics.
Glycerol is considered as a promising substrate for biotechnological applications and the non-conventional yeast Yarrowia lipolytica has been used extensively for the valorization of this compound. Contrary to S. cerevisiae, Y. lipolytica seems to prefer glycerol over glucose and it has been reported previously that the presence of glycerol can suppress the consumption of glucose in co-substrate fermentations. Based on these observations, we hypothesized glycerol repression-like effects in Y. lipolytica, which are converse to well described carbon repression mechanisms ensuring the prioritized use of glucose (e.g., in S. cerevisiae). We therefore aimed to investigate this effect on the level of transcription. Strains varying in the degree of glucose suppression were chosen and characterized in high-resolution growth screenings, resulting in the detection of different growth phenotypes under glycerol-glucose mixed conditions. Two strains, IBT and W29, were selected and cultivated in chemostats using glucose, glycerol and glucose/glycerol as carbon sources, followed by an RNA-Seq-based transcriptome analysis. We could show that several transporters were significantly higher expressed in W29, which is potentially related to the observed physiological differences. However, most of the expression variation between the strains were regardless of the carbon source applied, and cross-comparisons revealed that the strain-specific carbon source responses underwent in the opposite direction. A deeper analysis of the substrate specific carbon source response led to the identification of several differentially expressed genes with orthologous functions related to signal transduction and transcriptional regulation. This study provides an initial investigation on potentially novel carbon source regulation mechanisms in yeasts.


Genome-based reclassification of Weissella jogaejeotgali as a later heterotypic synonym of Weissella thailandensis.
Members of the genus Weissella are mostly found in fermented plant material. Among the Weissella species, two species, Weissella thailandensis and Weissella jogaejeotgali, were isolated from foods fermented from marine animals. The two species showed a high level of 16S rRNA gene similarity (99.39 %), whereas they exhibited a moderate level of DNA-DNA hybridization relatedness (63.9 %) in an earlier study. In this study, we determined the whole genome sequence of W. thailandensis KCTC 3751T and compared it to those of W. jogaejeotgali FOL01T and other related species. The average nucleotide identity value between the type strains of W. thailandensis and W. jogaejeotgali was 96.4 %, which is clearly higher than the cut-off proposed for bacterial species. We, therefore, propose to reclassify W. jogaejeotgali as a later heterotypic synonym of W. thailandensis.


Explaining how the mind works: on the relation between cognitive science and philosophy.
In this paper, we argue that under certain prevalent interpretations of the nature and aims of cognitive science, theories of cognition generate a forced choice between a conception of cognition which depends on the possibility of a private language, and a conception of cognition which depends on mereological confusions. We argue, further, that this should not pose a fundamental problem for cognitive scientists since a plausible interpretation of the nature and aims of cognitive science is available that does not generate this forced choice. The crucial difference between these interpretations is that on the one hand the aim of theories of cognition is to tell us what thinking (etc.) is, and on the other it is to tell us what is causally necessary if an intelligent creature is to be able to think. Our argument draws heavily on a Wittgensteinian conception of philosophy in which no philosophical theory can explain what thinking, perceiving, remembering, etc. are, either. The positive, strictly therapeutic, purpose of a philosophy of cognitive science should be to show that, since the traditional problems which constitute the philosophy of mind are chimerical, there is nothing for philosophical theorizing in cognitive science to achieve.


[Antibodies interacting with the proteins of the mammary cancer virus (MMTV) in the sera of healthy women].
Using enzyme-linked immunoassay (ELISA), sera of 405 women without breast cancer were screened for the presence of antibodies to mouse mammary tumour virus proteins. 16 donors with positive sera were identified (3.96 +/- 0.97%). An attempt was made to establish the correlation between the age, ovarian Activity, benign breast disease and other factors and the appearance of antibodies to mouse mammary tumour virus. No statistically significant differences have been revealed among women aged 20-29 (3.92%), 30-39 (4.69%), 40-49 (4.08%) and 50-59 (2.38%), as well as in premenopausal (4.31%) and postmenopausal (4.5%) women and women with simple fibromatous disease (4.76%) and without any mammary gland pathology.


The tools of the trade: a state of the art "How to Assess Cognition" in the patient with Parkinson's disease.
Cognitive impairment in Parkinson's disease is heterogeneous both in severity and pattern and subject to influences both integral to and external to the disease. Diagnostic Criteria have been developed by the Movement Disorders Society that help to guide clinicians and researchers to an accurate diagnosis of Parkinson's disease - mild cognitive impairment or Parkinson's disease dementia. To operationalize these criteria, and to assess the pattern and severity of cognitive dysfunction we need: (1) Valid measures of cognitive abilities covering the major domains of cognition, (2) amethod to determine whether or not the performance represents a decline from a person's previous level of functioning, and (3) an assessment of how the individual's cognitive abilities enable (or disable) function in day to day activities. This paper will discuss the methods of assessment and the measures that can be used to make a comprehensive assessment of cognition in Parkinson's disease.


Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children.
Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.


Natural populations of lactic acid bacteria isolated from vegetable residues and silage fermentation.
Natural populations of lactic acid bacteria (LAB) and silage fermentation of vegetable residues were studied. Fifty-two strains of LAB isolated from cabbage, Chinese cabbage, and lettuce residues were identified and characterized. The LAB strains were gram-positive and catalase-negative bacteria, which were divided into 6 groups (A to F) according to morphological and biochemical characteristics. The strains in group A were rods that did not produce gas from glucose and formed the d and l isomers of lactate. Groups B and C were homofermentative cocci that formed l-lactic acid. Groups D, E, and F were heterofermentative cocci that formed d-lactic acid. Based on 16S rDNA gene sequence analysis, group A to F strains were identified as Lactobacillus plantarum, Lactococcus piscium, Lactococcus lactis, Leuconostoc citreum, Weissella soli and Leuconostoc gelidum, respectively. The prevalent LAB, predominantly homofermentative lactobacilli, consisted of Lactobacillus plantarum (34.6%), Weissella soli (19.2%), Leuconostoc gelidum (15.4%), Leuconostoc citreum (13.5%), Lactococcus lactis (9.6%), and Lactococcus piscium (7.7%). Lactobacillus plantarum was the dominant member of the LAB population in 3 types of vegetable residues. These vegetable residues contained a high level of crude protein (20.2 to 28.4% of dry matter). These silages prepared by using a small-scale fermentation system were well preserved, with low pH and a relatively high content of lactate. This study suggests that the vegetable residues contain abundant LAB species and nutrients, and that they could be well preserved by making silage, which is a potentially good vegetable protein source for livestock diets.


A multicriteria decision analysis model and risk assessment framework for carbon capture and storage.
Multicriteria decision analysis (MCDA) has been applied to various energy problems to incorporate a variety of qualitative and quantitative criteria, usually spanning environmental, social, engineering, and economic fields. MCDA and associated methods such as life-cycle assessments and cost-benefit analysis can also include risk analysis to address uncertainties in criteria estimates. One technology now being assessed to help mitigate climate change is carbon capture and storage (CCS). CCS is a new process that captures CO2 emissions from fossil-fueled power plants and injects them into geological reservoirs for storage. It presents a unique challenge to decisionmakers (DMs) due to its technical complexity, range of environmental, social, and economic impacts, variety of stakeholders, and long time spans. The authors have developed a risk assessment model using a MCDA approach for CCS decisions such as selecting between CO2 storage locations and choosing among different mitigation actions for reducing risks. The model includes uncertainty measures for several factors, utility curve representations of all variables, Monte Carlo simulation, and sensitivity analysis. This article uses a CCS scenario example to demonstrate the development and application of the model based on data derived from published articles and publicly available sources. The model allows high-level DMs to better understand project risks and the tradeoffs inherent in modern, complex energy decisions.


Symbiotic and Nonsymbiotic Members of the Genus Ensifer (syn. Sinorhizobium) Are Separated into Two Clades Based on Comparative Genomics and High-Throughput Phenotyping.
Rhizobium-legume symbioses serve as paradigmatic examples for the study of mutualism evolution. The genus Ensifer (syn. Sinorhizobium) contains diverse plant-associated bacteria, a subset of which can fix nitrogen in symbiosis with legumes. To gain insights into the evolution of symbiotic nitrogen fixation (SNF), and interkingdom mutualisms more generally, we performed extensive phenotypic, genomic, and phylogenetic analyses of the genus Ensifer. The data suggest that SNF likely emerged several times within the genus Ensifer through independent horizontal gene transfer events. Yet, the majority (105 of 106) of the Ensifer strains with the nodABC and nifHDK nodulation and nitrogen fixation genes were found within a single, monophyletic clade. Comparative genomics highlighted several differences between the "symbiotic" and "nonsymbiotic" clades, including divergences in their pangenome content. Additionally, strains of the symbiotic clade carried 325 fewer genes, on average, and appeared to have fewer rRNA operons than strains of the nonsymbiotic clade. Initial characterization of a subset of ten Ensifer strains identified several putative phenotypic differences between the clades. Tested strains of the nonsymbiotic clade could catabolize 25% more carbon sources, on average, than strains of the symbiotic clade, and they were better able to grow in LB medium and tolerate alkaline conditions. On the other hand, the tested strains of the symbiotic clade were better able to tolerate heat stress and acidic conditions. We suggest that these data support the division of the genus Ensifer into two main subgroups, as well as the hypothesis that pre-existing genetic features are required to facilitate the evolution of SNF in bacteria.


Atonia-related regions in the rodent pons and medulla.
Electrical stimulation of circumscribed areas of the pontine and medullary reticular formation inhibits muscle tone in cats. In this report, we present an analysis of the anatomical distribution of atonia-inducing stimulation sites in the brain stem of the rat. Muscle atonia could be elicited by electrical stimulation of the nuclei reticularis pontis oralis and caudalis in the pons as well as the nuclei gigantocellularis, gigantocellularis alpha, gigantocellularis ventralis, and paragigantocellularis dorsalis in the medulla of decerebrate rats. This inhibitory effect on muscle tone was a function of the intensity and frequency of the electrical stimulation. Average latencies of muscle-tone suppressions elicited by electrical stimulation of the pontine reticular formation were 11.02 +/- 2.54 and 20.49 +/- 3.39 (SD) ms in the neck and in the hindlimb muscles, respectively. Following medullary stimulation, these latencies were 11.29 +/- 2.44 ms in the neck and 18.87 +/- 2. 64 ms in the hindlimb muscles. Microinjection of N-methyl-D-aspartate (NMDA, 7 mM/0.1 microliter) agonists into the pontine and medullary inhibitory sites produced muscle-tone facilitation, whereas quisqualate (10 mM/0.1 microliter) injection induced an inhibition of muscle tone. NMDA-induced muscle tone change had a latency of 31.8 +/- 35.3 s from the pons and 10.5 +/- 0. 7 s from the medulla and a duration of 146.7 +/- 95.2 s from the pons and 55.5 +/- 40.4 s from the medulla. The latency of quisqualate (QU)-induced reduction of neck muscle tone was 30.1 +/- 37.9 s after pontine and 39.5 +/- 21.8 s after medullary injection. The duration of muscle-tone suppression induced by QU injection into the pons and medulla was 111.5 +/- 119.2 and 169.2 +/- 145.3 s. Smaller rats (8 wk old) had a higher percentage of sites producing muscle-tone inhibition than larger rats (16 wk old), indicating an age-related change in the function of brain stem inhibitory systems. The anatomical distribution of atonia-related sites in the rat has both similarities and differences with the distribution found in the cat, which can be explained by the distinct anatomical organization of the brain stem in these two species.


H2 storage materials (22 KJ/mol) using organometallic Ti fragments as sigma-H2 binding sites.
Low-coordinate Ti (III) fragments with controlled geometries designed specifically for sigma-H2 binding were grafted onto mesoporous silica using tri- and tetrabenzyl Ti precursors. The hydrogen storage capacity was tested as a function of precursor and precursor loading level. At an optimal loading level of 0.2 mol equiv tetrabenzyl Ti the total storage capacity at -196 degrees C was 21.45 wt % and 34.10 kg/m(3) at 100 atm, and 3.15 wt % and 54.49 kg/m(3) for a compressed pellet under the same conditions. The adsorption value of this material was 1.66 wt %, which equates to an average of 2.7 H2 per Ti center. The adsorption isotherms did not reach saturation at 60 atm, suggesting that the theoretical maximum of 5 H2 per Ti in this system may be reached at higher pressures. The binding enthalpies rose with surface coverage to a maximum of 22.15 kJ/mol, which is more than double that of the highest recorded previously and within the range predicted for room temperature performance. The adsorption values of 0.99 at -78 degrees C and 0.69 at 25 degrees C demonstrate retention of 2.4 H2 and 1.1 H2 per Ti at these temperatures, respectively. These findings suggest that Kubas binding of H2 may be exploited at ambient temperature to enhance the storage capacities of high-pressure cylinders currently used in hydrogen test vehicles.


Mechanism of constitutive export from the golgi: bulk flow via the formation, protrusion, and en bloc cleavage of large trans-golgi network tubular domains.
Transport of constitutive cargo proteins from the Golgi complex to the plasma membrane (PM) is known to be mediated by large tubular-saccular carriers moving along microtubules. However, the process by which these large structures emerge from the trans-Golgi network (TGN) remains unclear. Here, we address the question of the formation of Golgi-to-PM carriers (GPCs) by using a suitable cluster of morphological techniques, providing an integrated view of their dynamics and three-dimensional structure. Our results indicate that exit from the TGN of a constitutive traffic marker, the VSVG protein, occurs by bulk flow and is a three-step process. First, the formation of a tubular-reticular TGN domain (GPC precursor) that includes PM-directed proteins and excludes other cargo and Golgi-resident proteins. Notably, this step does not require membrane fusion. Second, the docking of this preformed domain on microtubules and its kinesin-mediated extrusion. Finally, the detachment of the extruded domain by membrane fission. The formation of GPCs does not involve cargo concentration and is not associated with the presence of known coat proteins on GPC precursors. In summary, export from the Golgi occurs via the formation, protrusion and en bloc cleavage of specialized TGN tubular-saccular domains.


Meniscus suture repair: minimum 10-year outcomes in patients younger than 40 years compared with patients 40 and older.
Few studies have compared outcomes after meniscus suture repair in patients younger than 40 years versus patients 40 years and older. To document failure rates and long-term outcomes after meniscus suture repair by a single surgeon, using the inside-out technique, at a minimum 10-year follow-up in patients younger than 40 years versus those 40 years and older. Cohort study; Level of evidence, 3. This study included all patients 18 years or older who underwent meniscus suture repair with the inside-out technique by a single surgeon between January 1992 and December 2003. Patients were divided into 2 cohorts according to age: <40 years (cohort 1) and ≥40 years (cohort 2). If patients underwent subsequent knee surgery, all subsequent reports, whether performed by the original treating surgeon or by a different surgeon elsewhere, were reviewed by 2 independent reviewers not involved in the primary care of the patients. Reviewers classified surgeries as failures if the subsequent surgery treated the same area of the meniscus as repaired in the index surgery. Patients completed a subjective questionnaire at minimum of 10 years after arthroscopy. Outcomes measures included Lysholm, Tegner, and patient satisfaction with outcome. All data were collected prospectively. The surgeon performed 339 meniscus repairs between 1992 and 2003. The study included 181 knees in 178 patients, who had a mean age of 33 years (range, 18-70 years). Cohort 1 contained 136 knees; 16 patients (12%) were lost to follow-up and 47 (35%) underwent a subsequent knee arthroscopy. Cohort 2 contained 45 knees; 2 patients (4.4%) were lost to follow-up, 3 patients had a total knee arthroplasty, and 12 patients (28%) underwent a subsequent knee arthroscopy. In cohort 1, the meniscus repair failure rate was 5.5% (6/110), and in cohort 2 it was 5.3% (2/38) (P = .927). There was no significant difference in failure rate based on which meniscus was repaired (P = .257), concomitant anterior cruciate ligament (ACL) reconstruction (P = .092), or microfracture (P = .674). Average follow-up time for cohort 1 was 16.1 years (range, 10.0-21.9 years), with 82% follow-up (n = 73/89); average follow-up time for cohort 2 was 16.2 years (range, 10.1-21.0 years), with 93% follow-up (n = 28/30). There were no significant differences in outcomes scores after meniscus suture repair based on age cohort or meniscus side, presence of an ACL tear, or concomitant microfracture procedure. Meniscus repair failure rate was not different in patients who were younger than 40 years versus those who were 40 years or older at time of meniscus index surgery. Patients who underwent meniscus suture repair had high function and high patient satisfaction at an average of 16 years after meniscus suture repair, and no differences were seen based on age.


Differences in muscle cellularity and flesh quality between wild and farmed Coilia nasus (Engraulidae).
Populations of Coilia nasus, an anadromous fish, have declined dramatically in the Yangtze River estuary and its associated lakes owing to excessive fishing and changes in aquatic ecology. Recently, the success of artificial breeding programmes and advanced methods of propagation have allowed great increases in production of this species. Thus, to gain a better understanding of the flesh quality of C. nasus, muscle cellularity and quality parameters of the flesh were studied in wild and farmed specimens. Muscle cellularity was different between wild and farmed fish. Muscle fibre density was significantly higher in farmed specimens, while muscle fibre diameter was higher in wild specimens. Farmed fish had higher moisture, hydroxyproline and collagen contents and a lower fat content compared with wild fish. No significant differences in textural parameters were found between the two groups. Saturated (SFA), polyunsaturated (PUFA) and total n-6 fatty acid contents were significantly higher in farmed fish, but monounsaturated fatty acid (MUPA) content was higher in wild fish. The variation in the studied parameters determined significant differences in the flesh quality of wild and farmed C. nasus. Depending on muscle cellularity and fatty acid composition, farmed fish could be more suitable for human consumption than wild fish.


Lip projection analysis in brachycephalic, dolichocephalic and mesocephalic individuals of a Mexican population.
The aim of this study was to examine the lip projection of brachycephalic, dolichocephalic and mesocephalic Mexican patients and to analyze the relationship between dental protrusion and the lip position, to identify if a labial soft tissue projection exists and to determine what features predominated in this study. A total of 120 lateral radiographs of the skull were randomly selected from patients aged 16-25 years. The linear and angular data were measured, the values of the upper and lower lip projection relative to Ricketts E-line, Steiner S-line and Arnett TV-line were collected. The angles to be analyzed were the nasolabial, mandibular plane and interincisal, and the mentolabial groove depth. The statistical significance was determined by the Student t-test. A significant difference between mesocephalic and brachycephalic patients was observed measuring the angle between the Frankfurt plane and the mandibular plane (P<0.001). Between dolichocephalic and mesocephalic individuals significant differences were observed in the lower lip to E-line (P<0.031), lower lip to S-line (P<0.010), the interincisal angle (P<0.032) and the mandibular´s plane (P<0.001). A statistical significant difference was shown between brachycephalic and dolichocephalic individuals: lower lip to E-line (P<0.001), upper lip to S-line (P<0.037), lower lip to S-line (P<0.001), interincisal angle (P<0.034) and the angle between the mandibular´s plane (P<0.001). Lip soft tissue projection will depend on the population studied; we found some significant differences when compared with the cephalometric norms.


Examination of disruptive behavior outcomes and moderation in a randomized psychotherapy trial for mood disorders.
Multifamily psychoeducational psychotherapy (MF-PEP) is an efficacious treatment for children with mood disorders. Given the comorbidity between disruptive behaviors and mood disorders, this study examined associations between disruptive behaviors and impairment, impact of MF-PEP on disruptive behaviors, and whether disruptive behaviors affected treatment response of mood symptoms. Secondary analyses examined a randomized controlled trial of MF-PEP versus waitlist control (N = 165 children 8-11 years old with mood disorders and their parents). Comorbid behavioral diagnoses occurred in 97% of children. All participants continued treatment as usual. Greater degree of disruptive behaviors was associated with worse mood symptoms and impairment. Between-group analyses examining outcome of disruptive behaviors were nonsignificant. Within-group analyses and between-group effect sizes suggested that MF-PEP was associated with decreases in attention-deficit/hyperactivity disorder (d = 0.39), oppositional defiant disorder (d = 0.30), and overall disruptive behavior symptoms (d = 0.30), but not conduct disorder symptoms. Baseline severity of disruptive behaviors did not affect treatment response of mood symptoms to MF-PEP. MF-PEP is an effective intervention for children with mood disorders and provides some benefit for disruptive behaviors. Given that disruptive behavior severity does not affect children's ability to experience improved mood symptoms, MF-PEP may be an important early intervention for children with comorbid mood and disruptive behavior disorders. Subsequent intervention targeting behavioral symptoms after improvement in mood may be beneficial. Studies examining treatment sequencing for children with comorbid mood and disruptive behavior disorders are needed. Clinical trial registration information-Family psychoeducation for children with mood disorders; http://clinicaltrials.gov; NCT00050557.


Toward prediction of alkane/water partition coefficients.
Partition coefficients were measured for 47 compounds in the hexadecane/water ( P hxd) and 1-octanol/water ( P oct) systems. Some types of hydrogen bond acceptor presented by these compounds to the partitioning systems are not well represented in the literature of alkane/water partitioning. The difference, DeltalogP, between logP oct and logP hxd is a measure of the hydrogen bonding potential of a molecule and is identified as a target for predictive modeling. Minimized molecular electrostatic potential ( V min) was shown to be an effective predictor of the contribution of hydrogen bond acceptors to DeltalogP. Carbonyl oxygen atoms were found to be stronger hydrogen bond acceptors for their electrostatic potential than heteroaromatic nitrogen or oxygen bound to hypervalent sulfur or nitrogen. Values of V min calculated for hydrogen-bonded complexes were used to explore polarization effects. Predicted logP hxd and DeltalogP were shown to be more effective than logP oct for modeling brain penetration for a data set of 18 compounds.


The TCF4/β-catenin pathway and chromatin structure cooperate to regulate D-glucuronyl C5-epimerase expression in breast cancer.
D-glucuronyl C5-epimerase (GLCE) is a potential tumor-suppressor gene involved in heparan sulfate biosynthesis. GLCE expression is significantly decreased in breast tumors; however, the underlying molecular mechanisms remain unclear. This study examined the possible epigenetic mechanisms for GLCE inactivation in breast cancer. Very little methylation of the GLCE promoter region was detected in breast tumors in vivo and in breast cancer cells (MCF7 and T47D) in vitro and GLCE expression in breast cancer cells was not altered by 5-deoxyazacytidine (5-aza-dC) treatment, suggesting that promoter methylation is not involved in regulating GLCE expression. Chromatin activation by Trichostatin A (TSA) or 5-aza-dC/TSA treatment increased GLCE expression by two to 3-fold due to an increased interaction between the GLCE promoter and the TCF4/β-catenin transactivation complex, or H3K9ac and H3K4Me3 histone modifications. However, ectopic expression of TCF4/β-catenin was not sufficient to activate GLCE expression in MCF7 cells, suggesting that chromatin structure plays a key role in GLCE regulation. Although TSA treatment significantly repressed canonical WNT signaling in MCF7 cells, it did not influence endogenous TCF4/β-catenin mRNA levels and activated TCF4/β-catenin-driven transcription from the GLCE promoter, indicating GLCE as a novel target for TCF4/β-catenin complex in breast cancer cells. A correlation was observed between GLCE, TCF4 and β-catenin expression in breast cancer cells and primary tumors, suggesting an important role for TCF4/β-catenin in regulating GLCE expression both in vitro and in vivo. Taken together, the results indicate that GLCE expression in breast cancer is regulated by a combination of chromatin structure and TCF4/β-catenin complex activity.


Assessing discomfort after anaesthesia: should you ask the patient or read the record?
To assess the quality of anaesthesia care from the patients' viewpoint compared with the hospital record. Prospective study during 1988-9. Four teaching hospitals (A-D) in Canada. 15,960 inpatients receiving anaesthetic requiring at least an overnight stay, for whom an interview and review of hospital records within 72 hours of surgery were complete. Rates of postoperative symptoms of discomfort (nausea or vomiting, headache, back pain, sore throat, eye symptoms, and tingling) according to the hospital record versus interview and the relation between symptoms and patients' satisfaction with the anaesthetic experience. The preparation of completed interviews ranged from 31.0% to 72.7%, owing mainly to patients discharge (hospitals A and B) and severity of illness (C and D). Interviewed patients were similar to all inpatients in the hospitals but were younger and healthier and more had had effective operations and were general surgical than cardiovascular or neurosurgical patients. In all, 26% to 46% of patients at the four hospitals reported at least one symptom of discomfort. Agreement between interviews and hospital records was low, symptoms being more commonly reported by interview than in the record (for example, headache was reported for 5.8%-17% of patients compared with 0.3%-3.0% in hospital records). After controlling for case mix patients who reported at least one symptom were 2.91 times (95% confidence interval 1.89 to 4.50) more likely to be dissatisfied with their anaesthetic care than patients who did not. Anaesthesia services are typically neglected in studies of hospital quality, yet patients express considerable anxiety about anaesthetic care. Monitoring and recording patients' discomfort clearly need to be improved if the quality of anaesthesia is to be properly evaluated.


Patient & staff satisfaction with integrated services at Old Town Clinic: a descriptive analysis.
This quality improvement project provided a descriptive analysis of the patient population that received integrated mental and physical health care at Old Town Clinic, and evaluated patient and staff satisfaction with this model of care. Seventy-three patients and seven staff members were surveyed, using two satisfaction surveys distributed in January 2003. Survey data revealed that the majority of Old Town Clinic patients were homeless. Patients indicated high levels of satisfaction with the clinic's location, ease of accessing care, and health promotion and illness prevention education. Staff satisfaction with this model of care was reported to be moderate regarding accessibility, response time, communication, support, treatment, completeness of care, and education. Recommendations for further research and implications for practice are offered.


Chemosensitization of solid tumors by modulation of resistance mechanisms.
The number of drugs available for chemotherapy is growing exponentially, and this trend looks set to continue. Chemosensitization strategies use the administration of one drug or agent to render cancer cells more susceptible to a second agent. Modulation of resistance mechanisms due to xenobiotic membrane pumps such as the multidrug resistant proteins, MDR1/P-glycoprotein or MRP is feasible and a number of new agents have been produced to inhibit drug efflux resulting from expression of these molecules. However, tumor cells may express or upregulate more than one such molecule at one time, and this approach is unlikely to benefit every patient. Detoxification mechanisms mediated by glutathione conjugation or metallothionein are also responsible for resistance--the former has been linked to MRP-mediated resistance. Again, modulation is possible but may increase the toxicity of drugs to normal tissues and an increased therapeutic index is not guaranteed. Tumors exposed to DNA damaging agents often upregulate DNA repair mechanisms and this contributes to resistance. Different pathways perform the repair of different forms of DNA damage, and it is difficult to inhibit all of these. Nevertheless, inhibition of DNA repair can re-sensitize tumors to chemotherapy and is increasingly exploited. One of the most successful and widely used approaches is to combine gemcitabine with an alkylating or platinating agent. While gemcitabine may inhibit DNA polymerases directly, this cytidine analog is also likely to be incorporated by DNA repair leading to activity against non-cycling cells, which form the majority of the neoplastic cell population in most solid tumors. Oncologists should take account of potential resistance mechanisms when treating patients: it is often feasible to design combinations with old or new drugs which exploit these apparent weaknesses to the patient's advantage.


Rural people utilising city hospitals: issues for service provision.
The geographic distribution of health services in Australia means that rural people may need to travel long distances from their homes to obtain specialist services. Because sophisticated and expensive medical technologies are centralised, it is not uncommon for rural people to need to access metropolitan health services for many forms of treatment. This study sought to investigate the experiences of central Victorian people for whom illness or injury necessitated their admission to metropolitan hospitals. Because of distance from both metropolitan hospitals and social support structures, these people were likely to have differing experiences from city people admitted to hospital. However, it was found that not only were variables of rurality and social support significant, but socio-economic status and family structure were also found to be important. Even though respondents identified distress and other problems associated with the metropolitan admission, they rationalised the whole experience in terms of the specialised treatment they received; treatment that was not available in country hospitals.


Dynamic visualization of coexpression in systems genetics data.
Biologists hope to address grand scientific challenges by exploring the abundance of data made available through modern microarray technology and other high-throughput techniques. The impact of this data, however, is limited unless researchers can effectively assimilate such complex information and integrate it into their daily research; interactive visualization tools are called for to support the effort. Specifically, typical studies of gene co-expression require novel visualization tools that enable the dynamic formulation and fine-tuning of hypotheses to aid the process of evaluating sensitivity of key parameters. These tools should allow biologists to develop an intuitive understanding of the structure of biological networks and discover genes residing in critical positions in networks and pathways. By using a graph as a universal representation of correlation in gene expression, our system employs several techniques that when used in an integrated manner provide innovative analytical capabilities. Our tool for interacting with gene co-expression data integrates techniques such as: graph layout, qualitative subgraph extraction through a novel 2D user interface, quantitative subgraph extraction using graph-theoretic algorithms or by compound queries, dynamic level-of-detail abstraction, and template-based fuzzy classification. We demonstrate our system using a real-world workflow from a large-scale, systems genetics study of mammalian gene co-expression.


Thrombolytic treatment for myocardial infarction: an examination of practice in 39 United Kingdom hospitals. Myocardial Infarction Audit Group.
To examine use of thrombolytic drugs for myocardial infarction and use of contraindications to treatment in the United Kingdom. Observational study, based on a continuing audit. 39 hospitals in the United Kingdom. 30,029 patients admitted between November 1992 and June 1995 with suspected myocardial infarction. Of 13,628 patients with a final diagnosis of definite myocardial infarction 10,316 (75.7%) were considered eligible for thrombolytic treatment on the basis of typical cardiographic changes or new left bundle branch block. Of these, 8139 (59.7%) were diagnosed at admission to hospital and 6991 (85.9%) were administered thrombolytic drugs; 14.1% were considered too late for treatment or had a clinical contraindication. In 2177 patients (16% of 13,628)-thrombolytic treatment was given in the absence of contraindications and after the diagnosis of infarction had been confirmed by further electrocardiographic evidence. A further 591 (4.3%) with a final diagnosis of definite infarction without typical cardiographic changes also received thrombolytic treatment as did 1018 patients without a final diagnosis of definite infarction. In total, 9459 of 13,628 patients (71.6%) received thrombolytic treatment. The range of use of treatment between hospitals for a final diagnosis of infarction was 49.1-85.4%. This variation reflected differences in the frequency with which a diagnosis of definite myocardial infarction was made at admission, and the subsequent use of clinical contraindications to thrombolytic treatment. 75.7% of patients with a final diagnosis of definite myocardial infarction were eligible for thrombolytic treatment on the basis of cardiographic changes. Differences between hospitals in the frequency with which a diagnosis of infarction was made on admission, and differences in subsequent use of thrombolytic drugs, results in wide variation in treatment rates. Differences in use of thrombolytic treatment mainly reflect different thresholds for the use of clinical contraindications relating to haemorrhagic risk.


Effectiveness of guideline dissemination and implementation strategies on health care professionals' behaviour and patient outcomes in the cancer care context: a systematic review.
Health care professionals (HCPs) use clinical practice guidelines (CPGs) to make evidence-informed decisions regarding patient care. Although a large number of cancer-related CPGs exist, it is unknown which CPG dissemination and implementation strategies are effective for improving HCP behaviour and patient outcomes in a cancer care context. This review aimed to determine the effectiveness of CPG dissemination and/or implementation strategies among HCPs in a cancer care context. A comprehensive search of five electronic databases was conducted. Studies were limited to the dissemination and/or implementation of a CPG targeting both medical and/or allied HCPs in cancer care. Two reviewers independently coded strategies using the Mazza taxonomy, extracted study findings, and assessed study quality. The search strategy identified 33 studies targeting medical and/or allied HCPs. Across the 33 studies, 23 of a possible 49 strategies in the Mazza taxonomy were used, with a mean number of 3.25 (SD = 1.45) strategies per intervention. The number of strategies used per intervention was not associated with positive outcomes. Educational strategies (n = 24), feedback on guideline compliance (n = 11), and providing reminders (n = 10) were the most utilized strategies. When used independently, providing reminders and feedback on CPG compliance corresponded with positive significant changes in outcomes. Further, when used as part of multi-strategy interventions, group education and organizational strategies (e.g. creation of an implementation team) corresponded with positive significant changes in outcomes. Future CPG dissemination and implementation interventions for cancer care HCPs may benefit from utilizing the identified strategies. Research in this area should aim for better alignment between study objectives, intervention design, and evaluation measures, and should seek to incorporate theory in intervention design, so that behavioural antecedents are considered and measured; doing so would enhance the field's understanding of the causal mechanisms by which interventions lead, or do not lead, to changes in outcomes at all levels.


The development and implementation of the national evaluation strategy of Access to Care, a multi-site linkage to care initiative in the United States.
The Access to Care (A2C) is a multi-site initiative that seeks to increase the access to and retention in effective HIV healthcare and support services by people living with HIV across the United States. As the initiative implemented evidence-based programs in new settings with diverse populations, it was important to document these innovative efforts to contribute to the evidence base for best practices. In a partnership between Johns Hopkins University, AIDS United, and the A2C sites, a national evaluation strategy was developed and implemented to build knowledge about how linkage to care interventions could be most effectively implemented within the context of local, real-world settings. This article provides an overview of the efforts to develop and implement a national monitoring and evaluation strategy for a multi-site initiative. The findings may be of utility for other HIV interventions that are seeking to incorporate a monitoring and evaluation component into their efforts.


PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity.
Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single-nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy.


Dual inhibition of wound healing and oxidative process by montelukast in experimental colon anastomoses.
The authors aimed to investigate the effects of montelukast (ML) on the experimental rat colon anastomosis. A total of 80 Wistar albino rats were divided into 4 groups: sham-operated, colon anastomosis, and colon anastomosis with oral administration (OAML) and rectal administration of 10 mg/kg/d ML (RAML). Anastomotic bursting pressure, anastomotic hydroxyproline contents, malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPX), and superoxide dismutase (SOD) levels, and the expressions of Ki-67, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) with immunohistochemistry were assessed on postoperative day 5. Anastomotic bursting pressures and bFGF expressions were not changed, whereas tissue hydroxyproline concentrations and MDA levels and the expressions of Ki-67 and VEGF were significantly decreased, and GSH, GPX, and SOD levels were significantly increased in the OAML and RAML groups. ML causes impairment of wound healing without altering the anastomosis bursting pressure and reverses the oxidative damage of the colon anastomoses in rats.


Nonlinear pharmacokinetics of 5-methoxy-N,N-dimethyltryptamine in mice.
5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose-normalized AUC values, which were approximately 1.5- to 2.0-fold (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses.


Lasiodiplodia theobromae as a cause of keratomycoses.
Four cases of human keratitis caused by the tropical fungus Lasiodiplodia theobromae have been encountered in Miami, Florida bringing to 8 the number of cases reported in the world literature. Two of the ulcers were mild. Three patients recovered without severe impairment of vision after topical polyene treatment, but 1 patient with a severe ulcer required therapeutic keratoplasty after 11 days of topical natamycin. Histopathology revealed fungus deep in the cornea, invading Descemet's membrane. L. theobromae appeared to have collagenase activity in vitro. Inoculation of L. theobromae into the corneas of rabbits produced progressive ulcers. The fungus was endemic in Miami on home grown and imported bananas. Polyene antimycotic antibiotics were fungicidal for L. theobromae in vitro. Thiabendazole was effectively fungistatic but varied in fungicidal effect. Clotrimazole and miconazole were only incompletely fungistatic. Of 7 strains of L. theobromae tested, 4 were relatively resistant to 5-flurocytosine.


False-negative malaria rapid diagnostic test results and their impact on community-based malaria surveys in sub-Saharan Africa.
Surveillance and diagnosis of Plasmodium falciparum malaria relies predominantly on rapid diagnostic tests (RDT). However, false-negative (FN) RDT results are known to occur for a variety of reasons, including operator error, poor storage conditions, pfhrp2/3 gene deletions, poor performance of specific RDT brands and lots, and low-parasite density infections. We used RDT and microscopy results from 85 000 children enrolled in Demographic Health Surveys and Malaria Indicator Surveys from 2009 to 2015 across 19 countries to explore the distribution of and risk factors for FN-RDTs in sub-Saharan Africa, where malaria's impact is greatest. We sought to (1) identify spatial and demographic patterns of FN-RDT results, defined as a negative RDT but positive gold standard microscopy test, and (2) estimate the percentage of infections missed within community-based malaria surveys due to FN-RDT results. Across all studies, 19.9% (95% CI 19.0% to 20.9%) of microscopy-positive subjects were negative by RDT. The distribution of FN-RDT results was spatially heterogeneous. The variance in FN-RDT results was best explained by the prevalence of malaria, with an increase in FN-RDT results observed at lower transmission intensities, among younger subjects, and in urban areas. The observed proportion of FN-RDT results was not predicted by differences in RDT brand or lot performance alone. These findings characterise how the probability of detection by RDTs varies in different transmission settings and emphasise the need for careful interpretation of prevalence estimates based on surveys employing RDTs alone. Further studies are needed to characterise the cost-effectiveness of improved malaria diagnostics (eg, PCR or highly sensitive RDTs) in community-based surveys, especially in regions of low transmission intensity or high urbanicity.


Concentrates of buttermilk and krill oil improve cognition in aged rats.
Cognitive decline is one of the hallmarks of aging and can vary from mild cognitive impairment to dementia to Alzheimer's disease. In addition to some lifestyle interventions, there is room for the use of nutraceuticals/functional foods as pharma-nutritional tools to lessen the burden of cognitive decline before it worsens. We previously reported the promising molecular actions of milk fat globule membranes and krill oil concentrates in a rat model of aging. In this study, we concentrated on the activities on cognition, using an array of validated tests. We also performed lipidomic analyses of plasma, erythrocytes, and different brain areas. We report lower emotional memory (contextual fear conditioning) in aged rats supplemented with concentrates of polar lipids from buttermilk or krill oil at doses that approximate human consumption. No other behavioral parameter was significantly influenced by the supplements, calling for further research to confirm or not the purported salubrious activities of polar lipids, namely those rich in ω3 long-chain polyunsaturated fatty acids, on cognitive decline.


Recombinant soluble interleukin-11 (IL-11) receptor alpha-chain can act as an IL-11 antagonist.
We have expressed a soluble N-glycosylated form of the murine interleukin-11 (IL-11) receptor alpha-chain (sIL-11R) and examined signaling in cells expressing the gp130 molecule. In the presence of gp130 but not the transmembrane IL-11R, the sIL-11R mediated IL-11-dependent differentiation of M1 leukemic cells and proliferation in Ba/F3 cells. Early intracellular events stimulated by the sIL-11R including phosphorylation of gp130, STAT 3, and SHP-2 were similar to signaling through the transmembrane IL-11R. IL-11 bound to sIL-11R with low affinity (kd 10 to 50 nmol/L). Binding of sIL-11R to gp130 was IL-11 dependent with intermediate affinity (kd 1.5 to 3.0 nmol/L). However, the concentration of IL-11 required for signaling through the sIL-11R was 10- to 20-fold greater than that required for cells expressing the transmembrane IL-11R and gp130 in the absence of sIL-11R. Furthermore, the sIL-11R was capable of antagonizing the activity of IL-11 when tested on cells expressing the transmembrane IL-11R and gp130. We propose that the observed IL-11 antagonism by the sIL-11R may depend on limiting numbers of gp130 molecules on cells already expressing the transmembrane IL-11R.