Release of noradrenaline from the cat spleen by sodium deprivation.
1. The endogenous noradrenaline content of cat spleen slices was markedly reduced when the slices were incubated at 37 degrees C in a medium in which sodium was replaced by sucrose, lithium, choline or potassium. Depletion of tissue noradrenaline was accounted for by its release into the incubating medium. At an external sodium concentration of 20 mM, about 50% depletion was obtained in 2 hours.2. The enhanced release induced by sodium deprivation occurred in the absence of calcium, with or without ethyleneglycol-bis (beta-aminoethyl ether) N,N' tetraacetic acid. Manganese potentiated release, while magnesium was without effect.3. Ouabain caused a dose-dependent release of noradrenaline which was partially calcium-dependent. Removal of potassium from the incubation medium caused some release, which was potentiated in 25 mM sodium Krebs solution or by ouabain.4. At 4 degrees C, the release did not occur in sodium-free medium.5. Dinitrophenol did not affect the loss of noradrenaline caused by sodium withdrawal. Iodoacetic acid and N-ethylmaleimide caused a time-dependent depletion of noradrenaline. Tetracaine caused release and partly opposed the release caused by sodium deprivation. Tetrodotoxin had no effect. Guanethidine, but not phenoxybenzamine, released noradrenaline and potentiated the release induced by sodium withdrawal.6. The rate of release of (3)H-noradrenaline from reserpine-treated spleen slices was not altered by sodium withdrawal.7. Uptake-retention of (3)H-noradrenaline in slices depleted of their endogenous noradrenaline content by sodium deprivation was about 60% of the control slices. This was effectively blocked by cocaine. Release of (3)H-noradrenaline evoked by high potassium from both control and treated slices was calcium-dependent.8. It is suggested that sodium-potassium-activated ATPase maintains the integrity of the axonal membrane, and any procedure which depresses the activity of the enzyme or the sodium-potassium pump would cause transmitter release by causing temporary disturbance in the membrane. Evidence is presented to suggest that vesicles depleted of their endogenous noradrenaline content by sodium deprivation are re-used for the storage and release of transmitter.


Host Respiration Rate and Injury-Derived Cues Drive Host Preference by an Ectoparasite of Fruit Flies.
Host bioenergetics and energy fluxes can be applied to measure the ecological and physiological effects of parasitism. By measuring changes in host metabolic rate, one can estimate the physiological costs of infection. Additionally, metabolic rate dictates the rate of resource conversion within a host and, by extension, the resources available to a parasite. We hypothesize that parasites are selected to respond to cues that indicate high resource availability, that is, host metabolic state. We investigated whether an ectoparasite mite (Macrocheles subbadius) can differentiate between potential hosts (Drosophilia nigrospiracula) on the basis of relative carbon dioxide output as measured by respirometry. In pairwise choice tests, mites were allowed to choose between two size-matched fruit flies with differing metabolic rates or levels of CO2 output. Our results showed that mites preferentially infect flies with relatively higher respiration rates. Accordingly, we investigated whether fly respiratory rate (measured by CO2 production) changes in response to injury, potentially explaining a previously reported preference for injured flies. We also tested whether chemical cues released during injury influence preference for injured hosts. We determined that fly exudate (mostly consisting of hemolymph) applied to an uninjured fly released at the site of injury significantly increased the likelihood of infection, but injury did not significantly change the CO2 output of the flies. Our results suggest that parasites are relying on chemical cues not only for host finding but also to discriminate between hosts on the basis of the rate of respiration, with potentially important implications for the metabolic theory of ecology.


KA-Search, a method for rapid and exhaustive sequence identity search of known antibodies.
Antibodies with similar amino acid sequences, especially across their complementarity-determining regions, often share properties. Finding that an antibody of interest has a similar sequence to naturally expressed antibodies in healthy or diseased repertoires is a powerful approach for the prediction of antibody properties, such as immunogenicity or antigen specificity. However, as the number of available antibody sequences is now in the billions and continuing to grow, repertoire mining for similar sequences has become increasingly computationally expensive. Existing approaches are limited by either being low-throughput, non-exhaustive, not antibody specific, or only searching against entire chain sequences. Therefore, there is a need for a specialized tool, optimized for a rapid and exhaustive search of any antibody region against all known antibodies, to better utilize the full breadth of available repertoire sequences. We introduce Known Antibody Search (KA-Search), a tool that allows for the rapid search of billions of antibody variable domains by amino acid sequence identity across either the variable domain, the complementarity-determining regions, or a user defined antibody region. We show KA-Search in operation on the [Formula: see text]2.4 billion antibody sequences available in the OAS database. KA-Search can be used to find the most similar sequences from OAS within 30 minutes and a representative subset of 10 million sequences in less than 9 seconds. We give examples of how KA-Search can be used to obtain new insights about an antibody of interest. KA-Search is freely available at https://github.com/oxpig/kasearch .


On the interpretation of synchronization in EEG hyperscanning studies: a cautionary note.
EEG Hyperscanning is a method for studying two or more individuals simultaneously with the objective of elucidating how co-variations in their neural activity (i.e., hyperconnectivity) are influenced by their behavioral and social interactions. The aim of this study was to compare the performance of different hyper-connectivity measures using (i) simulated data, where the degree of coupling could be systematically manipulated, and (ii) individually recorded human EEG combined into pseudo-pairs of participants where no hyper-connections could exist. With simulated data we found that each of the most widely used measures of hyperconnectivity were biased and detected hyper-connections where none existed. With pseudo-pairs of human data we found spurious hyper-connections that arose because there were genuine similarities between the EEG recorded from different people independently but under the same experimental conditions. Specifically, there were systematic differences between experimental conditions in terms of the rhythmicity of the EEG that were common across participants. As any imbalance between experimental conditions in terms of stimulus presentation or movement may affect the rhythmicity of the EEG, this problem could apply in many hyperscanning contexts. Furthermore, as these spurious hyper-connections reflected real similarities between the EEGs, they were not Type-1 errors that could be overcome by some appropriate statistical control. However, some measures that have not previously been used in hyperconnectivity studies, notably the circular correlation co-efficient (CCorr), were less susceptible to detecting spurious hyper-connections of this type. The reason for this advantage in performance is discussed and the use of the CCorr as an alternative measure of hyperconnectivity is advocated.


Long-term cimetidine in children with cystic fibrosis: a randomized double-blind study.
A prospective, randomized double-blind study of 38 children with cystic fibrosis (CF) was designed to evaluate the effectiveness of cimetidine in improving fat absorption and clinical condition. The treatment consisted of cimetidine or placebo, 600 mg/m2 body surface/day, over a 4-mo period. Clinical state, weight, height, skinfold thickness, lung function tests, para-aminobenzoic acid (PABA) peptide test, and plasma lipid and lipoprotein determinations were performed before and after the treatment period. Compared with age-matched healthy children, patients showed decreased cholesterol (150.2 +/- 31.2 mg/dl, mean +/- SD), decreased high density lipoprotein cholesterol (44.1 +/- 11.8 mg/dl), and decreased low density lipoprotein cholesterol (84.1 +/- 25.5 mg/dl) whereas the triglycerides and the very low density lipoprotein triglycerides were slightly elevated (118.2 +/- 33.0 mg/dl and 60.5 +/- 17.5 mg/dl, respectively). Apoprotein B and AI were slightly reduced and Apoprotein AII was in the normal range. After the 4-mo treatment no significant change in clinical condition, weight, or lipoprotein patterns could be detected between the two groups. The total PABA recovery in urine also did not change significantly (36.6 +/- 19.4% of the dosage given before versus 28.7 +/- 12.9% after 4 mo in the cimetidine group). Cimetidine gave rise to bronchoconstriction as shown by an increase in airway resistance (mean increase 14.8%) whereas the placebo group had a decreased Raw with a mean of 8.3%. Patients with CF have a dyslipoproteinemia that was not influenced by cimetidine. We conclude that cimetidine does not improve fat absorption and has, therefore, no place and no benefit in the treatment of children with CF.


Heat-Induced Cytokinin Transportation and Degradation Are Associated with Reduced Panicle Cytokinin Expression and Fewer Spikelets per Panicle in Rice.
Cytokinins (CTKs) regulate panicle size and mediate heat tolerance in crops. To investigate the effect of high temperature on panicle CTK expression and the role of such expression in panicle differentiation in rice, four rice varieties (Nagina22, N22; Huanghuazhan, HHZ; Liangyoupeijiu, LYPJ; and Shanyou63, SY63) were grown under normal conditions and subjected to three high temperature treatments and one control treatment in temperature-controlled greenhouses for 15 days during the early reproductive stage. The high temperature treatments significantly reduced panicle CTK abundance in heat-susceptible LYPJ, HHZ, and N22 varieties, which showed fewer spikelets per panicle in comparison with control plants. Exogenous 6-benzylaminopurine application mitigated the effect of heat injury on the number of spikelets per panicle. The high temperature treatments significantly decreased the xylem sap flow rate and CTK transportation rate, but enhanced cytokinin oxidase/dehydrogenase (CKX) activity in heat-susceptible varieties. In comparison with the heat-susceptible varieties, heat-tolerant variety SY63 showed less reduction in panicle CTK abundance, an enhanced xylem sap flow rate, an improved CTK transport rate, and stable CKX activity under the high temperature treatments. Enzymes involved in CTK synthesis (isopentenyltransferase, LONELY GUY, and cytochrome P450 monooxygenase) were inhibited by the high temperature treatments. Heat-induced changes in CTK transportation from root to shoot through xylem sap flow and panicle CTK degradation via CKX were closely associated with the effects of heat on panicle CTK abundance and panicle size. Heat-tolerant variety SY63 showed stable panicle size under the high temperature treatments because of enhanced transport of root-derived CTKs and stable panicle CKX activity. Our results provide insight into rice heat tolerance that will facilitate the development of rice varieties with tolerance to high temperature.


The extract from Punica granatum (pomegranate) peel induces apoptosis and impairs metastasis in prostate cancer cells.
Prostate cancer is a big threat to male for its poor prognosis and high mortality rate. Natural compounds are important resources of many anticancer drugs. Pomegranate is a kind of antioxidant-rich fruit and its peel and seed has potential anticancer activities. In this study, we aimed to investigate the effects of pomegranate peel extract (PoPx) on the apoptosis and metastasis of prostate cancer cells and the related mechanism. We found that PoPx showed growth inhibition on prostate cancer cells. Nuclei morphological and flow cytometer (FCM) analysis indicated that PoPx could induce prostate cancer apoptosis. Further investigation indicated that mitochondrial mediated intrinsic pathway is involved in the apoptosis. Exposure to PoPx led to loss of mitochondrial transmembrane potential (Δym), accumulation of reactive oxygen species (ROS). Western blot analysis showed that PoPx could increase the expression ratio of Bax/Bcl2 and activation of apoptosis executor caspase 3. Wound healing assay and transwell migration and invasion assay implied that PoPx has the potential to inhibit migration and invasion, two critical steps in prostate cancer metastasis. Downregulation of MMP2/MMP9 and upregulation of TIMP2 showed accordance with the inhibition of migration and invasion. In summary, the present data showed that PoPx could be a promising drug candidate to treat prostate cancer, showing us a better way to develop novel drugs from natural compounds.


The educational attainment of immigrants: trends and implications.
"This paper uses the 1970, 1980, and 1990 U.S. Censuses to study trends in educational attainment of immigrants relative to natives. Immigrants have become relatively less highly educated, but have become more highly educated in an absolute sense. The effects of changes in relative educational attainment between immigrants and natives on earnings are studied. Educational differences are found to explain more than half the observed wage gap between the two groups. The paper also allows for non-linearities in returns to education. Sheepskin effects influence earnings in different ways for natives and immigrants. Differences in returns to pre- and post-migration education also appear. The paper also finds evidence that immigrants crowd natives out of education, although the effects are stronger in secondary than in postsecondary education."


Population-based analysis of pathological correlates of dementia in the oldest old.
The aim of this study was to analyze brain pathologies which cause dementia in the oldest old population. All 601 persons aged ≥85 years living in the city of Vantaa (Finland), on April 1st, 1991 formed the study population of the Vantaa85 + study, 300 of whom were autopsied during follow-up (79.5% females, mean age-at-death 92 ± 3.7 years). Alzheimer's disease (AD) pathology (tau and beta-amyloid [Aβ]), cerebral amyloid angiopathy (CAA) and Lewy-related pathologies were analyzed. Brain infarcts were categorized by size (<2 mm, 2-15 mm, >15 mm) and by location. Brain hemorrhages were classified as microscopic (<2 mm) and macroscopic. 195/300 (65%) were demented. 194/195 (99%) of the demented had at least one neuropathology. Three independent contributors to dementia were identified: AD-type tau-pathology (Braak stage V-VI), neocortical Lewy-related pathology, and cortical anterior 2-15 mm infarcts. These were found in 34%, 21%, and 21% of the demented, respectively, with the multivariate odds ratios (OR) for dementia 5.5, 4.5, and 3.4. Factor analysis investigating the relationships between different pathologies identified three separate factors: (1) AD-spectrum, which included neurofibrillary tau, Aβ plaque, and neocortical Lewy-related pathologies and CAA (2) >2 mm cortical and subcortical infarcts, and (3) <2 mm cortical microinfarcts and microhemorrhages. Multipathology was common and increased the risk of dementia significantly. These results indicate that AD-type neurodegenerative processes play the most prominent role in twilight cognitive decline. The high prevalence of both neurodegenerative and vascular pathologies indicates that multiple preventive and therapeutic approaches are needed to protect the brains of the oldest old.


[Agents of nursing in São Paulo health practices: from the bacteriological model to the health program (1889-1983)].
The historical roots of the nursing profession in public health in the state of São Paulo from 1900-1980 have been identified. Nurses have effectively participated to implement a new public health program--"Programação em Saúde", having the assignment to train, coordinate, supervise/manage other nurses who lacked specialized training. The nurse's understanding of her role in the health process was limited to individual performance with emphasis on technical ability, without understanding the purpose of her actions in the overall model.


Effects of aldosterone, methylprednisolone and triiodothyronine on the response to water loading in the conscious hypothyroid rat with diabetes insipidus.
The role of the antidiuretic hormone-independent mechanisms underlying the impairment of water excretion in hypothyroidism remains controversial. We examined the excretion of an oral water load (50 ml/kg b.w.) over a 3-hour period before and after the administration of aldosterone, methylprednisolone, both aldosterone and methylprednisolone, and triiodothyronine in 12 hypothyroid and 7 age-matched control Wistar rats of the homozygous Brattleboro strain (DI). Conscious animals were studied to circumvent the adverse influence of anesthetics and to facilitate the re-examination of the same animals. At baseline, the hypothyroid DI rats exhibited a marked impairment in their response to water administration. In comparison to control DI rats they had a lower urine volume, CH2O, CH2O/V and creatinine clearance, and higher urine osmolality (p less than 0.005-less than 0.001). Because of the possibility of decreased delivery of filtrate due to dehydration in the DI animals, a separate group of DI rats received saline in place of the water load. Despite improvement in urine flow with saline, CH2O generation remained decreased in the hypothyroid DI rats. Methylprednisolone increased both urine volume (p less than 0.001) and CH2O (p less than 0.001) in the hypothyroid group, but CH2O formation remained below the values obtained in the control animals. While aldosterone and methylprednisolone alone and in combination improved utilization of distally-delivered filtrate for the formation of CH2O (p less than 0.02-0.005), neither hormone, either alone or in combination, fully corrected the dilution defect. In contrast, the administration of triiodothyronine fully normalized all the observed abnormalities in the hypothyroid rats, suggesting that thyroid hormone deficiency is directly responsible for the abnormal water-excretion in experimental hypothyroidism.


The Cordon study of weight reduction based on behaviour modification.
A behaviour modification programme for the treatment of obesity was offered to a population of obese women, aged 51-67, being screened for breast cancer. The programme was offered in two forms: (1) A series of ten small group sessions under the guidance of a non-medical leader, with three follow-up meetings after the course (10 S programme). (2). A series of ten mailed lessons with a pre- and post-course interview and three follow-up meetings after the course (10 L programme). The drop-out rate during the course was 12 per cent for the 10 S programme and 37 per cent for the 10 L programme. Follow-up in the 10 S programme revealed an average weight loss of 5.2 kg after 3 months, 4.1 kg after 17 months, and 3.0 kg after 36 months. Comparable figures in the 10 L programme were 3.0 kg, 3.0 kg and 1.6 kg, respectively. Percentile distributions of weight loss after these intervals are presented. Results are compared with those in other obese women in the cancer screening programme who either had no plans for weight reduction or said they had opted for other kinds of intervention. These comparisons clearly favour the behaviour treatment programme, but the picture may have been influenced by a possibly higher motivation of those who followed the course.


Role of NO in modulating neuronal activity in superficial dorsal horn of spinal cord during exercise pressor reflex.
Static contraction of hindlimb skeletal muscle in cats induces a reflex pressor response. The superficial dorsal horn of the spinal cord is the major site of the first synapse of this reflex. In this study, static contraction of the triceps surae muscle was evoked by electrical stimulation of the tibial nerve for 2 min in anesthetized cats (stimulus parameters: two times motor threshold at 30 Hz, 0.025-ms duration). Ten stimulations were performed and 1-min rest was allowed between stimulations. Muscle contraction caused a maximal increase of 32 +/- 5 mmHg in mean arterial pressure (MAP), which was obtained from the first three contractions. Activated neurons in the superficial dorsal horn were identified by c-Fos protein. Distinct c-Fos expression was present in the L6-S1 level of the superficial dorsal horn ipsilateral to the contracting leg (88 +/- 14 labeled cells per section at L7), whereas only scattered c-Fos expression was observed in the contralateral superficial dorsal horn (9 +/- 2 labeled cells per section, P < 0.05 compared with ipsilateral section). A few c-Fos-labeled cells were found in control animals (12 +/- 5 labeled cells per section, P < 0.05 compared with stimulated cats). Furthermore, double-labeling methods demonstrated that c-Fos protein coexisted with nitric oxide (NO) synthase (NOS) positive staining in the superficial dorsal horn. Finally, an intrathecal injection of an inhibitor of NOS, N-nitro-L-arginine methyl ester (5 mM), resulted in fewer c-Fos-labeled cells (58 +/- 12 labeled cells per section) and a reduced maximal MAP response (20 +/- 3 mmHg, P < 0.05). These results suggest that the exercise pressor reflex induced by static contraction is mediated by activation of neurons in the superficial dorsal horn and that formation of NO in this region is involved in modulating the activated neurons and the pressor response to contraction.


Evaluation of the effects of SKF 82526 and LY 171555 on presynaptic (DA2) and postsynaptic (DA1) dopamine receptors in rat kidney.
Effects of dopamine receptor agonists, SKF 82526 and LY 171555 on presynaptic (DA2) and postsynaptic (DA1) dopamine receptors were studied in the isolated perfused rat kidney. SKF 82526 failed to alter [3H]NA release elicited during periarterial nerve stimulation in the kidney whereas LY 171555 caused a concentration-dependent inhibition of the stimulus-induced release of [3H]NA. This inhibitory action of LY 171555 could be antagonized by sulpiride but not by SCH 23390. SKF 82526 caused concentration-dependent renal vasodilation which could be antagonized by SCH 23390. LY 171555 did not produce significant changes in renal perfusion pressure over a wide range of concentrations. These results show that SKF 82526 and LY 171555 are selective agonists at DA1 and DA2 receptors respectively. These agents represent an important class of compounds that would be useful for pharmacological characterization of peripheral dopamine receptors.


Role of sphingosine kinase activity in protection of heart against ischemia reperfusion injury.
Sphingosine kinase (SKase) has been implicated in the protection of hearts from ischemia/reperfusion injury. This hypothesis was further examined. Changes in SKase activity and cardiac function (left ventricular developed pressure, LVDP, and infarct size) in response to ischemia and reperfusion were studied in adult rat hearts by the ex vivo Langendorff method. Following initial equilibration or preconditioning, there was 45 min no-flow ischemia and then 45 min of reperfusion. SKase activity declined 61% during ischemia and did not recover upon reperfusion. LVDP also did not recover upon reperfusion and the infarct size was 47%. A short 30 min period of ischemia was associated with variable recovery of SKase activity that directly correlated with LVDP recovery. Preconditioning of hearts reduced the decrease in SKase activity during ischemia by half, and upon reperfusion activity returned to normal. The LVDP recovered 79% and infarct size was small. Preconditioned hearts had higher S-1-P levels after ischemia/reperfusion relative to non-preconditioned hearts. The decline in SKase activity during ischemia of preconditioned hearts could not be mimicked in vitro by treatment with protein phosphatases. Attempts to alter activity of SKase from control, preconditioned, ischemic, or reperfused hearts by phosphorylation with ERK1/2 were unsuccessful. Treatment of non-preconditioned hearts at reperfusion with 100 nM S-1-P improved recovery of LVDP. The SKase inhibitor dimethylsphingosine blocked hemodynamic recovery in preconditioned hearts. The data support a role for SKase activity in recovery of hemodynamic function after ischemic injury and also in the cardioprotective effect of preconditioning.


Speech and melody recognition in binaurally combined acoustic and electric hearing.
Speech recognition in noise and music perception is especially challenging for current cochlear implant users. The present study utilizes the residual acoustic hearing in the nonimplanted ear in five cochlear implant users to elucidate the role of temporal fine structure at low frequencies in auditory perception and to test the hypothesis that combined acoustic and electric hearing produces better performance than either mode alone. The first experiment measured speech recognition in the presence of competing noise. It was found that, although the residual low-frequency (<1000 Hz) acoustic hearing produced essentially no recognition for speech recognition in noise, it significantly enhanced performance when combined with the electric hearing. The second experiment measured melody recognition in the same group of subjects and found that, contrary to the speech recognition result, the low-frequency acoustic hearing produced significantly better performance than the electric hearing. It is hypothesized that listeners with combined acoustic and electric hearing might use the correlation between the salient pitch in low-frequency acoustic hearing and the weak pitch in the envelope to enhance segregation between signal and noise. The present study suggests the importance and urgency of accurately encoding the fine-structure cue in cochlear implants.


Radiography, CT, and MRI Diagnosis of Enzootic Nasal Tumor in Goats Infected With Enzootic Nasal Tumor Virus.
The aim of this study was to describe radiography, computed tomography (CT), and magnetic resonance imaging (MRI) findings of enzootic nasal tumors in goats infected with enzootic nasal tumor viruses. Five of six goats with a mean age of 2 years, showed clinical signs of respiratory disease. Head radiographs showed increased density of the unilateral or bilateral nasal cavity in four goats, and a CT scan showed that the space-occupying lesion of the nasal cavity originated from the ethmoid bone and was enhanced homogeneously postcontrast in all goats. The nasal concha was destroyed and the paranasal sinus mucosa was thickened and filled with fluid in some goats. On MRI, the mass exhibited equal or slightly higher signal intensity on T2 weighted images, equal signal intensity on T1 weighted images, a high signal on fluid-attenuated inversion recovery images and heterogeneous enhancement postcontrast. After dissection, histopathological examination of the mass and virus genome detection of the nasal secretions confirmed that the intranasal mass was a low-grade adenocarcinoma and that the goats were infected with enzootic nasal tumor virus type 2. In conclusion, CT and MRI have high diagnostic values for enzootic nasal tumors because they match the postmortem findings and are more accurate than radiography.


How we enhanced medical academics skills and reduced social inequities using an academic teaching program.
The training of future physicians should be concurrent with the development of different skills and attitudes. This warrants the need to regularly provide students with opportunities for self-development throughout their academic career. This approach was exemplified in a medical school in the Brazilian Amazon, where students were allowed to play the role of high school teachers. As part of this exercise, they conducted reinforcement classes for high school students to increase the number of university admissions. The medical students were solely responsible for organizing and implementing this project, giving them the opportunity to develop teaching and leadership skills, enhance their understanding of communication and administration and contribute toward the society.


Unraveling lipid metabolism in maize with time-resolved multi-omics data.
Maize is the cereal crop with the highest production worldwide, and its oil is a key energy resource. Improving the quantity and quality of maize oil requires a better understanding of lipid metabolism. To predict the function of maize genes involved in lipid biosynthesis, we assembled transcriptomic and lipidomic data sets from leaves of B73 and the high-oil line By804 in two distinct time-series experiments. The integrative analysis based on high-dimensional regularized regression yielded lipid-transcript associations indirectly validated by Gene Ontology and promoter motif enrichment analyses. The co-localization of lipid-transcript associations using the genetic mapping of lipid traits in leaves and seedlings of a B73 × By804 recombinant inbred line population uncovered 323 genes involved in the metabolism of phospholipids, galactolipids, sulfolipids and glycerolipids. The resulting association network further supported the involvement of 50 gene candidates in modulating levels of representatives from multiple acyl-lipid classes. Therefore, the proposed approach provides high-confidence candidates for experimental testing in maize and model plant species.


A retrospective study of the diagnostic accuracy of a community hospital-based PET center for the detection of coronary artery disease using rubidium-82.
A retrospective analysis has been carried out to determine the diagnostic accuracy of PET of the heart with 82Rb at a community hospital based center. Utilization statistics were derived from a total of 1460 patients scanned for the first 36 mo of the center's operation. Diagnostic accuracy for detection of coronary artery disease (CAD) was assessed using three readers blinded to the clinical information. A total of 287 rest and dipyridamole-stress scans of patients who had coronary angiograms within 6 mo of the PET scan were selected by the computer for this study. Each rest/stress scan was read by at least two of the three readers. The average sensitivity for all three readers was 87% for greater than 67% diameter stenosis and the average specificity was 88% for myocardial regions perfused by normal coronary arteries. The average accuracy was 88% for patients with greater than 67% diameter stenosis. Sensitivity and accuracy improved to 92% and 91% respectively for stenosis greater than 90% in diameter. These results compare well with published results from major hospital-based centers and the recently published results from a private PET center in Georgia.


Simple, rapid and cost-effective method for high quality nucleic acids extraction from different strains of Botryococcus braunii.
This study deals with an effective nucleic acids extraction method from various strains of Botryococcus braunii which possesses an extensive extracellular matrix. A method combining freeze/thaw and bead-beating with heterogeneous diameter of silica/zirconia beads was optimized to isolate DNA and RNA from microalgae, especially from B. braunii. Eukaryotic Microalgal Nucleic Acids Extraction (EMNE) method developed in this study showed at least 300 times higher DNA yield in all strains of B. braunii with high integrity and 50 times reduced working volume compared to commercially available DNA extraction kits. High quality RNA was also extracted using this method and more than two times the yield compared to existing methods. Real-time experiments confirmed the quality and quantity of the input DNA and RNA extracted using EMNE method. The method was also applied to other eukaryotic microalgae, such as diatoms, Chlamydomonas sp., Chlorella sp., and Scenedesmus sp. resulting in higher efficiencies. Cost-effectiveness analysis of DNA extraction by various methods revealed that EMNE method was superior to commercial kits and other reported methods by >15%. This method would immensely contribute to area of microalgal genomics.


Enhancement of Black Tea Aroma by Adding the β-Glucosidase Enzyme during Fermentation on Black Tea Processing.
Black tea aroma is one of the essential attributes in determining the quality of black tea. β-Glucosidases were investigated for their ability to enhance the aroma of black tea by hydrolyzing the glycoside compound. The addition of β-glucosidase was done by dissolving the enzyme on a sodium citrate buffer (pH 5.0), which was then sprayed on tea leaves during black tea processing. The β-glucosidase treatment significantly increases the volatile compound from glycoside precursors such as linalool, geraniol, and methyl salicylate. Moreover, the volatile compound from carotenoid and lipid precursors (nerolidol and β-cyclocitral) was also increased with β-glucosidase treatment.


Inactivation of the inducible nitric oxide synthase by peroxynitrite.
The simultaneous production of superoxide and nitric oxide by stimulated human neutrophils leads to the formation of peroxynitrite, a physiologically important bactericidal agent. We have investigated two possible pathways for the inactivation of inducible nitric oxide synthase (NOS-II) by peroxynitrite: inactivation of NOS-II through oxidation of the tightly bound cofactor calmodulin (CaM) and direct interaction of ONOO-/ONOOH with the NOS-II protein. Studies of two model peptides indicated that the Ca2+-dependent binding to CaM of a typical high-affinity sequence, melittin, significantly prevented Met oxidation in CaM by ONOO-/ONOOH. In contrast, binding of the putative CaM-binding domain of human hepatocyte NOS-II (NOS-II509-534) to CaM only marginally prevented the oxidation of Met residues in CaM. When the native NOS-II/CaM complex was exposed to peroxynitrite, CaM was inert toward oxidation. Nevertheless, even small amounts of peroxynitrite abolished the activity of NOS-II through direct interaction with the heme. The loss of activity was paralleled by a decrease in heme absorbance and a shift of the absorbance maximum from 419 to 409 nm. The presence of the cofactor tetrahydrobiopterin during peroxynitrite exposure did not prevent inactivation of the enzyme but altered the change of the heme spectrum, i.e., a shift of lambda(max) from 419 to 420 nm rather than to 409 nm. In conclusion, peroxynitrite inactivates NOS-II through changes in the heme or its environment in NOS-II rather than via oxidation of the cofactor CaM.


Early-life adversity and adolescent depression: mechanisms involving the ventral striatum.
Early-life adversity is a well-established risk factor for the development of depression later in life. Here we discuss the relationship between early-life adversity and depression, focusing specifically on effects of early-life caregiver deprivation on alterations in the neural and behavioral substrates of reward-processing. We also examine vulnerability to depression within the context of sensitive periods of neural development and the timing of adverse exposure. We further review the development of the ventral striatum, a limbic structure implicated in reward processing, and its role in depressive outcomes following early-life adversity. Finally, we suggest a potential neurobiological mechanism linking early-life adversity and altered ventral striatal development. Together these findings may help provide further insight into the role of reward circuitry dysfunction in psychopathological outcomes in both clinical and developmental populations.


Diastereoselective noncovalent synthesis of hydrogen-bonded double-rosette assemblies.
Chiral centers present either in the dimelamine components of calix[4]arene 1 or in the cyanurate components CA quantitatively induce one handedness (P or M) in the corresponding hydrogen-bonded assemblies 1(3).(CA)(6) (de>98 %). The high degree of chiral induction results from the presence of six chiral centers in close proximity (C(alpha)) to the core of the assembly. A much lower level of chiral induction is observed for assemblies with chiral centers that are more remote (C(beta)). All diastereomerically pure assemblies 1(3).(CA)(6) exhibit very high CD activities (deltavarepsilon(max) approximately 100 L mol(-1) cm(-1)), in sharp contrast to the low CD activities (deltavarepsilon(max)<or=8 L mol(-1) cm(-1)) shown by the free components. The assemblies display spontaneous resolution under thermodynamically controlled conditions (i.e., heteromeric assemblies containing both peripheral R and S centers are not observed. Remarkable assembly behavior is observed if both components 1 and CA are chiral. In general, formation of well-defined assemblies is only observed when both components contain unidirectional information for the induction of either M or P chirality.


IP6K1 Reduces Mesenchymal Stem/Stromal Cell Fitness and Potentiates High Fat Diet-Induced Skeletal Involution.
Mesenchymal stem/stromal cells (MSCs) are the predominant source of bone and adipose tissue in adult bone marrow and play a critical role in skeletal homeostasis. Age-induced changes in bone marrow favor adipogenesis over osteogenesis leading to skeletal involution and increased marrow adiposity so pathways that prevent MSC aging are potential therapeutic targets for treating age-related bone diseases. Here, we show that inositol hexakisphosphate kinase 1 (Ip6k1) deletion in mice increases MSC yields from marrow and enhances cell growth and survival ex vivo. In response to the appropriate stimuli, Ip6k1-/- versus Ip6k1+/+ MSCs also exhibit enhanced osteogenesis and hematopoiesis-supporting activity and reduced adipogenic differentiation. Mechanistic-based studies revealed that Ip6k1-/- MSCs express higher MDM2 and lower p53 protein levels resulting in lower intrinsic mitochondrial reactive oxygen species (ROS) levels as compared to Ip6k1+/+ MSCs, but both populations upregulate mitochondrial ROS to similar extents in response to oxygen-induced stress. Finally, we show that mice fed a high fat diet exhibit reduced trabecular bone volume, and that pharmacological inhibition of IP6K1 using a pan-IP6K inhibitor largely reversed this phenotype while increasing MSC yields from bone marrow. Together, these findings reveal an important role for IP6K1 in regulating MSC fitness and differentiation fate. Unlike therapeutic interventions that target peroxisome proliferator-activated receptor gamma and leptin receptor activity, which yield detrimental side effects including increased fracture risk and altered feeding behavior, respectively, inhibition of IP6K1 maintains insulin sensitivity and prevents obesity while preserving bone integrity. Therefore, IP6K1 inhibitors may represent more effective insulin sensitizers due to their bone sparing properties. Stem Cells 2017;35:1973-1983.


[Clinical effects of long-term lithium treatment on sleep, appetite and sexuality].
The authors try to determine the incidence of long-term lithium treatments on sleep, appetite and sexual behaviour. The study was conducted in fifty outpatients of both sexes who have been for at least six months on lithium only and whose mood disturbances are stabilized. In two thirds of the cases of this clinical study, lithium seems to have beneficient qualitative and quantitative effects on sleep as opposed to other psychotropic drugs which cause discomforting sleepiness. Lithium seems to influence appetite slightly although it is responsible for the gain in weight in a fourth of the treated outpatients. Half of the subjects consider that lithium modifies their sexuality towards a decrease of the desire without modifying their capacities of realization. In a comparison study conducted with the psychotropic drugs that had been administered before, the repercussions of lithium on sexuality appear thus opposite to those of psychotropic drugs, major tranquilizers and antidepressants which impair the capacities without reducing the desire. Despite the specific side effects on some instinctive functions, lithium seems to be a treatment well lived by the subjects.


Synthesis, characterization, interaction with DNA and cytotoxicity of Pd(II) and Pt(II) complexes containing pyridine carboxylic acid ligands.
Four metal complexes [Pd(L(1))Cl(2)·2H(2)O] (1), [Pt(L(1))Cl(2)·2H(2)O] (2), [Pd(L(2))Cl(2)·H(2)O] (3) and [Pt(L(2))Cl(2)·H(2)O] (4) (L(1) = 2,2'-bipyridyl-5,5'-dicarboxylic acid, L(2) = 2,2'-bipyridyl-4,4'-dicarboxylic acid) have been synthesized under hydrothermal conditions and fully characterized by IR and (1)H-NMR spectra, elemental analysis, and X-ray single crystal diffraction analysis. Interactions of these complexes with fish sperm DNA (FS-DNA) were investigated using UV-Vis absorption and fluorescence spectroscopic methods. Further insight was brought by quantum chemistry calculations by means of G03 package and taking B3LYP functional Lanl2dz Gen basis set. Agarose gel electrophoresis run on pBR322 plasmid DNA gave proof that all four complexes exhibit efficient DNA cleavage. Complexes 1-4 manifested cytotoxic specificity and a significant cancer cell inhibitory rate. Independent apoptosis tests under the light microscope, performed on hematoxylin-eosin stained HeLa cells, evidenced morphological changes induced by all the complexes.


Prognostic value of an automated sperm analysis in IVF or insemination therapy.
During the course of sterility treatment semenograms of 271 IVF and 316 insemination patients were carried out by two automated semen analysers. The parameters of these analyses were correlated to pregnancies resulting from the treatment. Semen samples were analysed in the ejaculate and after swim-up preparation. In addition, the swim-up suspension of IVF patients was measured again 18 h after sperm preparation. Patients were divided into three groups: (1) couples who achieved a pregnancy, (2) couples who did not achieve a pregnancy, and (3) IVF patients with no fertilization of the oocytes. Because of large standard deviations in the quality of ejaculates, the results in the IVF group show no significant differences in the semen parameters of husbands of pregnant and non-pregnant women. In contrast husbands of women with no fertilization have a significantly lower sperm motility. After swim-up preparation these differences no longer occur. A further measurement, taken 18 h later, reveals that there are no differences in the sperm parameters between the pregnant and non-pregnant group. However, the semen quality in the group with no fertilization is significantly reduced. The results of the insemination patients are similar to those of the IVF group. Thus, the results from automated sperm analysers cannot replace either the microscopic or biochemical analysis of an ejaculate and, moreover, cannot be used as prognosis for the fertilization capacity of sperms or a following pregnancy.


Clinical and pathological features of children with Henoch-Schoenlein purpura nephritis: risk factors associated with poor prognosis.
To clarify the risk factors related to prognosis in patients with Henoch-Schoenlein purpura nephritis (HSPN), we investigated the cases with HSPN on long-term observation. We enrolled 114 patients who had been diagnosed with HSPN from 1974-1997. These patients were divided into 2 groups based upon features at last follow-up. One group, designated "favorable", consisted of 69 patients with normal urine and 25 patients with minor urinary abnormalities, and the second group, designated "unfavorable", consisted of 15 patients with active renal disease and 5 patients with renal failure. The clinical features, laboratory data and pathological findings were investigated in 2 groups. Nephrotic syndrome, decreased factor XIII activity, hypertension and renal failure at onset were more frequent in "unfavorable" than in "favorable". The rate of glomeruli with crescents, macrophage infiltrations, tubulointerstitial changes and acute exacerbation in "unfavorable" were higher than those in "favorable". There were 5 cases with renal insufficiency, and renal survival rate was 95.6% for over 15 years. These results suggest that the above mentioned risk factors play an important role in prognosis of the patients with active renal disease and renal failure.


Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene.
Hereditary papillary renal carcinoma (HPRC) is a newly recognized inherited disorder characterized by a predisposition to develop multiple bilateral papillary renal carcinomas. Individuals affected with HPRC have been shown to have germ-line mutations in the tyrosine kinase domain of the MET proto-oncogene. We identified a novel mutation in exon 16 of the MET gene in two large North American HPRC families. The H1112R MET mutation segregated with the disease, was not present in 320 normal chromosomes, and caused malignant transformation of NIH 3T3 cells. By examining individuals with the H1112R mutation, we determined the age-dependent penetrance of this mutation and identified additional nonrenal malignancies that occurred in mutation carriers. Affected members of the two families shared the same haplotype within and immediately distal to the MET gene, suggesting a founder effect. The identification of the H1112R mutation will facilitate predictive testing in HPRC and guide future studies of the MET gene in human neoplasia.


Starvation responses impact interaction dynamics of human gut bacteria Bacteroides thetaiotaomicron and Roseburia intestinalis.
Bacterial growth often alters the environment, which in turn can impact interspecies interactions among bacteria. Here, we used an in vitro batch system containing mucin beads to emulate the dynamic host environment and to study its impact on the interactions between two abundant and prevalent human gut bacteria, the primary fermenter Bacteroides thetaiotaomicron and the butyrate producer Roseburia intestinalis. By combining machine learning and flow cytometry, we found that the number of viable B. thetaiotaomicron cells decreases with glucose consumption due to acid production, while R. intestinalis survives post-glucose depletion by entering a slow growth mode. Both species attach to mucin beads, but only viable cell counts of B. thetaiotaomicron increase significantly. The number of viable co-culture cells varies significantly over time compared to those of monocultures. A combination of targeted metabolomics and RNA-seq showed that the slow growth mode of R. intestinalis represents a diauxic shift towards acetate and lactate consumption, whereas B. thetaiotaomicron survives glucose depletion and low pH by foraging on mucin sugars. In addition, most of the mucin monosaccharides we tested inhibited the growth of R. intestinalis but not B. thetaiotaomicron. We encoded these causal relationships in a kinetic model, which reproduced the observed dynamics. In summary, we explored how R. intestinalis and B. thetaiotaomicron respond to nutrient scarcity and how this affects their dynamics. We highlight the importance of understanding bacterial metabolic strategies to effectively modulate microbial dynamics in changing conditions.


Reversible conduction block in isolated toad sciatic nerve by emulsified isoflurane.
Studies have shown that the local use of volatile anesthetics can produce local anesthetic effects. We designed this study to evaluate the characteristics of nerve conduction block of emulsified isoflurane (EI) and compare its nerve blockade with 1%lidocaine, by measuring compound nerve action potential (CNAP) parameters in isolated toad sciatic nerve. One hundred isolated toad sciatic nerves were selected and randomly assigned to 10 groups of 10 each, administered 2% to 8% EI (v/v) (EI(8) group, etc.), 1% lidocaine, 30% Intralipid(R) (Huarui Pharmacy, Wuxi, Jiangsu, China), and Ringer solution (RS) for 10 minutes, respectively. All nerves were then washed and soaked with RS for 10 minutes and 30 minutes. The nerve conduction block effect was represented by CNAP parameters that were recorded by an extracellular recording technique per minute. The results showed that the negative amplitudes of CNAP were decreased by EI and lidocaine (P < 0.05), and the conduction velocities of CNAP were also decreased at some time points (D7-W3) (P < 0.05). After RS washing, the 2 parameters recovered gradually. The changes in the 2 parameters induced by EI had slower onset rates and faster recoveries than those produced by lidocaine (7 minutes vs 1 minute and 9 minutes vs 30 minutes). The nerve blockade induced by EI was dose dependent (P < 0.05), and the half maximal inhibition concentration of EI was 5.46%. EI produced completely reversible and dose-dependent nerve conduction inhibition, which had slower onset and faster recovery compared with those produced by lidocaine.


The use and misuse of short cognitive tests in the diagnosis of dementia.
Short cognitive tests are widely used in medicine to assess patients with memory problems but their role in the assessment of patients with cognitive problems is often misunderstood. They are a part of the examination of the patient and not tests for dementia or 'case-finding tools'. This misunderstanding leads to widespread misconceptions concerning short cognitive tests and could lead to major over diagnosis or under diagnosis of dementia. Their use in clinical practice particularly in response to national directives aimed at increasing diagnosis rates in dementia needs a clear understanding of their role and limitations. A new classification of short cognitive tests is proposed with guidance on their use in clinical medicine.


CD28-inducible transcription factor DEC1 is required for efficient autoreactive CD4+ T cell response.
During the initial hours after activation, CD4(+) T cells experience profound changes in gene expression. Co-stimulation via the CD28 receptor is required for efficient activation of naive T cells. However, the transcriptional consequences of CD28 co-stimulation are not completely understood. We performed expression microarray analysis to elucidate the effects of CD28 signals on the transcriptome of activated T cells. We show that the transcription factor DEC1 is highly induced in a CD28-dependent manner upon T cell activation, is involved in essential CD4(+) effector T cell functions, and participates in the transcriptional regulation of several T cell activation pathways, including a large group of CD28-regulated genes. Antigen-specific, DEC1-deficient CD4(+) T cells have cell-intrinsic defects in survival and proliferation. Furthermore, we found that DEC1 is required for the development of experimental autoimmune encephalomyelitis because of its critical role in the production of the proinflammatory cytokines GM-CSF, IFN-γ, and IL-2. Thus, we identify DEC1 as a critical transcriptional mediator in the activation of naive CD4(+) T cells that is required for the development of a T cell-mediated autoimmune disease.


Evaluation of the Effects of Platelet-Rich Plasma on Follicular and Endometrial Growth: A Literature Review.
Platelet-rich plasma (PRP) has been used in several areas of medicine due to its ability to promote tissue regeneration by growth factors and cytokines. This review addresses the use of PRP to rejuvenate ovarian follicles and increase the thickness of the endometrium to receive an embryo. PRP is obtained from the patient's own blood (autologous blood) - a fact that determines a lower chance of rejection reactions. Alpha granules of platelets provide and release supra physiological amounts of growth factors and cytokines, which provide a regenerative stimulus in tissues with low healing potential. In the ovary, PRP and its growth factors stimulate vascularization and recruitment of available primordial follicles that could no longer be otherwise stimulated. The rejuvenation of the ovary by PRP infusion aims to obtain new oocytes in ovaries with low numbers of follicles or low follicular reserve markers. In the preparation of the endometrium, PRP is used for its several growth factors that allow tissue proliferation and endometrial thickening, especially in cases of endometria that are difficult to prepare or that fail to reach an adequate minimum thickness (>7mm). To date, there are few studies of greater expression in the literature that support the use of PRP with the two purposes described above. Thus, although promising, the technique must still be validated by larger clinical trials.


Docking-generated multiple ligand poses for bootstrapping bioactivity classifying Machine Learning: Repurposing covalent inhibitors for COVID-19-related TMPRSS2 as case study.
In the present work we introduce the use of multiple docked poses for bootstrapping machine learning-based QSAR modelling. Ligand-receptor contact fingerprints are implemented as descriptor variables. We implemented this method for the discovery of potential inhibitors of the serine protease enzyme TMPRSS2 involved the infectivity of coronaviruses. Several machine learners were scanned, however, Xgboost, support vector machines (SVM) and random forests (RF) were the best with testing set accuracies reaching 90%. Three potential hits were identified upon using the method to scan known untested FDA approved drugs against TMPRSS2. Subsequent molecular dynamics simulation and covalent docking supported the results of the new computational approach.


Update on the optimal use of bortezomib in the treatment of multiple myeloma.
The proteasome inhibitor (PI) "bortezomib" has now been in routine clinical practice for over a decade. It is now considered an important backbone therapy for all stages of the disease, and data continue to grow to support its use in newly diagnosed patients, relapsed and relapsed/refractory disease, maintenance therapy, high risk, and renal failure. Much has been learnt about the most clinically effective way of delivering therapy, with patients often benefiting more from a triplet bortezomib combination compared to a doublet combination. It is well tolerated and can be administered in the outpatient setting with manageable toxicity. The key to good results is managing side effects so that patients remain on therapy with minimal interruptions. Therefore, proactive management of peripheral neuropathy and thrombocytopenia is advised using dose delay and reduction strategies. The recent introduction of second- and third-generation PIs with different chemical and biological properties has resulted in a plethora of new clinical studies and has confirmed the ongoing role of this class of drugs in future myeloma therapy.


Improvements in the delivery of resuscitation and newborn care after Helping Babies Breathe training.
To evaluate changes in neonatal resuscitation and postnatal care following Helping Babies Breathe (HBB) training at a community hospital in rural Honduras. We hypothesized that HBB training would improve resuscitation and essential newborn care interventions. Direct observation and video recording of delivery room care spanned before and after an initial HBB workshop held in August 2013. Rates of essential newborn care interventions were compared in resuscitations performed by individuals who had and had not received HBB training, and run charts recording performance of newborn care practices over time were developed. Ten percent of deliveries (N=250) were observed over the study period, with 156 newborn resuscitations performed by individuals without HBB training, compared to 94 resuscitations performed by HBB trainees. After HBB training, significant improvements were seen in skin-to-skin care, breastfeeding within 60 min of age, and delayed cord clamping after 1 min (all P<0.01). More babies cared for by HBB trainees received basic neonatal resuscitation such as drying and stimulation. Run charts tracking these practices over time showed significant improvements after HBB training that were sustained during the study period, but remained below ideal goals. With improvement in drying/stimulation practices, fewer babies required bag/mask ventilation. In a rural Honduran community hospital, improvements in basic neonatal resuscitation and postnatal essential newborn care practices can be seen after HBB training. Further improvements in newborn care practices may require focused quality improvement initiatives for hospitals to sustain high quality care.


Immune responses to Plasmodium falciparum antigens during a malaria vaccine trial in Tanzanian children.
Among Tanzanian children living in an area of intense and perennial malaria transmission, prevalence of naturally acquired IgG antibodies that recognize SPf66, NANP, p190 and a 19 kDa fragment of the merozoite surface protein-1 (MSP-1) is high and increases with age. This possibly reflects the high level of natural exposure of the children to P. falciparum. The prevalences of IgG antibodies that recognize the three putative merozoite derived sequences contained in the malaria vaccine SPf66 (83.1, 55.1 and 35.1) is low but also show some age dependence. Three doses of the SPf66 vaccine induce a strong IgG antibody response against both the SPf66 construct, NANP and the three individual peptides. Vaccination with SPf66 did not result in an increase of anti19 kDa fragment antibodies. This reflects the specificity of the humoral immune response induced by the SPf66 construct. Among vaccinated children, antibody titres against SPf66 decreased over time following the third dose. However, 18 months after the third dose, SPf66 recipients still had significantly higher IgG titres and stimulation indices of peripheral blood mononuclear cells (PBMC) than placebo recipients. Within the vaccine group, there is a trend for increasing anti-SPf66 IgG titre to be associated with decreasing risk of clinical malaria but this was not statistically significant. Results also show the difficulties of establishing whether antibody responses are related to protection in field trials in endemic areas.


Light and transmission electron microscopy of immature camelus dromedarius oocyte.
In order to provide a consistent system for laboratory production of embryos, the characteristics of immature camel oocyte must first be described. The objective of this study was to define ultrastructural features of immature camel oocyte. Ovaries were obtained from camels at a local abattoir, and then transported to the laboratory within 2 h. Camelus cumulus oocyte complexes (COCs) were aspirated from 2-6 mm follicles using a 22-gauge needle. Excellent and good quality COCs were selected and prepared for transmission electron microscopy study using a cavity slide. The fine structure of camel oocyte is morphologically similar to that of other mammalian oocytes. However, some minor differences exist between COC of camel and other mammalian species. Different size and shape of membrane-bound vesicles, lipid droplet, mitochondria and cortical granules were distributed throughout the ooplasm. Discrete or in association with endoplasmic reticulum, Golgi complexes were observed in the periphery of the oocytes. The majority of the oocytes were in the germinal vesicle stage.


Mild cognitive impairment: long-term course of four clinical subtypes.
To empirically validate the expanded concept of mild cognitive impairment (MCI), which differentiates between four clinical subtypes-amnestic MCI-single domain, amnestic MCI-multiple domains, nonamnestic MCI-single domain, and nonamnestic MCI-multiple domains-and to examine the prevalence, course, and outcome of these four clinical MCI subtypes. We studied a community sample of 980 dementia-free individuals aged 75 years or older who participated in the Leipzig Longitudinal Study of the Aged (LEILA 75+). All participants were examined by neuropsychological testing based on 6 years of observation. The diagnoses of the four clinical MCI subtypes were made according to the original and to slightly modified criteria by Petersen et al. (2001) (both with a cutoff of 1.0 SD and with a cutoff of 1.5 SD). The complete range of outcome types (dementia, death, improvement, stable diagnosis, unstable diagnosis) was described for all subtypes. The relative predictive power of stable MCI for dementia onset was determined. MCI-single domain is more frequent than MCI-multiple domains, and the nonamnestic MCI type is as frequent as the amnestic MCI type. The "MCI modified, 1.0 SD" criteria have the highest relative predictive power for the development of dementia (sensitivity = 74%, specificity = 73%). Alzheimer disease (AD) was the most common type of dementia at follow-up in all but one MCI subtype. Participants with nonamnestic MCI-multiple domains were more likely to progress to a non-AD dementia. It has been assumed that each MCI subtype is associated with an increased risk for a particular type of dementia. We can only partially agree with this.


Advances in Rational Protein Engineering toward Functional Architectures and Their Applications in Food Science.
Protein biomolecules including enzymes, cagelike proteins, and specific peptides have been continuously exploited as functional biomaterials applied in catalysis, nutrient delivery, and food preservation in food-related areas. However, natural proteins usually function well in physiological conditions, not industrial conditions, or may possess undesirable physical and chemical properties. Currently, rational protein design as a valuable technology has attracted extensive attention for the rational engineering or fabrication of ideal protein biomaterials with novel properties and functionality. This article starts with the underlying knowledge of protein folding and assembly and is followed by the introduction of the principles and strategies for rational protein design. Basic strategies for rational protein engineering involving experienced protein tailoring, computational prediction, computation redesign, and de novo protein design are summarized. Then, we focus on the recent progress of rational protein engineering or design in the application of food science, and a comprehensive summary ranging from enzyme manufacturing to cagelike protein nanocarriers engineering and antimicrobial peptides preparation is given. Overall, this review highlights the importance of rational protein engineering in food biomaterial preparation which could be beneficial for food science.


Adrenergic nerves and the delay phenomenon.
The present study indicates that adrenergic nerves can in part explain the delay phenomenon. Data presented suggest that degeneration in release of norepinephrine might be deleterious to critical parts of a skin flap. This could be avoided by performing a delay procedure, as no release of norepinephrine will occur after the second operation.


Gastrointestinal nematodes and the deworming of mouflon (Ovis aries musimon) from Goleniowska Forest in West Pomerania province, Poland
Ruminants often live in environments where the natural balance has been disturbed by humans. As a result, there is a transfer of parasitosis to domestic animals and sometimes humans. The aim of the study was to determine the annual species composition and level of gastrointestinal nematode infection of mouflon (Ovis aries musimon) from the half-open breeding colonizing areas of the Goleniowska Forest, and to assess the effectiveness of deworming. The course of the parasitic infection of mouflon depends largely on geoclimatic and breeding factors. These diseases are caused by more than 17 species of nematodes with varying degrees of pathogenicity. Due to the high degree of parasitic infections in deer, both in Poland and abroad, it is necessary to develop specific preventive programs using preparations with a broad spectrum of action.


Coronary Artery Bypass Grafting with Arterial Grafts in Patients with Kawasaki Disease Affecting the Coronary Artery: a Korean Single-Center Study.
This study aimed to review the long-term clinical outcomes and graft patency of coronary artery bypass grafting (CABG) using arterial grafts in patients with Kawasaki disease (KD) affecting the coronary artery. Twenty patients with KD who underwent CABG from January 2002 to June 2014 were enrolled. There were 4 male (20%) and 16 female (80%) patients with ages at operation ranging from 2 to 42 years (median, 17.5 years). Our routine operative strategy was off-pump CABG with arterial grafts. The mean follow-up duration was 59.5 ± 48.5 months (range, 1-159 months). Coronary angiogram or computed tomography angiogram was used to evaluate graft patency in 16 patients (80%). All patients survived CABG without late mortality. Left internal thoracic arteries were used in 19 patients, while right internal thoracic arteries were used in 10 patients. Right gastroepiploic arteries were used in 3 patients, and a saphenous vein graft (SVG) was used in 1 patient. Among the 20 patients, 2 patients underwent coronary reintervention with balloon angioplasty because of graft failure. Two patients underwent coronary reintervention because of new obstructive lesions that were not significant at the time of the initial operation. Patency rates at 5 and 10 years were 94% and 87%, respectively. The rate of freedom from coronary reintervention at 10 years was 82%. Off-pump CABG with mainly arterial graft revascularization may be considered a good surgical option for coronary lesions caused by KD.


Lifestyle risk factors for atherosclerosis in adults with type 1 diabetes.
The objective of this study was to compare the amount of self-reported physical activity, alcohol and tobacco use in a large sample of adults with type 1 diabetes and non-diabetic subjects. A second aim is to test the hypothesis that these lifestyle risk factors are associated cross-sectionally with coronary artery calcification. In 2000-2002, the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study applied validated questionnaires for smoking, alcohol and physical activity to 582 type 1 diabetes subjects and 724 non-diabetic subjects. More type 1 diabetes subjects reported current smoking than non-diabetic subjects (12.3% versus 8.6%, p=0.027). Overall, reported physical activity did not differ by diabetes status (p=0.79). More type 1 diabetes subjects reported never having consumed alcohol (10% versus 4%, p<0.0001) and those who drank consumed less alcohol (p=0.0015) than non-diabetic subjects. Physical activity and smoking were significantly associated with the presence of coronary artery calcification (adjusted OR=0.9, 95% CI: 0.8-0.996, p=0.045, and OR=1.7, CI: 1.1-2.6, p=0.03, respectively). Type 1 diabetes was independently associated with increased odds of coronary artery calcification (OR=3.5, 95% CI: 2.5-5.0, p<0.0001). Differences exist in lifestyle-related cardiovascular risk factors in men and women with type 1 diabetes compared with non-diabetic subjects in the CACTI study.


[Mammographic screening: results and perspectives in evaluation of reproductive health and prevention of cancer].
8542 local women, aged over 40, were screened using digital high-sensitivity equipment. High incidence of hormonal dysfunction of the breast and other breast diseases in healthy subjects were reported (60.1% +/- 9.3) (diffuse hormonal dysfunction--33.8% +/- 14.6). Early breast tumors (up to 1 cm), which generally remain undetectable, amounted to 0.19%. It was shown that mammographic data may be used in forming groups of risk for pre-morbid or morbid pathology among those requiring etiotropic therapy. In this connection, the role of timely medical advice can hardly be overestimated.


Cyclic GMP-specific phosphodiesterase-5 regulates motility of sea urchin spermatozoa.
Motility, chemotaxis, and the acrosome reaction of animal sperm are all regulated by cyclic nucleotides and protein phosphorylation. One of the cyclic AMP-dependent protein kinase (PKA) substrates in sea urchin sperm is a member of the phosphodiesterase (PDE) family. The molecular identity and in vivo function of this PDE remained unknown. Here we cloned and characterized this sea urchin sperm PDE (suPDE5), which is an ortholog of human PDE5. The recombinant catalytic domain of suPDE5 hydrolyzes only cyclic GMP (cGMP) and the activity is pH-dependent. Phospho-suPDE5 localizes mainly to sperm flagella and the phosphorylation increases when sperm contact the jelly layer surrounding eggs. In vitro dephosphorylation of suPDE5 decreases its activity by approximately 50%. PDE5 inhibitors such as Viagra block the activity of suPDE5 and increase sperm motility. This is the first PDE5 protein to be discovered in animal sperm. The data are consistent with the hypothesis that suPDE5 regulates cGMP levels in sperm, which in turn modulate sperm motility.


Topical treatment modalities for old world cutaneous leishmaniasis: a review.
Diagnosis and therapy of cutaneous leishmaniasis (CL) can be difficult due to the variability of the clinical pictures and resistance to therapy. There is no vaccine currently available for CL. The aim of the present review is to describe different topical treatment modalities for old world CL. The mainstays of treatment for old world CL are pentavalent antimony compounds which are administered parenterally or intralesionally. New topical treatment alternatives have been available within the past few years. Amongst several treatments used topically, physical therapies including cryotherapy, heat therapy and CO2 laser are promising for the treatment of old world CL. Along with that, other randomized placebo controlled trials should be designed to find new effective therapeutic regimens.


Beyond Genes: Inclusion of Alternative Splicing and Alternative Polyadenylation to Assess the Genetic Architecture of Predisposition to Voluntary Alcohol Consumption in Brain of the HXB/BXH Recombinant Inbred Rat Panel.
Post transcriptional modifications of RNA are powerful mechanisms by which eukaryotes expand their genetic diversity. For instance, researchers estimate that most transcripts in humans undergo alternative splicing and alternative polyadenylation. These splicing events produce distinct RNA molecules, which in turn yield distinct protein isoforms and/or influence RNA stability, translation, nuclear export, and RNA/protein cellular localization. Due to their pervasiveness and impact, we hypothesized that alternative splicing and alternative polyadenylation in brain can contribute to a predisposition for voluntary alcohol consumption. Using the HXB/BXH recombinant inbred rat panel (a subset of the Hybrid Rat Diversity Panel), we generated over one terabyte of brain RNA sequencing data (total RNA) and identified novel splice variants (via StringTie) and alternative polyadenylation sites (via aptardi) to determine the transcriptional landscape in the brains of these animals. After establishing an analysis pipeline to ascertain high quality transcripts, we quantitated transcripts and integrated genotype data to identify candidate transcript coexpression networks and individual candidate transcripts associated with predisposition to voluntary alcohol consumption in the two-bottle choice paradigm. For genes that were previously associated with this trait (e.g., Lrap, Ift81, and P2rx4) (Saba et al., Febs. J., 282, 3556-3578, Saba et al., Genes. Brain. Behav., 20, e12698), we were able to distinguish between transcript variants to provide further information about the specific isoforms related to the trait. We also identified additional candidate transcripts associated with the trait of voluntary alcohol consumption (i.e., isoforms of Mapkapk5, Aldh1a7, and Map3k7). Consistent with our previous work, our results indicate that transcripts and networks related to inflammation and the immune system in brain can be linked to voluntary alcohol consumption. Overall, we have established a pipeline for including the quantitation of alternative splicing and alternative polyadenylation variants in the transcriptome in the analysis of the relationship between the transcriptome and complex traits.


Light diffusion through a turbid parallelepiped.
Solutions of the diffusion approximation to the radiative transport equation are derived for a turbid (rectangular) parallelepiped using the method of image sources and applying extrapolated boundary conditions. The derived solutions are compared with Monte Carlo simulations in the steady-state and time domains. It is found that the diffusion theory is in good agreement with Monte Carlo simulations provided that the light is detected sufficiently far from the incident beam. Applications of the derived solutions, including the determination of the optical properties of the turbid parallelepiped, are discussed.


PHYLOGEOGRAPHY OF THE SARDINES (SARDINOPS SPP.): ASSESSING BIOGEOGRAPHIC MODELS AND POPULATION HISTORIES IN TEMPERATE UPWELLING ZONES.
Sardines (Sardinops spp.) occupy temperate upwelling zones in the coastal regions of the Indian and Pacific Oceans, including locations in Japan, California, Chile, Australia, and South Africa. East and West Pacific populations are separated by vast expanses of open ocean, and northern and southern hemisphere populations are separated by tropical waters which are lethal to sardines. The relative importance of these barriers has been the focus of a longstanding debate between vicariance and dispersal schools in biogeography. Comparisons of a 500 bp fragment of the mitochondrial (mt) DNA control region reveal strong geographic structuring of mtDNA lineages but shallow divergence both within and between regional populations. Regional populations are related to one another in a stepping-stone pattern, the apparent result of a series of Pleistocene dispersal events around the continental margins of the Indian-Pacific Basin. These mtDNA data, combined with an electrophoretic survey of variability at 34 nuclear loci (Grant and Leslie 1996), indicate that the five regional forms of Sardinops (considered separate taxa by most authorities) probably diverged within 500,000 years BP, a much shorter timeframe than predicted by vicariance models based on plate tectonics. High mtDNA haplotype diversity, coupled with an excess of rare alleles in the protein electrophoretic dataset, may indicate exponential growth from a small ancestral population. The mtDNA and allozyme data are concordant with climate records and fossil evidence in portraying regional populations as recent, unstable, and ephemeral. Regional populations of sardines have probably been extinguished and recolonized over short evolutionary timescales in response to changes in climate and the oceanography of coastal upwelling zones.


A hospital-based matched case-control study to identify risk factors for clinical infection with OXA-48-producing Klebsiella pneumoniae in rectal carriers.
Asymptomatic colonisation of the gastrointestinal tract by carbapenemase-producing Enterobacteriaceae is an important reservoir for transmission, which may precede infection. This retrospective observational case-control study was designed to identify risk factors for developing clinical infection with OXA-48-producing Klebsiella pneumoniae in rectal carriers during hospitalisation. Case patients (n = 76) had carbapenemase-producing K. pneumoniae (CPKP) infection and positive rectal culture for CPKP. Control patients (n = 174) were those with rectal colonisation with CPKP but without CPKP infection. Multivariate analysis identified the presence of a central venous catheter (OR 4·38; 95% CI 2·27-8·42; P = 0·008), the number of transfers between hospital units (OR 1·27; 95% CI (1·06-1·52); P < 0·001) and time at risk (OR 1·02 95% CI 1·01-1·03; P = 0·01) as independent risk factors for CPKP infection in rectal carriers. Awareness of these risk factors may help to identify patients at higher risk of developing CPKP infection.


Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients.
The prevalence of BRCA1/2 variants in Chinese breast cancer patients varies among studies. Germline or somatic BRCA1/2 mutations are associated with sensitivity to poly(ADP-ribose) polymerase-1 inhibitors and DNA-damaging agents. We aimed to investigate the distribution of both somatic and germline BRCA1/2 variants in unselected Chinese breast cancer patients, and explore their roles in tumor phenotype and disease prognosis. 507 breast cancer patients, unselected for family history of breast cancer or age at diagnosis, were prospectively enrolled from West China Hospital between Feb. 2008 and Feb. 2014. BRCA1/2 variants in the exons/flanking regions were detected in fresh-frozen tumors using next-generation sequencing and confirmed by independent methods. Germline/somatic status was validated by Sanger sequencing in paired blood/normal tissue. BRCA1/2 pathogenic or likely pathogenic (P/LP) variants were detected in 50 patients (9.9%), including 40 germline carriers (18 in BRCA1, 22 in BRCA2), 9 patients with somatic variants (3 in BRCA1, 6 in BRCA2), and 1 patient with concurrent germline/somatic variants in BRCA2. The triple-negative (21.4%) and Luminal B (9.7%) subtypes had higher rates of BRCA1/2 variants. In patients with disease stage 0~II, presence of a germline or somatic BRCA1 P/LP variant increased the risk of relapse as compared to non-carriers [univariate hazard ratio (HR): 3.70, P = 0.04]. Germline BRCA1 P/LP variants, which were associated with aggressive tumor phenotypes, predicted worse disease-free survival in the subgroup of stage 0~II (HR: 4.52, P = 0.02) and N0 (HR: 5.4, P = 0.04) compared to non-carriers. A high frequency of germline and somatic BRCA1/2 P/LP variants was detected in unselected Chinese breast cancer patients. Luminal B subtype should be considered as a high-risk population of BRCA1/2 mutation, in addition to triple-negative breast cancer. BRCA1 status was associated with aggressive tumor phenotype and worse disease progression in early stage breast cancer patients.


Reactions of psychiatric outpatients to teaching interviews.
In an attempt to assess some of the reactions of psychiatric outpatients attending a teaching clinic, a group of patients who received a letter warning them of the possible presence of students were compared with a group who did not receive such a letter. The "letter" group were generally more satisfied with their interview and were less likely to say that they had consciously withheld information. Greater satisfaction was also expressed by patients over 35.When asked whether they preferred to see one student in private and then the psychiatrist with a small group of other students, or to have the whole interview conducted by the psychiatrist in front of the group, patients expressed a clear preference for the former choice. This former method may also allow more responsible and active participation by the students.


[Cuproptosis-related lncRNAs to predict biochemical recurrence of prostate cancer].
To construct a cuproptosis-related lncRNA model and obtain some new ideas and methods for predicting the biochemical recurrence (BCR) of PCa. We identified cuproptosis-related lncRNAs from the gene expression data, mutation load data and clinical data on PCa patients in the Cancer Genome Atlas (TCGA) database and divided the patients into a training group and a verification group. We constructed a prognostic risk scoring model based on the cuproptosis -related lncRNAs, verified the validity of the model by BCR-free survival analysis, logistic regression analysis and independent prognosis analysis, and visualized the results using ROC curve analysis, Kaplan-Meier survival curves and the correlation heat map. We performed differential analysis and survival analysis of the tumor mutation burden (TMB), and assessed the value of the model and TMB in predicting the BCR of PCa. A prognostic risk scoring model was successfully constructed based on the 6 cuproptosis -related lncRNAs identified from the PCa cases in the training group, which were divided into a high- and a low-risk groups according to the median value. The incidence of BCR rose with the increase of the risk score, and the BCR-free time was significantly shorter in the high-risk group (P < 0.05). The model also exhibited a high differentiation value in different age groups (P < 0.05), which was shown to be a reliable and independent prognostic indicator for predicting the BCR of PCa, even more valuable than other clinicopathological indicators. TMB was differentially expressed in the high- and low-risk groups (P < 0.01) and significantly correlated with BCR. The highest rate of BCR-free survival was found in the patients with low risk scores and low TMB (P < 0.01). A cuproptosis -related lncRNA model was successfully constructed, which can accurately predict the risk of BCR in PCa patients. The higher the prognostic risk score, the greater the possibility of BCR. TMB is high in patients with a high risk, and the TMB level has certain suggestive significance for BCR.


Autosomal dominant inheritance of Weaver syndrome.
Most report of Weaver syndrome have been sporadic cases and the genetic basis of the syndrome is uncertain. This report of an affected father and daughter provides evidence for autosomal dominant inheritance.


Characterization of Industrial Coolant Fluids and Continuous Ageing Monitoring by Wireless Node-Enabled Fiber Optic Sensors.
Environmentally robust chemical sensors for monitoring industrial processes or infrastructures are lately becoming important devices in industry. Low complexity and wireless enabled characteristics can offer the required flexibility for sensor deployment in adaptable sensing networks for continuous monitoring and management of industrial assets. Here are presented the design, development and operation of a class of low cost photonic sensors for monitoring the ageing process and the operational characteristics of coolant fluids used in an industrial heavy machinery infrastructure. The chemical, physical and spectroscopic characteristics of specific industrial-grade coolant fluids were analyzed along their entire life cycle range, and proper parameters for their efficient monitoring were identified. Based on multimode polymer or silica optical fibers, wide range (3-11) pH sensors were developed by employing sol-gel derived pH sensitive coatings. The performances of the developed sensors were characterized and compared, towards their coolants' ageing monitoring capability, proving their efficiency in such a demanding application scenario and harsh industrial environment. The operating characteristics of this type of sensors allowed their integration in an autonomous wireless sensing node, thus enabling the future use of the demonstrated platform in wireless sensor networks for a variety of industrial and environmental monitoring applications.


Decoding agency attribution using single trial error-related brain potentials.
Being able to distinguish between self and externally generated actions is a key factor influencing learning and adaptive behavior. Previous literature has highlighted that whenever a person makes or perceives an error, a series of error-related potentials (ErrPs) can be detected in the electroencephalographic (EEG) signal, such as the error-related negativity (ERN) component. Recently, ErrPs have gained a lot of interest for the use in brain-computer interface (BCI) applications, which give the user the ability to communicate by means of decoding his/her brain activity. Here, we explored the feasibility of employing a support vector machine classifier to accurately disentangle self-agency errors from other-agency errors from the EEG signal at a single-trial level in a sample of 23 participants. Our results confirmed the viability of correctly disentangling self/internal versus other/external agency-error attributions at different stages of brain processing based on the latency and the spatial topographical distribution of key ErrP features, namely, the ERN and P600 components, respectively. These results offer a new perspective on how to distinguish self versus externally generated errors providing new potential implementations on BCI systems.


Fast screening of Bifidobacterium longum sublethal stress conditions in a novel two-stage continuous culture strategy.
A central issue in the application of probiotics as food additives is their fastidious production and their sensitivity to many environmental stresses. The importance of inducible cell-protective mechanisms triggered by application of sublethal stresses for survival under stress conditions has been demonstrated. Continuous cultures could be a suitable and more efficient method to test stress factors on one culture instead of several repeated batch cultures. In this study, the application of a two-stage continuous culture of Bifidobacterium longum NCC2705 was investigated. The first reactor was operated under fixed conditions at 37 °C and pH 6.0 and used to produce cells with controlled physiology, mimicking cells in the late exponential growth phase. Stress pretreatment combinations of pH (6.0, 5.0 and 4.0), temperature (37, 45 and 47 °C) and NaCl (0, 5 and 10%) were tested in the second reactor. Of all tested combinations, only those of pH 4.0 significantly decreased cell viability in the second reactor compared to control conditions (37 °C, pH 6.0, 0% NaCl) and, therefore, could not be considered as sublethal stresses. Pretreatments with 5 or 10% NaCl had a negative effect on cell viability after gastric lethal stress. A significant improvement in cell resistance to heat lethal stress (56 °C, 5 min) was observed for cells pretreated at 47 °C. In contrast, heat pretreatment negatively affected cell viability after freeze drying and osmotic lethal stresses. The two-stage continuous culture allowed for efficient screening of several stress pretreatments during the same experiment with up to four different conditions tested per day. Optimal sublethal stress conditions can also be applied for producing cells with traditional batch cultures.


Arthritis associated with adjuvant mycobacterial treatment for carcinoma of the bladder.
A patient who developed an inflammatory polyarthritis following intravesical administration of bacillus Calmette-Guérin (BCG) used in the treatment of bladder cancer is described. An inflammatory synovitis comprising predominantly T lymphocytes was demonstrated on synovial biopsy. The synovitis resolved spontaneously within 14 days in this 'human model' of adjuvant arthritis.


Eptifibatide: a review of its use in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention.
Eptifibatide (Integrilin) is a highly specific, reversible, intravenously administered glycoprotein (GP) IIb/IIIa receptor antagonist that acts at the final common step of the platelet aggregation pathway. Data from large clinical trials indicate that intravenous eptifibatide as adjunctive therapy to standard care is effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI). In the ESPRIT (Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy) trial in patients undergoing PCI with stenting, eptifibatide, compared with placebo, achieved significant reductions in death and ischaemic complications and was better than a strategy of reserving treatment for the bailout situation. In the large PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial in patients with NSTE ACS, eptifibatide was associated with a significant reduction in the incidence of death or myocardial infarction (MI) compared with placebo. Eptifibatide is well tolerated in these trials. Ongoing trials are currently investigating the efficacy and tolerability of regimens that include this agent in other indications, including ST-segment elevation MI (STEMI).


Ethics, deception, and 'Those Milgram experiments'.
Critics who allege that deception in psychology experiments is unjustified frequently cite Stanley Milgram's 'obedience experiments' as evidence. These critics say that arguments for justification tend to downplay the risks involved and overstate the benefits from such research. Milgram, they add, committed both sins. Critics are right to point out that research oversight is often susceptible to self-serving abuse. But stating a priori how beneficial a given experiment will be is a tall order for psychologists, or anyone else. At the same time, critics themselves have difficulty in showing what is wrong with deception, and how subjects in these experiments suffer. Hence, it becomes unclear what the psychologists, including Milgram, are prone to downplay. There is also room to wonder how the Milgram studies can illuminate the debate over deception. Although Milgram probably exaggerated the scientific significance of his own work, critics who exaggerate its moral and historical significance do little to clarify the status of deception.


Threshold-Based Ordering of Sequential Actions during Drosophila Courtship.
Goal-directed animal behaviors are typically composed of sequences of motor actions whose order and timing are critical for a successful outcome. Although numerous theoretical models for sequential action generation have been proposed, few have been supported by the identification of control neurons sufficient to elicit a sequence. Here, we identify a pair of descending neurons that coordinate a stereotyped sequence of engagement actions during Drosophila melanogaster male courtship behavior. These actions are initiated sequentially but persist cumulatively, a feature not explained by existing models of sequential behaviors. We find evidence consistent with a ramp-to-threshold mechanism, in which increasing neuronal activity elicits each action independently at successively higher activity thresholds.


Biosynthesis of Arginine and Polyamines.
Early investigations on arginine biosynthesis brought to light basic features of metabolic regulation. The most significant advances of the last 10 to 15 years concern the arginine repressor, its structure and mode of action in both E. coli and Salmonella typhimurium, the sequence analysis of all arg structural genes in E. coli and Salmonella typhimurium, the resulting evolutionary inferences, and the dual regulation of the carAB operon. This review provides an overall picture of the pathways, their interconnections, the regulatory circuits involved, and the resulting interferences between arginine and polyamine biosynthesis. Carbamoylphosphate is a precursor common to arginine and the pyrimidines. In both Escherichia coli and Salmonella enterica serovar Typhimurium, it is produced by a single synthetase, carbamoylphosphate synthetase (CPSase), with glutamine as the physiological amino group donor. This situation contrasts with the existence of separate enzymes specific for arginine and pyrimidine biosynthesis in Bacillus subtilis and fungi. Polyamine biosynthesis has been particularly well studied in E. coli, and the cognate genes have been identified in the Salmonella genome as well, including those involved in transport functions. The review summarizes what is known about the enzymes involved in the arginine pathway of E. coli and S. enterica serovar Typhimurium; homologous genes were identified in both organisms, except argF (encoding a supplementary OTCase), which is lacking in Salmonella. Several examples of putative enzyme recruitment (homologous enzymes performing analogous functions) are also presented.


Challenges of antibiotic prescribing for assisted living residents: perspectives of providers, staff, residents, and family members.
To better understand the antibiotic prescribing process in assisted living (AL) communities given the growing rate of antibiotic resistance. Cross-sectional survey. Four AL communities in North Carolina. Assisted living residents who received antibiotics (n = 30) from October 20, 2010, to March 31, 2011, a primary family member, staff, and the prescribing medical provider. Semistructured interviews that were conducted regarding prescribing included the information available at the time of prescribing and the perceptions of the quality of communication between providers, staff, residents and family members about the resident. Providers were asked an open-ended question regarding how to improve the communication process related to antibiotic prescribing for AL residents. For the 30 residents who received antibiotic prescriptions, providers often had limited information about the case and lacked familiarity with the residents, the residents' families, and staff. They also felt that cases were less severe and less likely to require an antibiotic than did residents, families, and staff. Providers identified several ways to improve the communication process, including better written documentation and staff and family presence. In a small sample of AL communities, providers faced an array of challenges in making antibiotic prescribing decisions. This work confirms the complex nature of antibiotic prescribing in AL communities and indicates that further work is needed to determine how to improve the appropriateness of antibiotic prescribing.


Quality assurance of histamine analysis in fresh and canned fish.
Histamine determination is relevant for fish safety, quality and trade. Recently a study by the European Union (EU) compared the Codex and the EU mandated methods for the analysis of histamine and observed that they underestimated and overestimated the results, respectively. To solve this problem, a simple and efficient procedure for the extraction and quantification of histamine by ion-pair HPLC method with post-column derivatization and fluorimetric detection is proposed. It was optimized and validated for the analysis of histamine in fish. The method attended the performance criteria established by Commission Decision 2002/657/CE. The method was also submitted to proficiency testing; uncertainty was calculated; and the stability of solutions and standards was investigated. There was no matrix effect. The LOD, LOQ, CCα and CCβ were fit for the purpose. The method was successfully used in the analyses of freshwater fish and fresh and canned tuna.


Patterns of Time Use across the Chronic Obstructive Pulmonary Disease Severity Spectrum.
Descriptions of time use patterns in people with chronic obstructive pulmonary disease (COPD) are scarce and the relationship between use-of-time and COPD severity remains unclear. This study aimed to describe a typical day for people with COPD and to explore the differences in time-use patterns across the Body Mass-Index, Airflow Obstruction, Dyspnoea and Exercise Capacity (BODE) index using compositional analyses. Using a cross-sectional design, 141 adults with clinically stable COPD had their demographics, objective measures of function (pulmonary, exercise capacity and physical activity), and self-reported COPD-related impairment recorded. Daily time-use compositions were derived from 24-h accelerometry and 24-h use-of-time recall interviews. Compositional multiple linear regression models were used to explore the relationship between the BODE index and 24-h time-use compositions. These models were used to predict daily time (min/d) that is spent in time-use components across the BODE index. The BODE index score was clearly associated with 24-h accelerometry (p < 0.0001) and 24-h use-of-time recall (p < 0.0001) compositions. Relative to the remaining time-use components, higher BODE index scores were associated with greater sedentary behaviour (p < 0.0001), Quiet time (p < 0.0001), Screen time (p = 0.001) and Self-care (p = 0.022), and less daily Chores (p < 0.0001) and Household administration (p = 0.015) time. As the BODE index scores increased, time-use predictions were strongly associated with decreases in Chores (up to 206 min/d), and increases in Screen (up to 156 min/d) and Quiet time (up to 131 min/d). Time-use patterns may provide a basis for planning interventions relative to the severity of COPD.


The regulation of growth and development of normal and leukaemic cells.
Numerous significant advances have been made in recent years in understanding those factors and conditions which influence the growth and differentiation of haemopoietic cells. This communication is primarily concerned with defining lineage-independent and lineage-restricted growth factors and some of the aberrations which may be involved in leukaemia.


Does arm lengthening affect the functional outcome in onlay reverse shoulder arthroplasty?
The concept of onlay design reverse shoulder arthroplasty has been introduced to overcome complications observed with the traditional Grammont-type prosthesis. The aim of this study was to determine the influence of arm lengthening on the short-term clinical outcome in onlay reverse shoulder arthroplasty and investigate the effect of humeral tray offset positioning on arm lengthening and range of motion. We retrospectively evaluated 56 patients undergoing reverse shoulder arthroplasty with the Aequalis Ascend Flex prosthesis (Tornier, Bloomington, MN, USA) at a minimum 2 years' follow-up. Arm lengthening was determined using bilateral scaled radiographs of the entire humerus. The Constant score and active range of motion were documented preoperatively and postoperatively. The relationship between arm lengthening, humeral tray offset position, and functional outcome was analyzed. The Constant score improved from 25.5 ± 9.5 points to 71.5 ± 13.8 points at a mean follow-up of 30.1 ± 5.2 months. Mean postoperative anterior elevation was 145.2° ± 21.1°, and external rotation was 30.7° ± 20.3°. Arm lengthening exceeding 2.5 cm was related to a decrease in anterior elevation. We found a relationship between arm lengthening averaging 2.2 ± 1.7 cm and increased Constant score values. Humeral tray positioning demonstrated no influence on the functional outcome. There was a trend toward increased arm lengthening in lateral offset positioning. Onlay reverse shoulder arthroplasty yields good short-term clinical results. In our population, arm lengthening averaging 1 to 2.5 cm was found to be the best compromise on postoperative range of motion.