Photosynthetic reaction center as a quantum heat engine.
Two seemingly unrelated effects attributed to quantum coherence have been reported recently in natural and artificial light-harvesting systems. First, an enhanced solar cell efficiency was predicted and second, population oscillations were measured in photosynthetic antennae excited by sequences of coherent ultrashort laser pulses. Because both systems operate as quantum heat engines (QHEs) that convert the solar photon energy to useful work (electric currents or chemical energy, respectively), the question arises whether coherence could also enhance the photosynthetic yield. Here, we show that both effects arise from the same population-coherence coupling term which is induced by noise, does not require coherent light, and will therefore work for incoherent excitation under natural conditions of solar excitation. Charge separation in light-harvesting complexes occurs in a pair of tightly coupled chlorophylls (the special pair) at the heart of photosynthetic reaction centers of both plants and bacteria. We show the analogy between the energy level schemes of the special pair and of the laser/photocell QHEs, and that both population oscillations and enhanced yield have a common origin and are expected to coexist for typical parameters. We predict an enhanced yield of 27% in a QHE motivated by the reaction center. This suggests nature-mimicking architectures for artificial solar energy devices.


Sperm competition in tropical versus temperate zone birds.
Sperm competition represents an important component of post-copulatory sexual selection. It has been argued that the level of sperm competition declines in birds towards the equator. However, to date, sperm competition estimates have been available mainly for avian species inhabiting the northern temperate zone. Here we apply a novel approach, using the coefficient of between-male variation (CV(bm)) in sperm size as an index for sperm competition risk, in a comparative analysis of 31 Afrotropical and 99 northern temperate zone passerine species. We found no difference in sperm competition risk between the two groups, nor any relationship with migration distance. However, a multivariate model indicated that sperm competition risk was highest in species with a combination of low body mass and few eggs per clutch. The effect of clutch size was most pronounced in tropical species, which indicates that sperm competition risk in tropical and temperate species is differently associated with particular life-history traits. Although tropical species had lower sperm competition risk than temperate zone species for overlapping clutch sizes, the idea of a generally reduced risk of sperm competition in tropical birds was not supported by our analysis.


Are people with mild dementia able to (re)learn how to use technology? A literature review.
There is growing evidence that people with mild dementia can benefit from using tablets and apps. Due to their cognitive decline, people with dementia need support in learning how to use these devices. The objective of this review was to identify which training interventions work best to help people with mild dementia (re)learn how to use technologies, including handheld touchscreen devices. Because the uptake of these devices in people with dementia is quite new, training interventions for the use of other technologies were also included, such as technologies assisting people in Instrumental Activities of Daily Living (IADL). An electronic search was conducted in the following databases: PubMed, APA PsycInfo (EBSCO), and CINAHL (EBSCO). Themes discussed include the learning effects; training method (e.g. errorful (EF) and errorless (EL) learning); training intensity and setting; technology task type; dementia type and severity; and study design and outcome measures. In total, 16 studies were included. All studies reported positive learning effects and improved task performance in people with dementia, regardless of dementia severity, training intensity, setting, and the method used. Although the EL training method was successful more often than the EF training method, it would be inappropriate to conclude that the EL method is more effective, because the majority of studies only investigated EL training interventions with (multiple) single-case study designs. Future research should consider using more robust study designs, such as RCTs, to evaluate the effectiveness of training interventions for (re)learning technology-orientated tasks, including operating handheld touchscreen devices.


Protein kinase C δ-dependent regulation of Ubiquitin-proteasome system function in breast cancer.
Besides the crucial role of hyperinsulinemia in the development of breast cancer with Type 2 diabetes mellitus (T2DM), it has been shown that hyperglycemia could contribute to promote cancer progression. A remarkable association within hyperglycemia, PKCδ and Ubiquitin-proteasome system (UPS) has been reported, suggesting that PKCδ may mediate high glucose-induced UPS activation in breast cancer cells. Although the independent effects of PKCδ or UPS on breast cancer and T2DM are increasingly supported by experimental evidence, the complex interactional link between PKCδ and UPS is still unclear. Hence, we focus on the relationship between PKCδ and UPS in breast cancer with T2DM. We hypothesize that PKCδ may have the function to regulate the activity of UPS. Further, we speculate that PKCδ combine with proteasome α2 promoter, that indicate PKCδ regulate the function of UPS by change the composition of proteasome. Therefore, we surmise that PKCδ mediated high glucose-induced UPS activation in breast cancer cells, and specific PKCδ inhibitor rottlerin significantly suppressed elevated glucose induced the activity of UPS. We hope that our paper will stimulate further studies the relationship between PKCδ and UPS, and a new targeted therapy and early medical intervention for PKCδ could be a useful option for breast cancer cases complicated with T2DM or hyperglycemia.


Protein quality of feeding-stuffs. 7. Collaborative studies on the microbiological assay of available amino acids.
1. Twenty-two samples of high-protein feeding-stuffs, sixteen of them fish meals, were used in a collaborative study of the precision and the limits of discrimination of the Streptococcus zymogenes assay procedure, as applied to the estimation of available methionine, tryptophan and isoleucine contents. 2. All the participating laboratories ranked the test samples in much the same sequence with respect to content for all three amino acids. There were apparently systematic differences between laboratories which impaired the precision of some of the estimates, and these were greatly reduced by including common reference sample in the tests as an auxilliary standard. 3. Values for available methionine content for eleven test samples were highly correlated (r 0.86) and quantitatively similar to those obtained for chick growth assays, but those for available tryptophan content were markedly lower and were probably in error.


A unifying framework for multi-criteria fluence map optimization models.
Models for finding treatment plans for intensity modulated radiation therapy are usually based on a number of structure-based treatment plan evaluation criteria, which are often conflicting. Rather than formulating a model that a priori quantifies the trade-offs between these criteria, we consider a multi-criteria optimization approach that aims at finding the so-called undominated treatment plans. We present a unifying framework for studying multi-criteria optimization problems for treatment planning that establishes conditions under which treatment plan evaluation criteria can be transformed into convex criteria while preserving the set of undominated treatment plans. Such transformations are identified for many of the criteria that have been proposed to date, establishing equivalences between these criteria. In addition, it is shown that the use of a nonconvex criterion can often be avoided by transformation to an equivalent convex criterion. In particular, we show that models employing criteria such as tumour control probability, normal tissue complication probability, probability of uncomplicated tumour control, as well as sigmoidal transformations of (generalized) equivalent uniform dose are equivalent to models formulated in terms of separable voxel-based criteria that penalize dose in individual voxels.


The mortality of boot and shoe makers, with special reference to cancer.
The study describes the mortality of 5 017 men known to have been employed in the boot and shoe manufacturing industry in three towns in Great Britain in 1939. At the end of 1982, 97.5% of the men were traced, and 3 434 (68.4%) were known to be dead. Expected numbers were calculated according to the person-years method and were adjusted according to the standardized mortality ratios of the counties in which the towns were situated. The mortality experience of the men for all causes, all cancers combined, and all other causes was favorable. The anticipated excess of deaths from nasal cancer (10 observed, 1.87 expected) was found, and the excess was significant for workers in the finishing room. Deficits were found for other types of respiratory cancer. An excess mortality from leukemia was found for workers in one town (7 observed, 3.0 expected), and the excess was significant for workers in the lasting and making room, where glues and solvents, including benzene, were known to have been used. An excess mortality from rectal cancer was found for workers in two towns (61 observed, 47.6 expected), and it was significant for workers in the lasting and making rooms (25 observed, 12.4 expected). Some supporting evidence for a risk of rectal cancer in this industry was found in the literature.


[Temporary incapacity and emotional problems].
The author deals with temporary incapacity, as currently expressed by "sick leave." Minor psychiatric problems are involved more and more as a cause of temporary incapacity, and sometimes the duration of such leaves of absence is much longer than might be warranted by the nature of the problem. Challenges by paying agents and employers are more and more frequent. On the basis of literature of a very general nature the author distinguishes between a difficult personal situation, a symptom, an illness, functional limitations and invalidity, the last one being at the crossroads between medical, personal and social reasons. The author emphasizes the particular difficulties experienced by physicians faced with that kind of problem and describes the rapid intervention needed to deal with the underlying reasons for an obvious request for a leave of absence.


Derlin-1 regulates mutant VCP-linked pathogenesis and endoplasmic reticulum stress-induced apoptosis.
Mutations in VCP (Valosin-containing protein), an AAA ATPase critical for ER-associated degradation, are linked to IBMPFD (Inclusion body myopathy with Paget disease and frontotemporal dementia). Using a Drosophila IBMPFD model, we have identified the ER protein Derlin-1 as a modifier of pathogenic TER94 (the fly VCP homolog) mutants. Derlin-1 binds to TER94 directly, and this interaction is essential for Derlin-1 overexpression to suppress the pathogenic TER94-induced neurodegeneration. Derlin-1 overexpression reduces the elevated ATPase activity of pathogenic TER94, implying that IBMPFD is caused by ATPase hyper-activation. Under physiological condition, Derlin-1 expression is increased upon ER stress to recruit TER94 to the ER. However, in response to severe ER stress, Derlin-1 is required for activating apoptosis to eliminate damaged cells. This pro-apoptotic response is mimicked by Derlin-1 overexpression, which elicits acute ER stress and triggers apoptosis via a novel C-terminal motif (α). As this Derlin-1-dependent cell death is negated by TER94 overexpression, we propose that while Derlin-1 and VCP work cooperatively in ER stress response, their imbalance has a role in removing cells suffering prolonged ER stress.


Temperature- and touch-sensitive neurons couple CNG and TRPV channel activities to control heat avoidance in Caenorhabditis elegans.
Any organism depends on its ability to sense temperature and avoid noxious heat. The nematode Caenorhabditis elegans responds to noxious temperatures exceeding ∼35°C and also senses changes in its environmental temperature in the range between 15 and 25°C. The neural circuits and molecular mechanisms involved in thermotaxis have been successfully studied, whereas details of the thermal avoidance behavior remain elusive. In this work, we investigate neurological and molecular aspects of thermonociception using genetic, cell biological and physiological approaches. We show here that the thermosensory neurons AFD, in addition to sensing temperature within the range within which the animals can thrive, also contribute to the sensation of noxious temperatures resulting in a reflex-like escape reaction. Distinct sets of interneurons are involved in transmitting thermonociception and thermotaxis, respectively. Loss of AFD is partially compensated by the activity of a pair of multidendritic, polymodal neurons, FLP, whereas laser ablation of both types of neurons abrogated the heat response in the head of the animals almost completely. A third pair of heat sensory neurons, PHC, is situated in the tail. We find that the thermal avoidance response requires the cell autonomous function of cGMP dependent Cyclic Nucleotide-Gated (CNG) channels in AFD, and the heat- and capsaicin-sensitive Transient Receptor Potential Vanilloid (TRPV) channels in the FLP and PHC sensory neurons. Our results identify distinct thermal responses mediated by a single neuron, but also show that parallel nociceptor circuits and molecules may be used as back-up strategies to guarantee fast and efficient responses to potentially detrimental stimuli.


Effect of growth in low-Na+ medium on transport sites in cultured heart cells.
Increases in intracellular Na+ concentration ([Na+]i) lead to an increase in the number of Na+ pump sites in the cell membrane. To investigate further the role of [Na+]i in the regulation of Na+-K+-ATPase sites, we studied the effect of reduced [Na+]i on the number of Na+ pump sites and Na+-K+ pump activity using spontaneously beating cultured chick ventricular cells. Cells incubated in medium containing 60, 80, 100, or 140 mM Na+ for 24 or 48 h showed an extracellular [Na+]-dependent alteration in cellular Na+ content. The number of Na+ pump sites identified by [3H]ouabain binding binding declined with decreasing levels of Na+ in the medium in a time-dependent manner over 48 h, with a concomitant increase in cellular Na+ content. Verapamil (1 microM) or tetrodotoxin (1 microM) significantly reduced cellular Na+ content by 30 min of exposure and the number of Na+ pump sites by 48 h of incubation. Na+ pump activity determined from the ouabain-sensitive 42K+ uptake rate was significantly reduced in cells grown in low Na+ for 48 h, as was pump capacity, determined in Na+-loaded cells. These results support the view that [Na+]i exerts a long-term modulating effect on the number of physiologically functional Na+ pump sites.


Transcription-dependent nucleocytoplasmic distribution of hnRNP A1 protein in early mouse embryos.
A unique feature of certain members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins is that they shuttle continuously between nucleus and cytoplasm and their accumulation in the nucleus is transcription-dependent. An extensively characterised protein of this group is hnRNP A1. To date, most studies addressing the transcription-dependent transport of hnRNP A1 have been performed on cultured cell lines treated with transcription inhibitors. Here we have analysed the nucleocytoplasmic distribution of hnRNP A1 in early mouse embryos, where the haploid pronuclei remain transcriptionally inactive for a period of several hours. Consistent with its small molecular size (36 kDa), the hnRNP A1 protein diffuses passively through the nuclear pores and equilibrates between the nucleus and the cytoplasm of transcriptionally inactive embryos. In contrast, following transcriptional activation the A1 protein becomes accumulated in the nucleus. This accumulation of the A1 protein in the nucleus is blocked by the lectin wheat germ agglutinin (WGA), which binds to nuclear pore proteins and prevents translocation of receptor-cargo complexes through the pores. This indicates that a carrier-mediated transport pathway is required for the concentration of A1 in transcriptionally active nuclei. To further analyse how transcription is coupled to nucleocytoplasmic transport, we transplanted transcriptionally inactive pronuclei into the cytoplasm of transcriptionally active embryos. The results show that the presence of newly synthesised RNAs in the cytoplasm is not sufficient to induce the accumulation of hnRNP A1 in the nucleus. Rather, the appearance of nascent transcripts in the nucleus appears to be the crucial event. Since hnRNP A1 is a shuttling protein, an increase in its steady state nuclear concentration could be the result of either faster nuclear import or slower export to the cytoplasm. We propose that binding of A1 to nascent transcripts retards its export to the cytoplasm and therefore contributes to its concentration in the nucleus.


Posterior fossa ependymomas: new radiological classification with surgical correlation.
The key determinant of long-term outcome in infratentorial ependymomas remains the extent of surgical resection. We describe a new radiological classification system which is validated against surgical findings and correlated with risk of post-operative residual tumour. Twenty-five consecutive patients (12 females, mean age 4.9 years, range 0.5-17 years) with infratentorial ependymomas were studied. Lesions were classified on pre-operative MRI according to the pattern of extension, brainstem displacement and involvement of the obex, as lateral-type or midfloor-type tumours. Twenty-one operative records were reviewed with respect to the microanatomical tumour origin by a paediatric neurosurgeon, blinded to MRI findings. Follow-up imaging studies were evaluated for residual tumour. There were 15 cases of midfloor-type tumour (anterior displacement of brainstem, infiltration of obex) and 10 cases of lateral-type tumour (lateral displacement of brainstem, obex free of tumour). Extension into prepontine or cerebellopontine cisterns was more common in lateral-type tumours. Agreement between the radiological classification and tumour origin, as defined by operative records, was seen in 18 out of 20 cases. Risk of residual tumour in lateral-type tumours was more than twice that of midfloor-type tumours (80% vs. 33%, p=0.04). Risk of tumour residual was also significantly higher when vessel encasement or prepontine extension was observed. Infratentorial ependymomas can be pre-operatively classified as lateral-type or midfloor-type tumours. This correlates well with operative findings. Lateral-type tumours have significantly increased risk of residual tumour compared to midfloor- type tumours and this may influence intensity of imaging surveillance.


Primate social behavior as a method of analysis of drug action: studies with THC in monkeys.
The use of primate social behavior tests systems to characterize alteration of central nervous system (CNS) function by lesioning, telestimulation, and psychoactive drugs is discussed. Current observations of effects of acute and long-term chronic administration of delta9-tetrahydrocannabinol in group-caged rhesus monkeys are cited to demonstrate the sensitivity and specificity of primate social behavior test systems in characterization of CNS drugs. The time course of drug action proceeds from the acute intoxication stage (sedation, stimulation, decreased social interaction) through behavioral tolerance to the emergence of irritable aggressiveness (which is demonstrated in four different social contexts). The influence of social enviornmental factors and individual differences in social roles on the manifestation of drug effects are discussed. Possible mechanisms of drug action (on biogenic amines and synaptic receptors) compatible with the behavioral data are suggested.


Face-selective processing and the effect of pleasant and unpleasant emotional expressions on ERP correlates.
Previous studies have revealed that decoding of facial-expressions starts very early in the brain ( approximately 180 ms post-stimulus) and might be processed separately from the basic stage of face perception. In order to explore brain potentials (ERPs) related to decoding of facial-expressions and the effect of emotional valence of the stimulus, we analyzed 18 normal subjects. Faces with five basic emotional expressions (fear, anger, surprise, happiness, sadness) and neutral stimulus were presented in random order. The results demonstrated that an emotional face elicited a negative peak at approximately 230 ms (N230), distributed mainly over the posterior site for each emotion. The electrophysiological activity observed may represent specific cognitive processing underlying the decoding of emotional facial-expressions. Nevertheless, differences in peak amplitude were observed for high-arousal negative expressions compared with positive (happiness) and low-arousal expressions (sadness). N230 amplitude increased in response to anger, fear and surprise, suggesting that subjects' ERP variations are affected by experienced emotional intensity, related to arousal and unpleasant value of the stimulus.


Indications, effectiveness, and long-term dependency in permanent pacing after cardiac surgery.
The purposes of this study were to define predictors of long-term pacemaker dependency in patients having permanent pacemakers implanted shortly after cardiac surgery, and to evaluate short- and long-term results and survival in this population. Data from 120 adult patients with implantation since 1980 were retrospectively analyzed. Acute and chronic complication rates (4.2% and 16.6%, respectively) were not higher than those expected in the general paced population. In addition, continuous rhythm was evaluated by use of pacemaker inhibition in a subgroup of 20 patients to verify the validity of clinical criteria for pacemaker dependency. Of the patients evaluated for dependency, 41% eventually became nondependent. Prolonged monitoring with an inhibited pacemaker confirmed the accuracy of our method of clinical evaluation of pacemaker dependency. Significant predictors of long-term pacemaker dependency were complete atrioventricular block as the indication and bypass time of > 120 minutes (by multivariate and univariate analyses, respectively). Postoperative complete atrioventricular block is the most important predictor of pacemaker dependency, enabling an earlier decision on permanent pacemaker implantation (no later than the sixth and the ninth postoperative days for wide-complex and narrow-complex escape, respectively). Further prospective studies are needed to define optimal implantation times for indications other than complete atrioventricular block.


Probing ultra-fast processes with high dynamic range at 4th-generation light sources: Arrival time and intensity binning at unprecedented repetition rates.
Understanding dynamics on ultrafast timescales enables unique and new insights into important processes in the materials and life sciences. In this respect, the fundamental pump-probe approach based on ultra-short photon pulses aims at the creation of stroboscopic movies. Performing such experiments at one of the many recently established accelerator-based 4th-generation light sources such as free-electron lasers or superradiant THz sources allows an enormous widening of the accessible parameter space for the excitation and/or probing light pulses. Compared to table-top devices, critical issues of this type of experiment are fluctuations of the timing between the accelerator and external laser systems and intensity instabilities of the accelerator-based photon sources. Existing solutions have so far been only demonstrated at low repetition rates and/or achieved a limited dynamic range in comparison to table-top experiments, while the 4th generation of accelerator-based light sources is based on superconducting radio-frequency technology, which enables operation at MHz or even GHz repetition rates. In this article, we present the successful demonstration of ultra-fast accelerator-laser pump-probe experiments performed at an unprecedentedly high repetition rate in the few-hundred-kHz regime and with a currently achievable optimal time resolution of 13 fs (rms). Our scheme, based on the pulse-resolved detection of multiple beam parameters relevant for the experiment, allows us to achieve an excellent sensitivity in real-world ultra-fast experiments, as demonstrated for the example of THz-field-driven coherent spin precession.


Role of orthopedia homebox protein in subclassification of pulmonary carcinoid tumors: Retrospective analysis of 110 cases.
Orthopedia homeobox protein (OTP), highlighted as a sensitive and specific marker for pulmonary carcinoids, may provide a more objective criterion for subclassification. A total of 110 patients who underwent surgery for pulmonary carcinoids (2009-2019) were included. Gender, age, application complaint, tumor diameter and location, typical and atypical tumor type, lymph node involvement, stage, recurrence, and survival data were evaluated retrospectively with OTP nuclear staining. The sensitivity of OTP was 66.4%. OTP in subclassifying pulmonary carcinoids was not significant. There was no significant relationship between OTP and lymph node involvement, recurrence, and survival. OTP does not provide significant results in the subclassification of typical and atypical carcinoid tumors and the evaluation of recurrence and survival of carcinoid tumor cases.


Gain and loss from transcatheter intra-arterial limb infusion of cisplatin for extremity osteosarcoma: a retrospective study of 99 cases in the past six years.
We intend to analyze the gain and loss from transcatheter intra-arterial (IA) limb infusion of cisplatin for extremity osteosarcoma in the past six years. Between December 2009 and August 2014, a total of 99 patients were analyzed for efficiency and followed up for long-term survival. Based on the different administration methods of cisplatin, we divided them into the following two cohorts: IA infusion of cisplatin (n=48) and intravenous (IV) infusion of cisplatin (n=51). Except for cisplatin, all the other drugs were given intravenously. Cisplatin was given intra-arterially with an infusion time of 3 hrs or 6 hrs using a pump, whereas historical controls received IV infusion of cisplatin within 60 mins. Tumor neovascularity (TNV) was analyzed before infusion, and subsequent arteriograms were compared with the baseline to determine percent changes. Definitive surgery with intended wide resection and postoperative pathological evaluation were performed in all these patients. No local or overall survival benefit was found in the patients preoperatively treated with IA infusion of cisplatin compared with IV infusion (P=0.336 and 0.173, respectively). Furthermore, serial arteriography was used to predict a good histologic response with an accuracy of 73.1% and a sensitivity of 100%. There were sporadic cases with the telangiectatic subtype, which did not respond very well to IV chemotherapy, but later, the tumor obviously shrank after IA infusion of cisplatin. Our study also showed that the rates of the complication of skin and muscle necrosis were not so low as reported. We did not observe any survival advantage of chemotherapy using IA infusion in osteosarcoma of the extremities. Arteriography for TNV can be used to predict the tumor histologic response. Malposition of the catheter might severely increase the complication of skin or muscle necrosis.


Regulation of transport in the connecting tubule and cortical collecting duct.
The central goal of this overview article is to summarize recent findings in renal epithelial transport,focusing chiefly on the connecting tubule (CNT) and the cortical collecting duct (CCD).Mammalian CCD and CNT are involved in fine-tuning of electrolyte and fluid balance through reabsorption and secretion. Specific transporters and channels mediate vectorial movements of water and solutes in these segments. Although only a small percent of the glomerular filtrate reaches the CNT and CCD, these segments are critical for water and electrolyte homeostasis since several hormones, for example, aldosterone and arginine vasopressin, exert their main effects in these nephron sites. Importantly, hormones regulate the function of the entire nephron and kidney by affecting channels and transporters in the CNT and CCD. Knowledge about the physiological and pathophysiological regulation of transport in the CNT and CCD and particular roles of specific channels/transporters has increased tremendously over the last two decades.Recent studies shed new light on several key questions concerning the regulation of renal transport.Precise distribution patterns of transport proteins in the CCD and CNT will be reviewed, and their physiological roles and mechanisms mediating ion transport in these segments will also be covered. Special emphasis will be given to pathophysiological conditions appearing as a result of abnormalities in renal transport in the CNT and CCD.


Impact of Flaxseed Gums on the Colloidal Changes and In Vitro Digestibility of Milk Proteins.
Flaxseed (Linum usitatissimum L.) mucilage is one of the most studied plant seed gums in terms of its techno-functional and health-promoting properties. Nonetheless, the interplay of flaxseed gum (FG) with other food biopolymers, such as milk proteins, under in vitro digestion conditions remains underexplored. The aim of the present work was to investigate the colloidal interplay between flaxseed gum (golden or brown) and milk proteins (sodium caseinate or whey protein isolate) under simulated in vitro digestion conditions and its relationship with the attained in vitro protein digestibility. The presence of flaxseed gum in the milk protein food models and in the oral food boluses obtained was associated with the occurrence of segregative microphase separation. Flaxseed gum exhibited a prominent role in controlling the acid-mediated protein aggregation phenomena, particularly in the sodium caseinate gastric chymes. The addition of FG in the food models was associated with a higher amount of intact total caseins and β-lactoglobulin at the end of the gastric processing step. Monitoring of the intestinal processing step revealed a very advanced cleavage of the whey proteins (>98%) and caseins (>90%). The degree of the milk protein hydrolysis achieved at the end of the intestinal processing was significantly higher in the systems containing flaxseed gum (i.e., 59−62%) than their gum-free protein counterparts (i.e., 46−47%). It was postulated that the electrostatic milk protein complexation capacity and, to a lesser extent, the thickening effect of flaxseed gum influenced the in vitro digestibility of the milk proteins.


Molecular architecture of the KvAP voltage-dependent K+ channel in a lipid bilayer.
We have analyzed the local structure and dynamics of the prokaryotic voltage-dependent K+ channel (KvAP) at 0 millivolts, using site-directed spin labeling and electron paramagnetic resonance spectroscopy. We show that the S4 segment is located at the protein/lipid interface, with most of its charges protected from the lipid environment. Structurally, S4 is highly dynamic and is separated into two short helices by a flexible linker. Accessibility and dynamics data indicate that the S1 segment is surrounded by other parts of the protein. We propose that S1 is at the contact interface between the voltage-sensing and pore domains. These results establish the general principles of voltage-dependent channel structure in a biological membrane.


The interaction of felodipine with calcium-binding proteins.
Felodipine is unique among the dihydropyridine calcium antagonists in that it is the most potent in relaxing porcine coronary arteries (IC50 = 1.5 X 10(-10) M); it is not as sensitive to photoinactivation as nifedipine and nisoldipine, and it is fluorescent. The fluorescence of felodipine has allowed us to study many aspects of its interaction with various calcium-binding proteins in muscle, including calmodulin, skeletal troponin C, and cardiac troponin C. Calcium binding to the calcium-specific regulatory sites on these proteins exposes allosterically related felodipine-binding sites. The binding of other calmodulin antagonists and calcium antagonists, including prenylamine, R24571, and diltiazem, to these calcium-binding proteins abolishes the cooperativity between two felodipine-binding sites, resulting in felodipine binding to the remaining site with a 20-25-fold greater affinity. In addition, the binding of high-affinity drugs to these calcium-dependent hydrophobic sites on these calcium-binding proteins produces dramatic increases (40-50-fold) in their affinity for calcium. The affinity of felodipine for these calcium-binding proteins is 100-1,000 times lower than felodipine's IC50 for relaxing tension in coronary arteries, indicating that these calcium-binding proteins are probably not the primary receptors for felodipine. Similarities between the binding of dihydropyridines to the calcium channel and to these calcium-binding proteins have led us to suggest that a "calmodulin-like" calcium-binding protein on the calcium channel is the actual pharmacological receptor for dihydropyridine calcium channel antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)


Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblasts.
Integrins, which connect the cytoskeleton to the extracellular matrix and mediate a variety of signaling cascades, may transduce mechanical stimuli into biochemical signals. We studied integrin- and matrix-dependent activation of extracellular signal-regulated kinase (ERK2), c-Jun NH2-terminal kinase (JNK1), and p38 in response to 4% static biaxial stretch in rat cardiac fibroblasts. ERK2 and JNK1, but not p38, were rapidly activated by stretch when the fibroblasts were allowed to synthesize their own matrices. When the cells were limited to specific matrix substrates, ERK2 and JNK1 were differentially activated: ERK2 was only activated when the cells were plated on fibronectin, while JNK1 was activated when the cells were plated on fibronectin, vitronectin, or laminin. Plating cells on collagen before stretching did not activate either kinase. Adhesion to all matrices was integrin-dependent because it could be blocked by inhibitors of specific integrins. ERK2 activation could be blocked with a combination of anti-alpha4 and -alpha5 antibodies and an arginine-glycine-aspartic acid (RGD) peptide, while the antibodies or peptide used separately failed to block ERK2 activation. This result suggests that at least two integrins, alpha4beta1 and an RGD-directed, non-alpha5beta1 integrin, activate ERK2 in response to mechanical stimulation. Activation of JNK1 could not be blocked with the inhibitors, suggesting that an RGD-independent integrin or integrins other than alpha4beta1 can activate JNK1 in cells adherent to fibronectin. This study demonstrates that integrins act as mechanotransducers, providing insight into potential mechanisms for in vivo responses to mechanical stimuli.


Pharmacologically targeting intracellular allosteric sites of GPCRs for drug discovery.
G-protein-coupled receptors (GPCRs) are a family of cell surface proteins that can sense a variety of extracellular stimuli and mediate multiple signaling transduction pathways involved in human physiology. Recent advances in GPCR structural biology have revealed a relatively conserved intracellular allosteric site in multiple GPCRs, which can be utilized to modulate receptors from the inside. This novel intracellular site partially overlaps with the G-protein and β-arrestin coupling sites, providing a novel avenue for biological intervention. Here, we review evidence available for GPCR structures complexed with intracellular small-molecule allosteric modulators, elucidating drug-target interactions and allosteric mechanisms. Moreover, we highlight the potential of intracellular allosteric modulators in achieving biased signaling, which provides insights into biased allosteric mechanisms.


[Comparison of prognostic value of high-dose dobutamine stress-echocardiography and exercise testing in patients with idiopathic dilated cardiomyopathy].
It is of the utmost importance to make an accurate assessment of prognosis in patients with idiopathic dilated cardiomyopathy. Both high-dose dobutamine stress-echocardiography and exercise testing have been used for prognostic stratification of these patients. To make head-to-head comparison of high-dose dobutamine stress-echocardiography and exercise testing in prognostic stratification of patients with idiopathic dilated cardiomyopathy. A total of 63 consecutive patients (55 men, mean age 50.1 +/- 9.6 years, mean ejection fraction 19.2 +/- 8.4%) with idiopathic dilated cardiomyopathy, left ventricular end-diastolic diameter >60mm, ejection fraction <35%, and adequate echocardiographic window have been studied. Dobutamine stress echocardiography was performed using 5, 10, 20, 30 and 40 mcg/kg/min infusions, in progressive stages lasting 5 minutes each. Wall motion score index and ejection fraction were considered the indices of the left ventricular contractility. Contractile reserve was defined as the difference between the values of these indices obtained at peak dobutamine dose during the test and the baseline values. Exercise testing was performed as supine bicycle ergometry in progressive stages of 25 W lasting 120 seconds each. Patients were followed one year for combined end-point consisting of cardiac death, partial left ventriculectomy and hospitalization for congestive heart failure. Out of 61, 19 (31%) patients met combined end-point during follow-up [cardiac death in 6/61 (10%), partial left ventriculectomy in 4/61 (7%) and hospitalization for heart failure in 9/61 (15%) patients]. Kaplan-Meier survival analysis demonstrated that dobutamine-induced change of wall motion score index was the best parameter for separation of patients in terms of prognosis during the follow-up (log rank=25.34, p<0.001), followed by change of ejection fraction (log rank=16.83, p<0.001) and duration of exercise testing (log rank 13.85, p=0.002). Cox model identified dobutamine-induced change of wall motion score index as the only independent predictor (p<0.001) of combined end-point during one-year follow-up. There is a number of studies dealing with the left ventricular contractile indices. These studies are different with respect to studied population, method used to elicit the left ventricular contractile response and the indices of contractile reserve. A number of studies has suggested that the amount of pharmacologically or physically induced change of wall motion score index and ejection fraction can identify patients with dismal prognosis. Peak oxygen consumption is traditionally considered the most accurate prognostic index, but its usefulness has been recently questioned. Our data suggest that high-dose dobutamine stress-echocardiography may be superior to exercise testing for prognostic stratification of patients with idiopathic dilated cardiomyopathy. The reasons for such observation are not clear, but it can be hypothesized that this may be due to multifactorial nature of the exercise tolerance. The most serious potential drawback of methodology is that, because of technical limitations, we did not test peak oxygen consumption in our patients, but since it has been shown that oxygen consumption correlates well with the duration of exercise, we believe that our methodology is valid. Both high-dose dobutamine stress-echocardiography and exercise testing can identify patients with dismal prognosis during one-year follow-up, but it appears that dobutamine stress-echocardiography may yield better prognostic significance.


[Stabilization of omega-3-polyunsaturated acids in fat from Mallotus villosus (Osmeridae) by the nontoxic, sulfur-containing antioxidant CO-3].
The stabilizing effect of the newly produced sulfur-containing antioxidant SO-3 on the fatty acid composition of fat obtained from Mallotus villosus was studied at various temperatures. In the absence of the antioxidant, omega-3 polyunsaturated fatty acids were found in the fish fat during 1 month at -18 degrees storage, although the content of these fatty acids was decreased 2-fold in this case. After addition of the SO-3 stabilizer to the fish fat at final concentration 0.2%, content of the omega-3 fatty acids was unaltered within 1 month at - 18 degrees, 10 degrees and was half decreased only at room temperature. Thus, nontoxic antioxidant SO-3 may be used to preserve preparations containing omega-3 polyunsaturated fatty acids.


Plasma strings from ultraviolet laser filaments drive permanent structural modifications in fused silica.
Long self-trapped femtosecond ultraviolet filaments created in the bulk of pure fused silica are used to induce permanent structural changes in the medium. We monitor the laser pulse propagation as a filamentary structure and the plasma string left at its trail. We investigate and demonstrate the link of the filament-induced plasma to the permanent structural changes left in the medium. Specific electron density thresholds are found for the induced modifications.


Nucleic acids for recognition and catalysis: landmarks, limitations, and looking to the future
Combinatorial selection of nucleic acids has led to the discovery of novel ligands and catalysts that have implications for both chemistry and medicine. In the context of combinatorial chemistry, degenerate syntheses of nucleic acid libraries readily generate as many as 1015 different molecules in which a small percentage exhibit interesting binding and/or catalytic properties. The primary advantage of nucleic acids is that library coding is an intrinsic property; sequential composition directly determines the activity. At low temperatures, the sequential composition of single stranded nucleic acids governs folding into irregular tertiary structures resulting in interesting activities. At higher temperatures, the same structures are unfolded and decoded by polymerases to reveal sequential information. The use of PCR (polymerase chain reaction) permits amplification and thus enrichment of the selected activity which is then regenerated chemi-enzymatically. Iterative selection and amplification result in one of the highest throughput screens conceivable whereby each molecule encodes its own activity permitting the ultimate in parallel sampling. Finally, sequence information, and by extension the chemical composition, is obtained by simple sequencing techniques obviating the need for mass spectrometric deconvolution, parallel tagging, and/or large volumes needed for viral and cell culture. This review begins with an introduction of general concepts and considerations. The potential for nucleic acids to generate tight-binding ligands is of interest to structural biologists and medicinal chemists. The therapeutic implications to medicine are also touched upon. Since combinatorially selected nucleic acids and antibodies share many conceptual similarities, their respective advantages and limitations are compared. Theoretical and practical limitations for catalyst discovery are discussed along with the use of other chemical and physical approaches to address some current catalytic shortcomings. Finally some future directions are suggested.


Efficacy and tolerability of two formulations of ramipril in Korean adults with mild to moderate essential hypertension: an 8-week, multicenter, prospective, randomized, open-label, parallel-group noninferiority trial.
This study was designed to compare the efficacy and tolerability of a new generic formulation of ramipril (test) and the branded formulation of ramipril (reference) to satisfy regulatory requirements for marketing of the generic product for use in Korean patients with mild to moderate hypertension. This was an 8-week, multicenter, prospective, randomized, open-label, parallel-group non-inferiority trial in adult patients (age > 18 years) with mild to moderate essential hypertension (sitting dia-stolic blood pressure [SiDBP] 90-109 mm Hg). After a 2-week washout of previous antihypertensive medications, eligible patients were randomized to receive either ramipril 5 mg/d in the morning (low-dose group: baseline SiDBP 90-99 mm Hg) or ramipril 10 mg/d (high-dose group: baseline SiDBP 100-109 mm Hg) for the first 4 weeks. If SiDBP was > or = 90 mm Hg after 4 weeks of treatment, the dose was increased to 10 mg/d for the remaining 4 weeks in the low-dose group, and hydrochlorothiazide 12.5 mg was added to the regimen for the remaining 4 weeks in the high-dose group. The primary end point was the change in SiDBP from baseline to week 8. Secondary end points included a noninferiority analysis of the test and reference formulations with respect to the change in mean sitting systolic blood pressure (SiSBP) from baseline to week 8; SiDBP and SiSBP response rates (proportion of patients achieving an SiDBP < 90 mm Hg and SiSBP < 140 mm Hg, respectively) at 8 weeks; and changes from baseline in SiSBP, pulse wave velocity (PWV), exercise capacity, left-ventricular diastolic function (LVDF), and levels of brain natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP). Laboratory and clinical adverse events (AEs) were monitored at each study visit (4 and 8 weeks). The modified intent-to-treat population consisted of 89 patients (45 test, 44 reference; 60 men, 29 women; mean age, 49.7 years; mean weight, 69.9 kg). At week 8, mean (SD) SiSBP and SiDBP were significantly decreased from baseline in both groups (test: from 145.0 [9.7]/98.1 [5.3] mm Hg to 132.2 [11.1]/ 91.8 [7.1] mm Hg [P < 0.001]; reference: from 145.1 [11.4]/98.0 [5.7] mm Hg to 134.0 [14.6]/92.5 [7.9] mm Hg [P < 0.001]). The changes in blood pressure at week 8 did not differ significantly between the test and reference groups or between the low- and highdose groups in a subgroup analysis. Blood pressure response rates at 8 weeks did not differ significantly between the groups receiving the test and reference formulations (SiDBP: 26.7% and 31.8%, respectively; SiSBP: 37.8% and 40.9%). In addition, there were no significant between-group differences in the change in PWV (-63.8 and -38.7 cm/sec), LVDF at rest or after exercise, or levels of BNP or hs-CRP. The incidence of AEs was 64.4% in the test formulation group and 68.2% in the reference group formulation (P = NS). The most common AE in both groups was cough (10/45 [22.2%] and 10/44 [22.7%]). There were no significant differences in the efficacy and tolerability of the test and reference formulations of ramipril in these Korean adults with mild to moderate hypertension. The new generic formulation was noninferior to the reference formulation in terms of the change in SiDBP at week 8.


GPC3 and PEG10 peptides associated with placental gp96 elicit specific T cell immunity against hepatocellular carcinoma.
The placenta and tumors can exhibit a shared expression profile of proto-oncogenes. The basis of placenta-derived heat shock protein gp96, which induces prophylactic and therapeutic T cell responses against cancer including hepatocellular carcinoma (HCC), remains unknown. Here, we identified the associated long peptides from human placental gp96 using matrix-assisted laser desorption/ionization-time-of-flight and mass spectrometry and analyzed the achieved proteins through disease enrichment analysis. We found that placental gp96 binds to numerous peptides derived from 73 proteins that could be enriched in multiple cancer types. Epitope-harboring peptides from glypican 3 (GPC3) and paternally expressed gene 10 (PEG10) were the major antigens mediating anti-HCC T cell immunity. Molecular docking analysis showed that the GPC3- and PEG10-derived peptides, mainly obtained from the cytotrophoblast layer of the mature placenta, bind to the lumenal channel and client-bound domain of the gp96 dimer. Immunization with bone marrow-derived dendritic cells pulsed with recombinant gp96-GPC3 or recombinant gp96-PEG10 peptide complex induced specific T cell responses, and T cell transfusion led to pronounced growth inhibition of HCC tumors in nude mice. We demonstrated that the chaperone gp96 can capture antigenic peptides as an efficient approach for defining tumor rejection oncoantigens in the placenta and provide a basis for developing GPC3 and PEG10 peptide-based vaccines against HCC. This study provides insight into the underlying mechanism of the antitumor response mediated by embryonic antigens from fetal tissues, and this will incite more studies to identify potential tumor rejection antigens from placenta.


[Some problems in teaching anesthesiology and reanimatology at a higher medical educational establishment].
The paper describes the experience of the Department of Anesthesiology and Resuscitation, Chita Medical Academy, in upgrading the quality of teaching at the pre- and postgraduate stages of education and the prestigiousness of the specialty for students. The forms of collaboration of the department's collective body with the Academy's governing body and the territory's health care structures are described. These undertakings have doubled the hours of teaching the subjects that are a sphere of anesthesiology and resuscitation at the pregraduate stage. The authors' experience suggests that 2-year clinical residency is the minimum training period under the present conditions. The innovation approach to solving the organizational and professional problems, which is proposed and tested by the authors, resulted in the provision of the health care facilities of the Transbaikal Territory with educated anesthetists-resuscitators (by 98.8%). The use of innovation educational technologies, including internet bases and internet libraries, and audiovisual and telecommunication technologies for distance education and counseling, makes an educational process interesting to young specialists and, overall, serves to increase the prestigiousness of the specialty.


Effective control of the intrinsic DNA morphology by photosensitive polyamines.
Non-viral vectors for gene therapy such as DNA-cationic probe complexes offer important bio-safety advantages over viral approaches, due to their reduced pathogenicity, immunogenicity and cytotoxicity. In the present study we examine two polycationic water-soluble azobenzene derivatives (bis-Azo-2N and bis-Azo-3N) containing different linear unsubstituted polyamine moieties and we demonstrate the ability of such photochromes to destabilize the intrinsic B-DNA secondary structure in a concentration-dependent manner. Furthermore, through a detailed series of biophysical experiments, varying the photochrome conformation, temperature, salt and DNA concentration, we provide a detailed insight into the azobenzene-DNA binding pathway (Ka: bis-Azo-2N(trans)-DNA = 5.3 ± 0.3 × 104 M-1, Ka: bis-Azo-2N(cis)-DNA = 2.6 ± 0.2 × 104 M-1, Ka: bis-Azo-3N(trans)-DNA = 7.1 ± 0.4 × 104 M-1 and Ka: bis-Azo-3N(cis)-DNA = 5.1 ± 0.4 × 104 M-1) establishing the versatility of such materials as promising candidates for use in non-viral gene delivery systems.


Impaired responsiveness of the ventricular sensory receptor in hypertensive patients with left ventricular hypertrophy.
We studied the control of forearm vascular resistance (FVR) by cardiopulmonary receptors in seven patients with hypertension and left ventricular hypertrophy (LVH) and in seven normotensive control subjects. Increasing levels of lower body negative pressure (LBNP) (-10 and -40 mm Hg) induced a progressive decrease in central venous pressure (CVP) and an increase in FVR. The changes in these two variables were correlated both in normal subjects and patients with hypertension (slope for normal subjects = -29.9, for patients with hypertension = -40.3, NS). After propranolol, there was a significant reduction in the increase in FVR induced by -40 mm Hg LBNP in normal subjects (+107 +/- 5 vs +129 +/- 15 mm Hg/ml/sec, p less than .05) but not in patients with hypertension. Consequently, the slope of the delta CVP/delta FVR regression was reduced in normal subjects (-20.6, p less than .01) but not in patients with hypertension. In another seven normal subjects and seven patients with hypertension and LVH we assessed the effects of -10 and -40 mm Hg LBNP on left ventricular filling pressure (LVFP). LBNP induced similar changes in CVP, LVFP, and total peripheral resistance both in normal subjects and in patients with hypertension. Propranolol failed to modify the effects of LBNP on CVP and LVFP in both groups and reduced the response of total peripheral resistance to -40 mm Hg LBNP only in normal subjects. Propranolol did not reduce the response of FVR to the cold pressor test and sustained handgrip or the arterial baroreflex response to the injection of phenylephrine and increased neck tissue pressure. Thus, hypertension-induced LVH seems to be associated with a selective impairment of the left ventricular sensory receptors.


Distribution of IGF receptors in the plasma membrane of proximal tubular cells.
To characterize the distribution of receptors for insulin-like growth factors I and II (IGF I and II) in the plasma membrane of the renal proximal tubular cell, we measured binding of 125I-labeled IGF I and 125I-labeled IGF II to proximal tubular basolateral and brush-border membranes and characterized IGF I-stimulated phosphorylation of detergent-solubilized membranes. 125I-IGF I bound primarily to a 135,000 relative molecular weight (Mr) protein and IGF II to a 260,000 Mr protein in isolated membranes. Binding of 125I-IGF I was severalfold greater in basolateral than in brush-border membranes. IGF I-stimulated phosphorylation of the 92,000 Mr beta-subunit of its receptor could be demonstrated only in basolateral membranes. These findings are consistent with an asymmetrical distribution of receptors for IGF I in the plasma membrane of the renal proximal tubular cell, localization being primarily on the basolateral side. In contrast, binding of 125I-IGF II to isolated basolateral and brush-border membranes was equivalent, suggesting that receptors for this peptide are distributed more symmetrically in the plasma membrane. Our findings suggest that the actions of IGF I in proximal tubule are mediated via interaction of circulating peptide with specific receptors in the basolateral membrane. However, our findings establish the potential for actions of IGF II to be exerted in proximal tubule via interaction with both basolateral and/or brush-border membrane receptors.


Efficacy and tolerability of cancer neuroimmunotherapy with subcutaneous low-dose interleukin-2 and the pineal hormone melatonin - a progress report of 200 patients with advanced solid neoplasms.
The recent advances in psychoneuroimmunology have demonstrated the existence of a psychoneuroendocrine control of the antitumor immunity. Our previous preliminary studies indicated the possibility of amplifying the biological and therapeutic efficacy of IL-2 cancer immunotherapy by immunomodulating neurohormones, mainly the pineal indole melatonin (MLT), in most advanced solid tumors, including those which generally do not respond to IL-2 alone. This study reports on the results obtained by low-dose IL-2 plus MLT in 200 patients with advanced solid neoplasms, for whom no other effective standard therapy was available. Non-small cell lung cancer, pancreatic adenocarcinoma, hepatocarcinoma, colon cancer and gastric cancer were the neoplasms most frequently detected in our patients. In addition, all patients had a life expectancy less than 6 months. IL-2 was given subcutaneously at 3 million IU/day for 6 days/week for 4 weeks; MLT was given orally at 40 mg/day. In non-progressing patients, a second cycle was given after a 21-day rest period; then, patients underwent a maintenance period consisting of one week of therapy every month until progression. A complete response (CR) was achieved in 4 patients (hepatocarcinoma 2; pancreas 1; gastric cancer 1), a partial reasponse (PR) was achieved in 36 patients (lung 12; liver 6; stomach 4; pancreas 3; colon 3; breast 2; miscellaneous 6). Tumor response rate (CR+PR) was 40/200 (20%) patients. Longer than one year survival was achieved in 79 (39%) patients. Toxicity was mild in all patients, and therapy was administered as a home therapy. The present study confirms in a great number of patients the possibility to induce objective tumor regressions in most advanced solid tumor histotypes by low-dose IL-2 plus MLT. Thus, immunotherapy with IL-2 and MLT may be considered as a new well tolerated and effective therapy of almost all advanced solid tumors, including those which do not respond to IL-2 alone or to chemotherapy.


pH sensitivity of the basolateral membrane of the rabbit proximal tubule.
Conventional microelectrodes were used to study the effects of bath pH and bicarbonate concentrations on the basolateral membrane potential (Vbl) of cells from the superficial proximal convoluted (PCT) and proximal straight (PST) tubules of the rabbit kidney perfused in vitro. Bathing solution pH was varied over the range of 5.9-7.4 using either control (22-25 mM) or low bicarbonate (5.0-6.6 mM) Ringer solutions and the appropriate CO2 tensions. The results show a strong pH dependence of the steady-state values of Vbl in both the convoluted and straight tubule segments. The pH-dependent depolarization was approximately 35 mV/pH unit change of the bathing solution in the acid direction and could be demonstrated in CO2-free HEPES-buffered solutions. A depolarizing response to increased bath potassium concentration (HK) was observed that was linearly related to the absolute value of the Vbl under control conditions. Under acidotic conditions, reduced HK depolarizations indicate that a decrease in the relative potassium permeability of the basolateral membrane is the principle mechanism underlying the effects of bath pH on Vbl.


Regulation of extracellular ATP in human erythrocytes infected with Plasmodium falciparum.
In human erythrocytes (h-RBCs) various stimuli induce increases in [cAMP] that trigger ATP release. The resulting pattern of extracellular ATP accumulation (ATPe kinetics) depends on both ATP release and ATPe degradation by ectoATPase activity. In this study we evaluated ATPe kinetics from primary cultures of h-RBCs infected with P. falciparum at various stages of infection (ring, trophozoite and schizont stages). A "3V" mixture containing isoproterenol (β-adrenergic agonist), forskolin (adenylate kinase activator) and papaverine (phosphodiesterase inhibitor) was used to induce cAMP-dependent ATP release. ATPe kinetics of r-RBCs (ring-infected RBCs), t-RBCs (trophozoite-infected RBCs) and s-RBCs (schizont-infected RBCs) showed [ATPe] to peak acutely to a maximum value followed by a slower time dependent decrease. In all intraerythrocytic stages, values of ΔATP1 (difference between [ATPe] measured 1 min post-stimulus and basal [ATPe]) increased nonlinearly with parasitemia (from 2 to 12.5%). Under 3V exposure, t-RBCs at parasitemia 94% (t94-RBCs) showed 3.8-fold higher ΔATP1 values than in h-RBCs, indicative of upregulated ATP release. Pre-exposure to either 100 µM carbenoxolone, 100 nM mefloquine or 100 µM NPPB reduced ΔATP1 to 83-87% for h-RBCs and 63-74% for t94-RBCs. EctoATPase activity, assayed at both low nM concentrations (300-900 nM) and 500 µM exogenous ATPe concentrations increased approx. 400-fold in t94-RBCs, as compared to h-RBCs, while intracellular ATP concentrations of t94-RBCs were 65% that of h-RBCs. In t94-RBCs, production of nitric oxide (NO) was approx. 7-fold higher than in h-RBCs, and was partially inhibited by L-NAME pre-treatment. In media with L-NAME, ΔATP1 values were 2.7-times higher in h-RBCs and 4.2-times higher in t94-RBCs, than without L-NAME. Results suggest that P. falciparum infection of h-RBCs strongly activates ATP release via Pannexin 1 in these cells. Several processes partially counteracted ATPe accumulation: an upregulated ATPe degradation, an enhanced NO production, and a decreased intracellular ATP concentration.


Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma.
Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.


Multiple pathways of peroxynitrite cytotoxicity.
Peroxynitrite is a reactive oxidant produced from nitric oxide (NO) and superoxide, which reacts with a variety of biomolecules including proteins, lipids and DNA. Peroxynitrite is produced by the body in response to a variety of toxicologically relevant molecules including environmental toxins. It is also produced by the body in response to environmental toxins, as well as in reperfusion injury and inflammation. Here we overview the multiple pathways of peroxynitrite cytotoxicity. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na(+)/K(+) ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly-ADP ribosyl synthetase or polymerase (PARP), with eventual severe energy depletion and necrosis of the cells. Studies conducted with peroxynitrite decomposition catalysts suggest that neutralization of peroxynitrite is of significant therapeutic benefit after exposure to various environmental toxins as well as in a variety of inflammatory and reperfusion disease conditions.


Armed stem to stinger: a review of the ecological roles of scorpion weapons.
Scorpions possess two systems of weapons: the pincers (chelae) and the stinger (telson). These are placed on anatomically and developmentally well separated parts of the body, that is, the oral appendages and at the end of the body axis. The otherwise conserved body plan of scorpions varies most in the shape and relative dimensions of these two weapon systems, both across species and in some cases between the sexes. We review the literature on the ecological function of these two weapon systems in each of three contexts of usage: (i) predation, (ii) defense and (iii) sexual contests. In the latter context, we will also discuss their usage in mating. We first provide a comparative background for each of these contexts of usage by giving examples of other weapon systems from across the animal kingdom. Then, we discuss the pertinent aspects of the anatomy of the weapon systems, particularly those aspects relevant to their functioning in their ecological roles. The literature on the functioning and ecological role of both the chelae and the telson is discussed in detail, again organized by context of usage. Particular emphasis is given on the differences in morphology or usage between species or higher taxonomic groups, or between genders, as such cases are most insightful to understand the roles of each of the two distinct weapon systems of the scorpions and their evolutionary interactions. We aimed to synthesize the literature while minimizing conjecture, but also to point out gaps in the literature and potential future research opportunities.


Covalent Organic Framework-derived Composite Membranes for Water Treatment.
Water treatment has experienced a surge in the adoption of membrane separation technology. Covalent organic frameworks (COFs), a class of metal-free and open-framework materials, have emerged as potential membrane materials owing to their interconnected periodic porosity, tunability, and chemical stability. However, the challenges associated with processing COF powders into self-standing membranes have spurred the emergence of COF composite membranes. This review article highlights the rationale behind the development of COF composite membranes and their categories, including mixed matrix membranes (MMMs) and thin film composite (TFC) membranes. The common fabrication techniques of each category of membranes are presented. In addition, the influence of COF additives on the performance of the resultant composite membranes is systematically discussed, with a focus on the recent progress in applying COF composite membranes in the separation of different categories of water pollutants, including organic ions/molecules, toxic solvents, proteins, toxic heavy metals, and radionuclides.


Stereotactic radiosurgery for primary malignant spinal tumors.
We adopted stereotactic radiosurgery (SRS) to treat primary malignant spinal tumors. The objective of this study was to evaluate local control rate and to identify prognostic factors after SRS for primary malignant spinal tumors. Medical records and radiological data for 29 patients with primary malignant spinal tumors were retrospectively analyzed. The histological diagnoses were chordoma (11 cases), chondrosarcoma (5 cases), osteosarcoma (3 cases), synovial sarcoma (3 cases), plasmacytoma (2 cases), Ewing sarcoma (2 cases), malignant peripheral nerve sheath tumor (2 cases), and malignant fibrous histiocytoma (1 case). Patient age ranged from 11 to 68 years (median, 46 years). Surgical resection and percutaneous biopsy were chosen as initial treatments in 25 and 4 cases, respectively. Stereotactic radiosurgery was used as primary treatment method in 14 cases and as a salvage treatment for progressed lesions in 15 cases. Distant metastasis was noted in two sarcoma patients. Eleven patients had undergone previous conventional external beam radiation therapy (cEBRT) before SRS. Overall survival, local progression-free survival, and the prognostic factors affecting local recurrence were investigated. Tumor volume ranged from 2·0 to 235 cc (median, 14 cc). Delivered radiation doses were from 12 to 50 Gy with two to six sessions. The mean radiation dose converted into a biological effective dose (BED) was 60 Gy (range, 43-105 Gy). The mean follow-up period was 50 months (range, 8-126 months). The mean overall survival was 84 months for chordoma patients and 104 months for sarcoma patients. No factors that affected overall survival were found. The mean local progression-free survival was 56 months for chordoma patients and 73 months for sarcoma patients. The recurrent mode of presentation was predictive of local progression of spinal sarcomas (P = 0·009). However, in chordoma patients, no factors were found to correlate with local recurrence. These preliminary results suggest that SRS could provide good local control when applied as postoperative adjuvant or salvage treatment after cEBRT for primary malignant spinal tumors.


Aging and repetition priming for targets and distracters in a working memory task.
A combined working memory/repetition priming task was administered to 13 young (mean age 23) and 13 elderly (mean age 69) adults. Each participant memorized a sample target face at the beginning of a trial and then determined whether each of 13 serially presented test faces matched the sample target. In each trial, both the target and one particular distracter face were repeated during the test phase. Within-trial repetition priming effects indicated the contribution of implicit memory to task performance. Response times decreased as items were tested repeatedly within a trial, but this decrement was greater for distracters than for targets. Young and older participants were equally accurate at identifying targets, but elderly were slightly less accurate for distracters. Elderly participants showed repetition priming effects for both targets and distracters, while the young showed such effects only for distracters. The results suggest that active maintenance in working memory, but not inhibition or rejection of distracters, may suppress implicit memory systems.


Penile vascular evaluation and sexual function before and after radical retropubic prostatectomy: 5-year follow-up.
Sexual dysfunction is common after surgery for prostate cancer. The aetiology of changes in sexual potency after radical prostatectomy is probably multifactorial, including neurogenic, vascular and psychosexual factors. A prospective study was designed to investigate haemodynamic and psychosexual changes before and after radical retropubic prostatectomy (RRP) for organ-confined prostate cancer. Penile haemodynamic evaluation and an assessment of sexual excitement were performed preoperatively and 3 months after RRP by colour Doppler ultrasonography (CDU) with visual erotic stimulation combined with a single intracavernous injection of a mixture of papaverine/phentolamine. Questionnaires on sexual function [International Index of Erectile Function (IIEF)], general health and quality of life were sent to the patients preoperative, 3 months and 5 years after operation. Forty-eight men participated in the study. Mean age was 62.6 years (range 55-69). CDU did not show any significant reduction in mean peak systolic flow velocity and mean resistance index. From the men who preoperatively had normal arterial inflow 18% developed arteriogenic insufficiency. Some form of veno-occlusive insufficiency and low resistance indices were already present in the majority of normal potent men preoperatively. Surgical technique did not influence penile arterial blood flow after the operation. Three months and 5 years postoperatively, there was a highly significant reduction in erectile function, intercourse satisfaction, overall satisfaction, orgasmic function and sexual desire. However, with respect to the outcome at 3 months there was a significant improvement of orgasmic function 5 years after operation, especially after a bilateral nerve sparing procedure. Erections sufficient for vaginal penetration (questions 3 and 4 of the IIEF, score >or=8) improved from 2% to 11% 3 months and 5 years after RRP respectively. Total IIEF score was significantly better after a bilateral nerve-sparing procedure compared with non-nerve sparing. No structural vascular changes were observed 3 months after operation. Vascular factors appear to be less important in the aetiology of ED after RRP. There seems to be a trend of a better improvement of sexual function over time, especially orgasmic function, in patients with bilateral nerve-sparing surgery.


Evaluation of modified BACTEC 12B radiometric medium and solid media for culture of Mycobacterium avium subsp. paratuberculosis from sheep.
Definitive diagnosis of Johne's disease in ruminants depends on confirming the presence of the causative bacterium, Mycobacterium avium subsp. paratuberculosis, in tissues of the host. This is readily achieved in most ruminant species by culture. However, culture of clinical specimens from sheep in many countries has been unrewarding. Such a culture from sheep was achieved recently in Australia by using a radiometric culture medium. The aims of the present study were to evaluate the culture of M. avium subsp. paratuberculosis from sheep by using modified BACTEC 12B radiometric medium, to determine the sensitivity of culture in relation to histopathology, and to evaluate a range of solid media. Culture of M. avium subsp. paratuberculosis from sheep with Johne's disease is a sensitive method of diagnosis: intestinal tissues from all 43 animals with multibacillary disease and all 22 animals with paucibacillary disease were culture positive, while 98% of feces from 53 animals with multibacillary disease and 48% of feces from 31 animals with paucibacillary disease were culture positive. Of sheep without histological evidence of Johne's disease from infected flocks, intestinal tissue from 32% of 41 were culture positive, while feces from 17% of 41 were culture positive. Consequently, culture is recommended as the "gold standard" test for detection of ovine Johne's disease. Of the wide range of solid media that were evaluated, only modified Middlebrook 7H10 and 7H11 agars, which were very similar in composition to modified BACTEC 12B medium, yielded growth of ovine strains of M. avium subsp. paratuberculosis. The sensitivity of detection of M. avium subsp. paratuberculosis on solid media was slightly lower than that in modified BACTEC 12B radiometric medium. Both egg yolk and mycobactin J were essential additives for growth of ovine strains of M. avium subsp. paratuberculosis in both liquid and solid media.


[Effect of biliary high pressure on hemodynamics and autonomic nervous activity].
An acutely experimental study on biliary compression and decompression as well as right splanchnic major nerve blocking was completed in Japanese big ear white rabbits. Using a self-made catheter with a blind cyst at bile duct, the extrahepatic biliary system could be cannulated and an experimental biliary high pressure of 150 mmHg could be achieved as long as 2 hours by water infusion via the blind cyst of the catheter. The right splanchnic major nerve was dissected simultaneously for investigating the impulse frequency of the nerve and the artery blood pressure during the study. A significant decrease in blood pressure (P less than 0.01) and an elevation of nervous impulse frequency (P less than 0.01) were found in "simple type" acute biliary high pressure without infection. Biliary decompression would immediately reverse the above abnormalities (P less than 0.01). The decline of blood pressure would be dramatically weaken or less significant if a right splanchnic nerve blocking was processed prior to biliary compression.


The relationship between mean platelet volume levels and the inflammation in Helicobacter pylori gastritis.
Helicobacter pylori is a cause of chronic gastritis. Mean platelet volume (MPV) has been started to be used as a simple inflammatory indicator in some diseases. We have aimed especially to investigate the usability of MPV as a simple indicator that may reflect severity of inflammation in gastric mucosa. Included in the study were a total of 114 patients who visited the outpatient clinic of gastroenterology with complaint of dyspepsia. Blood MPV levels in hemogram results were evaluated. Esophagogastroduodenoscopy was performed on patients included in the study, and histological analysis was performed by obtaining 2 specimens from each of antrum, corpus, and incisura angularis. All specimens were evaluated according to the updated Sydney System. No statistically significant result was found among blood MPV levels, the intensity of H pylori, and the severity of inflammation of gastric mucosa. However, it is interesting that mean MPV levels in cases with lymphoid follicle were lower. We suggest that MPV level cannot be used as a simple marker to reflect H pylori intensity and severity of inflammation in gastric endoscopic biopsies.


A Survey on Sleep Disorders and Related Hormones in Patients with Newly Diagnosed Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is reportedly associated with sleep disorders. Thus, the present study aimed to investigate sleep disorders in newly diagnosed SLE patients. This study was conducted on patients with newly diagnosed SLE (ie, case group) and a control group. The case and control groups were matched in terms of gender, age, socioeconomic status, and educational level. Venous blood samples were obtained from the participants to measure prolactin and melatonin levels. Furthermore, they were subjected to polysomnography. The data were analysed by SPSS (version 16) at a significance level of 0.05. A total of 28 women were enrolled in this study (ie, 14 individuals in each group). The frequencies of sleep disorder in the case and control groups were obtained as 64.3% and 50%, respectively (P=0.4). These two groups had the mean sleep onset times of 10.76±10.64 and 8.67±7.12 min (P=0.5) and the respiratory disturbance indices of 9.20±10.23 and 8.44±9.27, respectively (P=0.8). The frequency of sleep apnoea was obtained at 50% for both case and control groups (P=1). There was no significant difference between these groups in terms of the mean serum prolactin and melatonin levels (P=0.3 and P=0.2, respectively). Serum melatonin level showed a direct correlation with sleep latency to N1 (i.e., the first part of non-rapid eye movement in sleep) and spontaneous arousal index in the case group (P=0.02, r=0.602 and P=0.04, r=0.544, respectively). According to the findings, there was no significant difference in the frequency of sleep disorders between the healthy subjects and patients at the onset of lupus. Additionally, melatonin and prolactin levels showed no significant difference between the groups. Our results are inconsistent with previous studies, due to the difference in disease duration probably. It seems that the chronicity and complications of the disease, as well as the adoption of glucocorticoid therapy for the chronic disease affect sleep quality in SLE patients more than disease duration.


Proteins of the kidney microvillar membrane. The 130 kDa protein in pig kidney, recognized by monoclonal antibody GK5C1, is an ectoenzyme with aminopeptidase activity.
The hybridoma GK5C1, secreting a monoclonal IgG1 antibody, was generated after immunizing a mouse with pig kidney microvillar membranes. An immunoradiometric assay showed that only kidney and intestine contained detectable amounts of the antigen recognized by the antibody, the highest concentration being observed in the ileum. Immunocytochemistry confirmed this observation and revealed that the antigen was associated with renal and intestinal brush borders. By 'Western' blotting, the antigen in kidney microvilli was shown to be a 130 kDa polypeptide. Papain treatment of the membrane before blotting converted the antigen to a 125 kDa polypeptide, no longer associated with membrane. Immunoaffinity chromatography of detergent-solubilized kidney membranes yielded a pure 130 kDa protein. When one purification was monitored by the immunoradiometric assay, the yield was 3.5% and the purification factor was 1000-fold. The antigen constituted about 0.8% of the microvillar membrane protein. The protein could be reconstituted into liposomes, where electron microscopy revealed an asymmetric orientation, similar to that of ectoenzymes in this membrane. The stalk length was about 3 nm. In electron micrographs the purified protein appeared to be dimeric. A search for enzymic activity was rewarded when L-leucyl-L-tryptophan was observed to be hydrolysed. Failure to hydrolyse N-blocked peptides and the ability to release the N-terminal residue from extended peptides, including Leu-Trp-Leu and Leu-Trp-Met-Arg, showed that the activity was that of an aminopeptidase. The enzyme was maximally active at pH 7.5 and irreversibly inactivated outside the range pH 6-10. This activity could not be attributed to trace contamination with aminopeptidase N. The best substrates so far identified for the 130 kDa protein were those with tryptophan in the P1', position. This protein is a new microvillar enzyme and it is proposed that it be called aminopeptidase W.


Corrigendum to "Workplace Lactation Support in Milwaukee County 5 Years After the Affordable Care Act".
Lennon, T., Blackwell, D., & Willis, E. (2017). Workplace lactation support in Milwaukee county 5 years after the Affordable Care Act. Journal of Human Lactation, 33(1), 214-219. (Original DOI: 10.1177/0890334416679617) In this article that appeared in the February 2017 issue of Journal of Human Lactation, the following corrections are required due to an inadvertent omission by the research team authoring the paper. 1) Dalvery Blackwell has been added as an author. The corrected author list is as follows: Tyler Lennon, BS, Dalvery Blackwell, BA, IBCLC, and Earnestine Willis, MD, MPH 2) The authors sincerely appreciate the significant contribution that the African American Breastfeeding Network (AABN) had in this project that resulted in a publication and wish to acknowledge them for their outstanding efforts in the Milwaukee communities. The authors regret not providing an authorship to the AABN with the original manuscript submission.


Chemometrics-Assisted Fast-Elution HPLC-DAD for the Quantification of Selected UV Filters and Parabens in Suncare Formulations.
In the present study, a fast LC method coupled with multivariate curve resolution (MCR) alternating least-squares (ALS) and alternating trilinear decomposition (ATLD) was developed for the determination of the resolution of and quantitation of benzophenone-3, 4-methylbenzylidene camphor, octocrylene, ethylhexyl dimethyl para-aminobenzoic acid, butyl methoxydibenzoilmethane, and methyl and propyl parabens in suncare products. Chromatographic separation was optimized using full factorial and Box-Behnken designs. MCR-ALS and ATLD performance in quantitating the analytes in synthetic mixtures (which were randomly prepared in ultra-pure water) and blank sunscreen products was studied, and satisfying results were obtained. Acceptable qualification and quantification results were also achieved in the presence of matrix interferences via a short chromatographic runtime (5 min), and the second-order advantage was fully exploited, with MCR-ALS clearly emerging as the superior model. Average recoveries ranged from 98.0 to 112.5%, and RSD values were lower than 6.5%. LODs between 0.066 and 0.243 μg/g were achieved. In addition to acceptable precision and accuracy, the merits of the proposed method are that the analysis is fast and there is minimal solvent consumption. Moreover, coelution of analytes and interference from components in the sample matrixes were overcome with multivariate analysis.


Revising the Self-Harm Antipathy Scale: validation among staff in psychiatric healthcare in Sweden.
Background: The Self-Harm Antipathy Scale (SHAS) is a questionnaire designed to measure nurses' attitudes towards self-harm. This can be useful to improve the quality of care provided to individuals who self-harm.Aim: The purpose of this study was to revise and adapt the SHAS for use in Sweden and evaluate the psychometric properties of this Swedish version (Self-Harm Antipathy Scale - Swedish Revised; SHAS-SR).Methods: A sample of 596 employees within psychiatric healthcare was recruited (from a total of 3507, response rate 17.0%), the majority encountering self-harming individuals regularly at work. Participants completed the SHAS-SR questionnaire along with a scale assessing community attitudes towards individuals with mental illness (New CAMI-S). The sample was randomly split in half (n = 298 each). Exploratory factor analysis was performed on one subsample and confirmatory on the other. Confirmatory factor analysis on the original SHAS model, and convergent validity testing against New CAMI-S, used the whole sample.Results: The final version of the SHAS-SR included 17 items forming three factors. Convergent validity was established (r = -0.57, ρ = -0.48, p < 0.001). The SHAS-SR and all its subscales demonstrated acceptable internal consistency (α = 0.73-0.79, ω = 0.78-0.79).Conclusion: This study indicates that the SHAS-SR is reliable and valid when assessing attitudes towards self-harm among a sample of Swedish psychiatric healthcare staff. The scale could be useful for assessing the impact of attitude interventions to improve healthcare services. It may, however, have limited applicability for staff not working in caring roles.


Dietary vegetable oils and alpha-tocopherol reduce lipid oxidation in rabbit muscle.
This experiment was conducted to study the effect of dietary vegetable oil on lipid oxidation in rabbit muscle. A control diet with no added fat and two diets with olive or sunflower oil (30 g/kg) were used. Within each treatment, one group was fed a low level of alpha-tocopheryl acetate (10 mg/kg diet), and the other a supplemental level (200 mg/kg). Rabbits were fed experimental diets from weaning (20 d) to slaughter (69 d). The supplemental level of dietary alpha-tocopheryl acetate produced higher alpha-tocopherol concentration in muscle (P < 0.006) and lower lipid oxidation (P < 0.004). Rabbits that received sunflower oil had higher concentrations of thiobarbituric acid reactive substances than rabbits that consumed olive oil (P < 0.05). Moreover, a significant effect due to fat inclusion in the diet was found. Muscles from rabbits fed diets not enriched with fat had higher susceptibility to lipid oxidation (P < 0.005) and higher concentration of (n-3) fatty acids in polar lipids (P < 0.04) than those from rabbits fed fat-enriched diets. A second experiment was conducted and confirmed the higher lipid oxidation in the muscle of rabbits fed diets not enriched with fat than in that of rabbits fed diets containing sunflower oil (28 g/kg) (P < 0.003) as well as in diets with identical digestible energy. In this experiment, alpha-tocopheryl acetate was at the lower level (10 mg/kg feed). Inclusion of oils rich in oleic (olive oil) or linoleic acid (sunflower oil) in rabbit diets reduces lipid oxidation in muscles.


The effect of word learning on the perception of non-native consonant sequences.
Previous research in cross-language perception has shown that non-native listeners often assimilate both single phonemes and phonotactic sequences to native language categories. This study examined whether associating meaning with words containing non-native phonotactics assists listeners in distinguishing the non-native sequences from native ones. In the first experiment, American English listeners learned word-picture pairings including words that contained a phonological contrast between CC and CVC sequences, but which were not minimal pairs (e.g., [ftake], [ftalu]). In the second experiment, the word-picture pairings specifically consisted of minimal pairs (e.g., [ftake], [ftake]). Results showed that the ability to learn non-native CC was significantly improved when listeners learned minimal pairs as opposed to phonological contrast alone. Subsequent investigation of individual listeners revealed that there are both high and low performing participants, where the high performers were much more capable of learning the contrast between native and non-native words. Implications of these findings for second language lexical representations and loanword adaptation are discussed.


The implications of nutrition services within the health care system on the quality of life and longevity, in developed countries: a re-analysis of 38 studies.
The United Nations' Global Population Pyramid is undertaking a shift from pyramid to cube. The concomitant decline in fertility and mortality rates produces a higher portion of older people, and, thus, an increased number of deaths due to cancer and cardiovascular disease (CVD). Limited studies have investigated the effect of health care services on longevity. In this work, findings from studies throughout the world are presented and re-analysed in order to evaluate the effect of health care services on population's health status. Studies that have assessed the associations of nutritional and other health care services (i.e., physicians supply, technical support, inter-collaboration) on longevity and health status were retrieved (searches in PubMed, EMBASE, Scopus, up to January 2010), and summarized here. Few studies, mostly located in the US and the UK, have evaluated the role of health care services on population's health status. The majority of the studies reported a beneficial association between the frequency of physicians and mortality, while some other studies reported weak or no associations between physician's supply and longevity. Also nutritional services (screening) seem to promote better clinical outcome. Although very few data are available, it seems that there is a positive correlation between the quality and quantity of health care services and longevity. Strong primary health care seems to be effective on the population's health outcome. Active health policy and enhancement of health and nutritional services within the health care system may contribute to improved population's health and their overall quality of life.


Aluminum access to the brain: a role for transferrin and its receptor.
The toxicity of aluminum in plant and animal cell biology is well established, although poorly understood. Several recent studies have identified aluminum as a potential, although highly controversial, contributory factor in the pathology of Alzheimer disease, amyotrophic lateral sclerosis, and dialysis dementia. For example, aluminum has been found in high concentrations in senile plaques and neurofibrillary tangles, which occur in the brains of subjects with Alzheimer disease. However, a mechanism for the entry of aluminum (Al3+) into the cells of the central nervous system (CNS) has yet to be found. Here we describe a possible route of entry for aluminum into the cells of the CNS via the same high-affinity receptor-ligand system that has been postulated for iron (Fe3+) delivery to neurons and glial cells. These results suggest that aluminum is able to gain access to the central nervous system under normal physiological conditions. Furthermore, these data suggest that the interaction between transferrin and its receptor may function as a general metal ion regulatory system in the CNS, extending beyond its postulated role in iron regulation.


A high pressure liquid chromatography study on the removal of DNA-bound aflatoxin B1 in rat liver and in vitro.
Following intraperitoneal administration of [3H] aflatoxin B1 (AFB1) to young adult male rats, there is rapid uptake of the carcinogen by the liver, the target organ for carcinogenesis, leading to DNA covalent binding. Acid hydrolysis of this DNA shows that after 2h, the major DNA adduct is trans 8,9-dihydro-8-(7-guanyl)-9-hydroxy AFB1 (AFB1-gua). By 24h after AFB1 administration the major DNA adduct is no longer AFB1-gua but a product with the identical retention time on h.p.l.c. to 8,9-dihydro-8-(N5-formyl-2',5',6' triamino-4' oxo-N5-pyrimidyl)-9-hydroxy AFB1 (AFB1-triamino-Py). 48h after carcinogen administration, only a small amount of AFB1-gua remains and the major product is AFB1-triamino-Py. The half-life of removal of AFB1-gua is 22h, while AFB1-triamino-Py is much more persistent. In vitro incubation studies on DNA isolated from rats treated 2h previously with [3H] AFB1 show that at pH 7.4 AFB1-gua is the major product released from the DNA with some release of 8,9-dihydro-8,9-dihydroxy AFB1, (AFB1-diol). If more extensively reacted AFB1-DNA is used than that obtained from in vivo administration, then the rate of AFB1-diol release is enhanced while that of AFB1-gua is reduced. It would appear, therefore, that much of the release of AFB1 from DNA in vivo within the first 24h is probably not through a DNA repair process but through chemical release arising from the positively charged N7-guanine. There is considerable conversion of AFB1-gua to AFB1-triamino-Py on in vitro incubation of DNA as well as AFB1-gua and AFB1-diol release. By 24h approximately 66% of the bound AFB1 is in the form of AFB1-triamino-Py and after 48h the conversion is complete. The complex pattern of AFB1-release from DNA may have important consequences in both the induction of mutations and in tumour initiation.


A rare aetiology of respiratory failure in a 10-year-old boy: inflammatory myofibroblastic tumour.
Primary neoplasms of the respiratory tract are rarely encountered in the paediatric population. Inflammatory myofibroblastic tumour (IMT) is a rare soft tissue mesenchymal tumour but a distinct disease entity accounting for less than 1% of all primary lung tumours. We report a case of a 10-year-old boy who presented with respiratory failure and left lung collapse. On flexible fiberoptic bronchoscopy, a pedunculated mass in the lower part of the trachea originating from the left main stem bronchus was identified. The patient subsequently underwent a left-sided pneumonectomy with complete resection of the mass. The histopathological analysis was consistent with IMT. Two years of follow-up and the patient remains well.


Establishment of a multiplex RT-PCR assay to detect different lineages of swine H1 and H3 influenza A viruses.
Classical swine H1N1, emerging European avian-like H1N1 and human-like H3N2 lineages are co-circulating in the swine population in China. The reverse transcriptase polymerase chain reaction (RT-PCR) assay is an effective method for use in influenza surveillance. In this study, a multiplex RT-PCR method was developed for simultaneous identification of hemagglutinin (HA) genes derived from the three lineages of swine influenza viruses. Three primer sets were designed and aimed specifically at HA genes of these viral lineages. The specificity of the assay showed that the established methods could efficiently differentiate the HA genes of classical swine H1N1, European avian-like H1N1, and human-like H3N2 viruses while other viruses such as classical swine fever virus, porcine reproductive and respiratory syndrome virus, pseudorabies virus, and porcine circovirus type 2, could not be detected. The assay showed a sensitivity of 1 x 10(2.5) 50% egg infectious dose for each virus lineage. The comparison of the results with those obtained from the analysis of 300 swine tracheal swab samples by means of virus isolation showed a high level of agreement. This multiplex RT-PCR method provides a rapid and specific swine influenza diagnostic tool that also has the potential for investigating the epidemiology of different lineages of swine influenza virus prevalent currently in China.


MnCo2O4 nanoparticles supported on nitrogen and sulfur co-doped mesoporous carbon spheres as efficient electrocatalysts for oxygen catalytic reactions.
The development of efficient bifunctional electrocatalysts for the oxygen reduction and oxygen evolution reactions is essential to address the challenge of sluggish reaction kinetics. MnCo2O4 nanoparticles supported on nitrogen and sulfur co-doped mesoporous carbon spheres are prepared as non-precious metal electrocatalysts by pyrolysis of thiourea and hydrothermal treatment. The co-doping of nitrogen and sulfur from thiourea into the carbon spheres plays an important role in bimetallic covalent coupling with manganese and cobalt oxides. The as-prepared catalysts exhibit promising catalytic performance of the oxygen reduction reaction compared to commercial platinum catalysts due to the existence of highly active sites. Remarkably, the as-prepared catalysts also exhibit promising catalytic activity of the oxygen evolution reaction, comparable to that of commercial ruthenium oxide in terms of the onset potentials and Tafel slope, and show better durability for both the oxygen reduction reaction and oxygen evolution reaction in an alkaline solution.


Retinal sensitivity and fundus autofluorescence in adult-onset foveomacular vitelliform dystrophy.
The present study aimed to compare retinal sensitivity (RS) at each stage and to evaluate the relationship between RS and fundus autofluorescence (FAF) pattern in adult-onset foveomacular vitelliform dystrophy (AOFVD). We retrospectively reviewed 17 eyes of 13 patients with AOFVD. In addition to best-corrected visual acuity (VA), RS within the affected lesion and optical coherence tomography (OCT) measurements were carried out in each participant. All the examined eyes were classified into 4 stages and 3 FAF patterns. RS was superimposed on OCT fundus image and RS within the affected lesion was calculated in each eye. The relationships between visual functions (VA and RS within the affected lesion) and stages and also FAF patterns were analyzed using the linear mixed model. As a result, RS within the affected lesion was significantly associated with FAF pattern, but not with stage. In contrast, VA was correlated with neither stages nor FAF patterns. Our current result suggested that RS within the affected lesion was related to FAF patterns but this was not the case with VA in eyes with AOFVD, demonstrating the usefulness of measuring RS, not only VA, to comprehend the disease status in AOFVD.


Cutaneous manifestations of biological warfare and related threat agents.
The specter of biological warfare (BW) looms large in the minds of many Americans. The US government has required that emergency response teams in more than 100 American cities be trained by the year 2001 to recognize and contain a BW attack. The US military is requiring active duty soldiers to receive immunization against anthrax. Dermatologists need not feel helpless in the face of a potential BW attack. Many potential agents have cutaneous manifestations that the trained eye of a dermatologist can recognize. Through early recognition of a BW attack, dermatologists can aid public health authorities in diagnosing the cause so that preventive and containment measures can be instituted to mitigate morbidity and mortality. This article reviews bacterial, viral, and toxin threat agents and emphasizes those that would have cutaneous manifestations following an aerosol attack. We conclude with clues that can help one recognize a biological attack.