Sodium glucose transporter protein 2 inhibitors: focusing on the kidney to treat type 2 diabetes.
Type 2 diabetes mellitus (T2DM) is increasing worldwide. Treatment of T2DM continues to present challenges, with a significant proportion of patients failing to achieve and maintain glycemic targets. Despite the availability of many oral antidiabetic agents, therapeutic efficacy is also offset by side effects such as weight gain and hypoglycemia. Therefore, the search for novel therapeutic agents with an improved benefit-risk profile continues. In the following review we focus on a novel class of oral antidiabetic drugs, the sodium glucose transporter protein 2 (SGLT2) inhibitors, which have unique characteristics. SGLT2 inhibitors focus on the kidney as a therapeutic target, where they inhibit the reabsorption of glucose in the proximal tubule, causing an increase in urinary glucose excretion. Doing this, they reduce plasma glucose independently of the β-cell function of the pancreas. SGLT2 inhibitors are effective at lowering hemoglobin A1c, but also induce weight loss and reduce blood pressure, with a low risk of hypoglycemia. In general, the SGLT2 inhibitors are well tolerated, with the most frequent adverse events being mild urinal and genital infections. Since their primary site of effect is the kidney, these drugs are less effective in patients with impaired kidney function but evidence is emerging that these drugs may also have a protective effect against diabetic nephropathy. This review focuses on the most extensively studied SGLT2 inhibitors dapagliflozin, canagliflozin and empagliflozin. Dapagliflozin and canagliflozin have already been approved for marketing by the US Food and Drug Administration. The European Medicines Agency has accepted all three drugs for marketing.


New generalized poisson mixture model for bimodal count data with drug effect: An application to rodent brief-access taste aversion experiments.
Pharmacodynamic (PD) count data can exhibit bimodality and nonequidispersion complicating the inclusion of drug effect. The purpose of this study was to explore four different mixture distribution models for bimodal count data by including both drug effect and distribution truncation. An example dataset, which exhibited bimodal pattern, was from rodent brief-access taste aversion (BATA) experiments to assess the bitterness of ascending concentrations of an aversive tasting drug. The two generalized Poisson mixture models performed the best and was flexible to explain both under and overdispersion. A sigmoid maximum effect (Emax ) model with logistic transformation was introduced to link the drug effect to the data partition within each distribution. Predicted density-histogram plot is suggested as a model evaluation tool due to its capability to directly compare the model predicted density with the histogram from raw data. The modeling approach presented here could form a useful strategy for modeling similar count data types.


Direct measurement of the extinction coefficient by differential transmittance.
A new procedure to measure the extinction coefficient k of film materials that are relatively transparent is presented. This procedure does not require the use of an optical-constant model or the knowledge of extra physical properties of the material, such as the specific heat capacity. It involves preparing a sample with two areas, at least one of them coated with the film, whereas the other may remain uncoated or may be coated with a different thickness of the same material. The differential transmittance between the two sample areas is shown to be proportional to k of the film material in the following measurement conditions: the incident light is p polarized and it impinges at the film material Brewster angle. The differential transmittance is obtained with a single measurement by making the light beam or the sample to oscillate with respect to one another and by using a lock-in amplifier; for normalization purposes, the transmittance in one of the sample areas is also measured. The proportionality factor between the normalized differential transmittance and k only involves the wavelength, the film thickness, and the Brewster angle. The knowledge of the film Brewster angle requires that the film refractive index (n) is measured beforehand; this can be performed with standard procedures, such as ellipsometry, since such techniques are efficient at measuring n of a transparent material, but are inefficient at measuring a small k. The procedure is exemplified with the calculation of k in the far ultraviolet of AlF3 films deposited by evaporation. The dependence of the uncertainty of k obtained with this procedure is analyzed in terms of the uncertainty of the film n, of wavelength, and of the degree of polarization of the incident beam. The selection of a substrate with similar n to the film material is also discussed. The uncertainties involved with the present procedure were analyzed for a specific example and an uncertainty of 2 × 10-5 in k calculation is considered feasible.


The value of antibiotics and the outcomes of antibiotic therapy in exacerbations of COPD.
COPD is the fifth leading cause of death in the United States, and acute respiratory infections account for a significant proportion of all primary care visits. Approximately one half of all exacerbations of COPD can be attributed to bacterial infection, and antibiotic therapy has been demonstrated to improve clinical outcomes and hasten clinical and physiologic recovery. The major pathogen continues to be Haemophilus influenzae, and resistance to beta-lactam antibiotics such as ampicillin can be expected in 20 to 40% of isolated strains. Certain high-risk patients, in whom the cost of clinical treatment failure is high, can be identified by simple clinical criteria. Patients with significant cardiopulmonary comorbidity, frequent purulent exacerbations of COPD, advanced age, generalized debility, malnutrition, chronic corticosteroid administration, long duration of COPD, and severe underlying lung function tend to fail therapy with older drugs, such as ampicillin, and early relapse can be expected. Treatment directed toward resistant pathogens with potent bactericidal drugs may be expected to lead to improved clinical outcomes and overall lower costs, particularly if hospital admissions and respiratory failure can be prevented. Future studies examining the role of antibiotics should enroll these high-risk patients to determine if new therapies have significant clinical, quality-of-life, and economic advantages over older agents.


Deactivation of macrophages by transforming growth factor-beta.
Macrophage activation--enhanced capacity to kill, in a cell that otherwise mostly scavenges--is essential for host survival from infection and contributes to containment of tumours. Both microbes and tumour cells, therefore, may be under pressure to inhibit or reverse the activation of macrophages. This reasoning led to the demonstration of macrophage deactivating factors from both microbes and tumour cells. In some circumstances the host itself probably requires the ability to deactivate macrophages. Macrophages are essential to the healing of wounds and repair of tissues damaged by inflammation. Yet the cytotoxic products of the activated macrophages can damage endothelium, fibroblasts, smooth muscle and parenchymal cells (reviewed in ref. 6). Thus, after an inflammatory site has been sterilized, the impact of macrophage activation on the host might shift from benefit to detriment. These concepts led us to search for macrophage deactivating effects among polypeptide growth factors that regulate angiogenesis, fibrogenesis and other aspects of tissue repair. Among 11 such factors, two proteins that are 71% similar proved to be potent macrophage deactivators: these are transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 2.


Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain-specific drug delivery.
Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain-specific delivery strategy targeting to pyrilamine-sensitive H+/OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H+/OC antiporter in a pH-dependent, Na+-independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC0-t and Cmax in the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo. Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H+/OC antiporter.


Tracking mouse movement in feature inference: category labels are different from feature labels.
In this article, we examine the role of category labels in inductive inference. Some leading research has suggested that information about category membership works just like any other feature in categorical inductions, whereas other research has proposed that the influence of category membership on induction goes beyond that of other features. To investigate these claims further, we developed an online measure of judgments that is akin to eyetracking. The judgment results and the mouse-tracking data jointly support the view that category labels do affect inductive inferences in a way distinct from that for feature information. When arbitrary labels conveyed category membership information, participants viewed these labels more often and earlier in a trial, in comparison with cases in which the same labels conveyed non-membership information. Our results suggest that category membership information works like a guide for inference. An ecological rationale for this induction strategy is also discussed.


NADP-dependent enzymes. I: Conserved stereochemistry of cofactor binding.
The ubiquitous redox cofactors nicotinamide adenine dinucleotides [NAD and NADP] are very similar molecules, despite their participation in substantially different biochemical processes. NADP differs from NAD in only the presence of an additional phosphate group esterified to the 2'-hydroxyl group of the ribose at the adenine end and yet NADP is confined with few exceptions to the reactions of reductive biosynthesis, whereas NAD is used almost exclusively in oxidative degradations. The discrimination between NAD and NADP is therefore an impressive example of the power of molecular recognition by proteins. The many known tertiary structures of NADP complexes affords the possibility for an analysis of their discrimination. A systematic analysis of several crystal structures of NAD(P)-protein complexes show that: 1) the NADP coenzymes are more flexible in conformation than those of NAD; 2) although the protein-cofactor interactions are largely conserved in the NAD complexes, they are quite variable in those of NADP; and 3) in both cases the pocket around the nicotinamide moiety is substrate dependent. The conserved and variable interactions between protein and cofactors in the respective binding pockets are reported in detail. Discrimination between NAD and NADP is essentially a consequence of the overall pocket and not of a few residues. A clear fingerprint in NAD complexes is a carboxylate side chain that chelates the diol group at the ribose near the adenine, whereas in NADP complexes an arginine side chain faces the adenine plane and interacts with the phosphomonoester. The latter type of interaction might be a general feature of recognition of nucleotides by proteins. Other features such as strand-like hydrogen bonding between the NADP diphosphate moieties and the protein are also significant. The NADP binding pocket properties should prove useful in protein engineering and design.


Self-Forming Interlocking Interfaces on the Immiscible Polymer Bilayers via Gelation-Mediated Phase Separation.
Gelation-mediated phase separation is applied to prepare immiscible polymer bilayer films with an interlocking interface structure. Polymer systems consisting of copolymer of urea and polydimethylsiloxane and epoxy are selected to demonstrate the feasibility. When the epoxy fraction exceeds 25 wt%, well-defined bilayer structures self-form by a one-pot casting method in which the phase separation state is fixed by an evaporation-induced gelation. Microscopy studies of the resulting bilayers clearly reveal that interlocking structures form during the bilayer films construct. The interlocking structures lead to an enhanced interfacial adhesion and higher fracture energy. The current strategy might offer a facile way to in situ create an interlocking interface between immiscible polymer systems.


The effects of bile acids on colonic motility in the rabbit.
The content of the rabbit colon has been examined and found to contain the secondary bile acid deoxycholate. Infusions of sodium deoxycholate stimulated colonic motor activity, but the infusion of the primary bile acid sodium glycocholate did not have this effect. Infusions of control amounts of distilled deionized water and isotonic saline were not followed by a significant change in motor activity. Histological damage was caused by 15 mmol.l-1 solutions but was not severe till above 24 mmol.l-1. The possibility that mucosal damage produced motor activity was discounted by the fact that this damage was also present in rabbits treated by sodium glycocholate with no observed motor response. It is postulated that the secondary bile acid, sodium deoxycholate, could have a role in the production of colonic motor activity in the rabbit.


Writing epilepsy.
Two patients complained of myoclonic jerks precipitated by writing. They had suffered only sporadic seizures triggered by reading. Laboratory assessment demonstrated that typing was the most powerful stimulus in triggering spike-wave discharges associated with myoclonic seizures. Sodium Valproate (20 mg/Kg/die) led to a complete remission of seizures in both cases.


The synthesis of DNA complementary to polyadenylate-containing RNA from Bacillus subtilis.
We had shown earlier (Gopalakrishna, Y., Langley, D., Sarkar, N. (1981) Nucleic Acid Res. 9, 3545-3554) that a substantial fraction of mRNA of various bacterial species carries 3'-terminal polyadenylate sequences. In this paper, we show that poly(A)-containing RNA from Bacillus subtilis can serve as template for the synthesis of complementary DNA by avian myeloblastosis virus reverse transcriptase, provided that oligodeoxythymidylate is added as primer. Poly(A)-RNA purified by affinity chromatography on oligo(dT)-cellulose was 20 times more effective as template for cDNA formation than total bacterial RNA, whereas rRNA was inactive. The average chain length of the cDNA was 400 nucleotides (range = 230-800 nucleotides), and 95% of the cDNA could be degraded by the single-strand specific S1 nuclease after denaturation. The small fraction (5%) that was resistant to S1 nuclease may represent duplex hairpin structures. Annealing with poly(A)-RNA protected cDNA from degradation by S1 nuclease, indicating that cDNA indeed contains nucleotide sequences complementary to poly(A)-RNA. These results constitute independent evidence that a large fraction (about 40%) of B. subtilis mRNA is polyadenylated. Moreover, the synthesis of cDNA to bacterial mRNA provides an important new tool for the study of bacterial mRNA structure.


Chronic cranial window with access port for repeated cellular manipulations, drug application, and electrophysiology.
Chronic cranial windows have been instrumental in advancing optical studies in vivo, permitting long-term, high-resolution imaging in various brain regions. However, once a window is attached it is difficult to regain access to the brain under the window for cellular manipulations. Here we describe a simple device that combines long term in vivo optical imaging with direct brain access via glass or quartz pipettes and metal, glass, or quartz electrodes for cellular manipulations like dye or drug injections and electrophysiological stimulations or recordings while keeping the craniotomy sterile. Our device comprises a regular cranial window glass coverslip with a drilled access hole later sealed with biocompatible silicone. This chronic cranial window with access port is cheap, easy to manufacture, can be mounted just as the regular chronic cranial window, and is self-sealing after retraction of the pipette or electrode. We demonstrate that multiple injections can be performed through the silicone port by repetitively bolus loading calcium sensitive dye into mouse barrel cortex and recording spontaneous cellular activity over a period of weeks. As an example to the extent of its utility for electrophysiological recording, we describe how simple removal of the silicone seal can permit patch pipette access for whole-cell patch clamp recordings in vivo. During these chronic experiments we do not observe any infections under the window or impairment of animal health.


TASK-1 potassium channel is not critically involved in mediating hypoxic pulmonary vasoconstriction of murine intra-pulmonary arteries.
The two-pore domain potassium channel KCNK3 (TASK-1) is expressed in rat and human pulmonary artery smooth muscle cells. There, it is associated with hypoxia-induced signalling, and its dysfunction is linked to pathogenesis of human pulmonary hypertension. We here aimed to determine its role in hypoxic pulmonary vasoconstriction (HPV) in the mouse, and hence the suitability of this model for further mechanistic investigations, using appropriate inhibitors and TASK-1 knockout (KO) mice. RT-PCR revealed expression of TASK-1 mRNA in murine lungs and pre-acinar pulmonary arteries. Protein localization by immunohistochemistry and western blot was unreliable since all antibodies produced labelling also in TASK-1 KO organs/tissues. HPV was investigated by videomorphometric analysis of intra- (inner diameter: 25-40 μm) and pre-acinar pulmonary arteries (inner diameter: 41-60 μm). HPV persisted in TASK-1 KO intra-acinar arteries. Pre-acinar arteries developed initial HPV, but the response faded earlier (after 30 min) in KO vessels. This HPV pattern was grossly mimicked by the TASK-1 inhibitor anandamide in wild-type vessels. Hypoxia-provoked rise in pulmonary arterial pressure (PAP) in isolated ventilated lungs was affected neither by TASK-1 gene deficiency nor by the TASK-1 inhibitor A293. TASK-1 is dispensable for initiating HPV of murine intra-pulmonary arteries, but participates in sustained HPV specifically in pre-acinar arteries. This does not translate into abnormal rise in PAP. While there is compelling evidence that TASK-1 is involved in the pathogenesis of pulmonary arterial hypertension in humans, the mouse does not appear to serve as a suitable model to study the underlying molecular mechanisms.


Condomless Anal Sex Among HIV-Positive Men Who Have Sex with Men: Biomedical Context Matters.
Data from Medical Monitoring Project was used to determine if partner type is associated with condomless anal sex (CAS) and insertive condomless anal sex (ICAS) among HIV-positive men who have sex with men. Participants reported HIV status and PrEP use of up to five anal sex partners. Partner type was categorized as HIV-positive, HIV status unknown, HIV-negative on PrEP or HIV-negative not on PrEP. To account for correlation of multiple observations per participant, generalized estimating equations were used to calculate adjusted prevalence ratios and 95% confidence intervals of CAS and ICAS. Condom use during anal sex and insertive anal sex varied based on partner type. There was a higher prevalence of CAS and ICAS in partnerships with HIV-positive partners or HIV-negative partners on PrEP compared to HIV-negative partners not on PrEP.


Assessing the role of particulate matter size and composition on gene expression in pulmonary cells.
Identifying the mechanisms by which air pollution causes human health effects is a daunting task. Airsheds around the world are composed of pollution mixtures made up of hundreds of chemical and biological components with an extensive array of physicochemical properties. Current in vivo approaches are limited to the identification of associations between pollutants and health but do not allow for the identification of precise biological mechanisms of effect or the component(s) responsible for the effect. High-throughput in vitro methods using relevant cell culture systems and microarray technology allow researchers to evaluate the mechanisms by which air pollutants affect human health. Our studies have used human airway epithelial cells primarily to test the toxicological effects of particles of different sizes and of various particle components from several cities across the United States. Chemical mass balance analysis is also being used to analyze these samples to establish links between physicochemical properties of particulate matter (PM) and potential sources. The ultimate goal of this line of research is to link the mechanistic data to the PM source data in order to gain an understanding about how the components and sources of PM affect human health.


In vivo efficacy of HD0471953: a novel GPR119 agonist for the treatment of type 2 diabetes mellitus.
G-protein coupled receptor 119 (GPR119) has emerged as a promising new target for the treatment of type 2 diabetes mellitus. The expression of GPR119 on the pancreatic B cells and intestinal L cells provides a unique opportunity for a single drug to promote insulin and GLP-1 secretion. In this study, we identified a novel small molecule GPR119 agonist, HD0471953, from our large library of synthetic compounds based on its ability to anti-hyperglycemic effects on T2DM murine models. We have tested the acute efficacy of HD0471953 by the oral glucose tolerance test (OGTT) with normal C57BL/6J mice. Then, chronic administrations of HD0471953 were performed to evaluate the efficacy on various diabetic rodent models. Single administration of HD0471953 showed improved glycemic control with a dose-dependent manner in OGTT with normal mice, and the insulin and GLP-1 were also increased. To identify chronic efficacy, we have observed a decline of blood glucose and fasting insulin in a dose-dependent manner of 10, 20, and 50 mpk in db/db mice. The results suggest that HD0471953 may be a potentially promising anti-hyperglycemic agent for the treatment of patients with type 2 diabetes mellitus.


Assessment of disrupted brain functional connectome in tuberous sclerosis complex using resting-state fMRI.
Tuberous sclerosis complex (TSC) is a rare genetic disorder with multisystem involvement. TSC is characterized by benign hamartomas in multiple organs, including the brain, and its clinical phenotypes may be associated with abnormal functional connections. We aimed to use resting-state functional connectivity to provide findings of disrupted functional brain networks in TSC patients using graph theoretical analysis (GTA) and network-based statistic (NBS) analysis.Forty TSC patients (age = 24.11+/-11.44 years old) and 18 age-matched (25.13+/- 10.01 years old) healthy controls were recruited; they underwent resting-state functional magnetic resonance imaging using a 3T magnetic resonance imaging scanner. After image preprocessing and removing physiological noises, GTA was used to calculate the topological parameters of the brain network. NBS analysis was then used to determine the differences in cerebrum functional connectivity between the 2 groups.In GTA, several topological parameters, including the clustering coefficient, local efficiency, transitivity, and modularity, were better in controls than in TSC patients (P < .05). In NBS analysis, the edges of the brain networks between the groups were compared. One subnetwork showed more edges in controls than in TSC patients (P < .05), including the connections from the frontal lobe to the temporal and parietal lobe.The study results provide the findings on disrupted functional connectivity and organization in TSC patients compared with controls. The findings may help better understand the underlying physiological mechanisms of brain connection in TSC.


Dielectrophoretic recovery of DNA from plasma for the identification of chronic lymphocytic leukemia point mutations.
Circulating cell free (ccf) DNA contains information about mutations affecting chronic lymphocytic leukemia (CLL). The complexity of isolating DNA from plasma inhibits the development of point-of-care diagnostics. Here, we introduce an electrokinetic method that enables rapid recovery of DNA from plasma. ccf-DNA was isolated from 25 µl of CLL plasma using dielectrophoresis. The DNA was used for PCR amplification, sequencing and analysis. The ccf-DNA collected from plasma of 5 CLL patients revealed identical mutations to those previously identified by extracting DNA from CLL cells from the same patients. Rapid dielectrophoresis isolation of ccf-DNA directly from plasma provides sufficient amounts of DNA to use for identification of point mutations in genes associated with CLL progression.


[Clinical study of neoadjuvant intraarterial chemotherapy (I A-MAC) for advanced bladder cancer].
The clinical efficacy of intraarterial neoadjuvant chemotherapy with MTX, ADR and CDDP in 88 patients with advanced bladder cancer (> or = T2 or TCC G3) was evaluated. The intraarterial chemotherapy was performed using Seldinger's method. The three drugs were administered at the same time among 60 patients. In sixteen patients MTX was administered intravenously before intraarterial infusion of ADR and CDDP. In twelve patients, a high dose of CDDP (more than 100 mg/m2) was administered. The mean regression rate was 70%. That of the high-dose CDDP group was rather superior to the other two groups. However, the adverse reaction and duration of recovery were inferior to those of the other two groups. When intraarterial chemotherapy is performed as a neoadjuvant chemotherapy, care must be taken to determine the suitable dose.


Detection of condensin I and II in maturing pig oocytes.
The multiprotein complexes known as condensins (I and II) are major players in chromosome dynamics in mitotic and meiotic cells. Here, we report for the first time the detection of different condensin subunits from both complexes in mammalian oocytes. Using immunoblotting analysis we examined expression levels of condensin subunits during meiotic maturation of porcine oocytes. The expression of the core subunit structural maintenance of chromosomes 2 (SMC2), identical in both condensin complexes, did not change significantly during maturation. Similarly, there was no significant change in the expression of the chromosome associated protein (CAP)-H and CAP-H2 subunits, components of condensin I and II, respectively. Conversely, the expression profiles of CAP-G, CAP-D2 (condensin I) and CAP-D3 (condensin II) were more interesting. At least two isoforms of the CAP-D2 subunit were detected, along with three isoforms of the CAP-D3 and CAP-G subunits. We suggest that this diverse migration of subunit isoforms is due to post-translational modification. Earlier, it was reported that non-SMC proteins are phosphorylated by cyclin-dependent kinase 1. In the present study, we analysed the phosphorylation status of the three subunits in oocyte extracts using alkaline phosphatase treatment and we found that at least the fastest migrating form of CAP-D3 was likely to be phosphorylated in maturing porcine oocytes. In addition, the localisation of CAP-H and CAP-H2 subunits was examined using immunofluorescence staining with specific antibodies, as well as following microinjection of their enhanced green fluorescent protein-tagged mRNA into germinal vesicle-stage oocytes. CAP-H was found in the cytoplasm, whereas CAP-H2 was localised within the nucleus.


Is retroflexion a stable cue for distributional learning for speech sounds across languages? Learning for some bilingual adults, but not generalisable to a wider population in a well powered pre-registered study.
Bilinguals are widely reported to have certain kinds of cognitive advantages, including language learning advantages. One possible pathway is a language-specific transfer effect, whereby sensitivity to structural regularities in known languages can be brought to to-be-acquired languages that share particular features. Here we tested for transfer of a specific linguistic property, sensitivity to retroflexion as contrastive phonemic feature. We designed a task for bilinguals with homogeneous language exposure (i.e., bilingual in the same languages) and heterogeneous feature representation (i.e., differing levels of proficiency). Hindi and Mandarin Chinese both have retroflexion in phoneme contrasts (Hindi: stop consonants, Mandarin: sibilants). In a preregistered study, we conducted a statistical learning task for the Hindi dental-retroflex stop contrast with a group of early parallel English-Mandarin bilinguals, who varied in their Mandarin understanding levels. We based the target sample size on power analysis of a pilot study with a Bayesian stop-rule after minimum threshold. Contrary to the pilot study (N = 15), the main study (N = 50) did not find evidence for a learning effect, nor language-experience variance within the group. This finding suggests that statistical effects for the feature in question may be more fragile than commonly assumed, and may be evident in only a small subsample of the general population (as in our pilot). These stimuli have previously shown learning effects in children, so an additional possibility is that neural commitment to adults' languages prevents learning of the fine-grained stimulus contrast in question for this adult population.


Glucose-dependent insulinotropic action of cholecystokinin and caerulein in the isolated perfused rat pancreas.
The effect of pure natural porcine cholecystokinin (CCK) and synthetic caerulein on endocrine and exocrine pancreatic secretion was investigated in the isolated perfused rat pancreas in the presence of physiological concentrations of glucose. CCK (0.25 mU/ml) or caerulein (0.01 ng/ml) potentiated the insulin secretion induced by 5.6 mM glucose; a significant increase in pancreatic exocrine secretion was also observed at these doses of CCK or caerulein. Further increases in the concentration of CCK (0.25 to 1 mU/ml) or caerulein (0.01 to 1 ng/ml) resulted in dose-dependent increases in both insulin and pancreatic exocrine secretion. The effectiveness of CCK and caerulein as insulinotropic agents depended on the glucose concentration; they were more effective at higher concentrations of glucose. Thus, CCK or caerulein significantly and coincidentally stimulated both insulin secretion and pancreatic exocrine function if 5.6 mM or more glucose is present, whereas in previous studies using 2.8 mM glucose, stimulation of insulin secretion was elicited only with concentrations of the peptides supramaximal for an effect on pancreatic exocrine secretion. CCK may contribute to the entero-insular axis.


Key components of the delirium syndrome and mortality: greater impact of acute change and disorganised thinking in a prospective cohort study.
Delirium increases the risk of mortality during an acute hospital admission. Full syndromal delirium (FSD) is associated with greatest risk and subsyndromal delirium (SSD) is associated with intermediate risk, compared to patients with no delirium - suggesting a dose-response relationship. It is not clear how individual diagnostic symptoms of delirium influence the association with mortality. Our objectives were to measure the prevalence of FSD and SSD, and assess the effect that FSD, SSD and individual symptoms of delirium (from the Confusion Assessment Method-short version (s-CAM)) have on mortality rates. Exploratory analysis of a prospective cohort (aged ≥70 years) with acute (unplanned) medical admission (4/6/2007-4/11/2007). The outcome was mortality (data censored 6/10/2011). The principal exposures were FSD and SSD compared to no delirium (as measured by the CAM), along with individual delirium symptoms on the CAM. Cox regression was used to estimate the impact FSD and SSD and individual CAM items had on mortality. The cohort (n = 610) mean age was 83 (SD 7); 59% were female. On admission, 11% had FSD and 33% had SSD. Of the key diagnostic symptoms for delirium, 17% acute onset, 19% inattention, 17% disorganised thinking and 17% altered level of consciousness. Unadjusted analysis found FSD had an increased hazard ratio (HR) of 2.31 (95% CI 1.71, 3.12), for SSD the HR was 1.26 (1.00, 1.59). Adjusted analysis remained significant for FSD (1.55 95% CI 1.10, 2.18) but nonsignificant for SSD (HR = 0.92 95% CI 0.70, 1.19). Two CAM items were significantly associated with mortality following adjustment: acute onset and disorganised thinking. We observed a dose-response relationship between mortality and delirium, FSD had the greatest risk and SSD having intermediate risk. The CAM items "acute-onset" and "disorganised thinking" drove the associations observed. Clinically, this highlights the necessity of identifying individual symptoms of delirium.


Chryseobacterium meningosepticum infection and cardiac tamponade in a long-term hemodialysis patient.
Chryseobacterium meningosepticum is a lactose-nonfermenting gram-negative bacilli ubiquitously found in the natural and hospital environment. Clinical infection caused by C. meningosepticum is very rare among healthy adults. We present the case of a patient with end-stage renal disease who developed purulent pericarditis with C. meningosepticum infection, which rapidly evolved into cardiac tamponade and death. To our knowledge, this is the first case in which C. meningosepticum caused fatal purulent pericarditis in a hemodialysis patient.


Effects of preformed immune complexes on liver enzymes & their serum clearance in mice.
Two different performed HSA-anti-HSA immune aggregates, insoluble complex at equivalence (IC-E) and soluble complex with 5 times antigen excess (IC-S)-were administered iv in experimental mice to study their interaction with liver cells. Both complexes produced no appreciable change in the levels of liver enzymes like acid phosphatase, cathepsin D and gamma-glutamyl transferase. However, marked reduction in the level of liver pseduocholinesterase (as much as 93%) was recorded in the treated animals under identical conditions of administration of both the complexes. Hepatic uptake studies revealed that within 5 min, maximal sequestration of IC occurred within the liver (10 to 18%) and the blood (70 to 82%) when computed in terms of total injected radioactive IC. After 4 h, radioactivity dropped to 3 per cent in liver and 50-40 per cent in blood. The liver seemed to be incapable of scavenging all the serum complexes at a time. Significant consumption of serum complement occurred, when freshly prepared complexes were administered to the animals, but the reduced complement level showed a tendency to reach normalcy after 2 h. The soluble and equivalence zone IC failed to exhibit identifiable discrimination facets with respect to handling by liver. The complexes IC-E and IC-S also behaved in a similar manner.


Stability analysis with general fuzzy measure: An application to social security organizations.
An effective method for evaluating the efficiency of peer decision-making units (DMUs) is data envelope analysis (DEA). In engineering sciences and real-world management problems, uncertainty in input and output data always exists. To achieve reliable results, uncertainties must be taken into account. In this research, a General Fuzzy (GF) approach is designed to cope with uncertainty in the presence of fuzzy observations for categorizing and specifying stability radius and alterations ranges of efficient and inefficient DMUs, which is applicable to real-world decision-making problems. For this purpose, a DEA sensitivity analysis model is presented, which will be modeled by fuzzy sets. Then, by applying the General Fuzzy (GF) approach, the fuzzy DEA sensitivity analysis model is transformed into the equivalent crisp form of fuzzy chance constraints according to specific confidence levels. Finally, a numerical example and a case study of branches of the social security organization are presented to illustrate sensitivity and stability analysis in the presence of fuzzy data. The obtained results provide the input and output changes of the evaluated units according to the attitude and preference of the decision maker with different confidence levels so that the data changes in the fuzzy environment do not change the units' classification from efficient to inefficient and vice versa.


Coarsening Dynamics of True Morphological Phase Separation in Unstable Thin Films.
Unstable thin films can spontaneously phase separate into two equilibrium flat-film morphologies of different thicknesses under the influence of gravity or favorable combinations of apolar and polar excess intermolecular forces. Two distinct pathways and associated dynamics of this morphological phase separation are presented based on numerical simulations of the 2-D thin film equation. The two pathways are (1) the "direct pathway" whereby the thicker phase forms directly and concurrently with the thinner phase and (2) the "defect pathway" whereby the thicker phase forms by the coarsening of defects of intermediate thickness and appears much later than the thinner phase. The defect pathway is favored by films whose initial thickness lies closer to the thickness of the thinner phase. Both pathways show an initial power law decay with exponent -1/4 in time followed by a plateau in the number density of domains/defects. Thereafter, the defect pathway shows another universal power law decay with exponent -1/3 and ends with a logarithmic decay, which is specific to the d = 2 case as there is no interfacial curvature in d = 2. The direct pathway skips the second power law decay and goes directly to the logarithmic decay.


In situ visualization of DNA double-strand break repair in human fibroblasts.
A method was developed to examine DNA repair within the intact cell. Ultrasoft x-rays were used to induce DNA double-strand breaks (DSBs) in defined subnuclear volumes of human fibroblasts and DNA repair was visualized at those sites. The DSBs remained in a fixed position during the initial stages of DNA repair, and the DSB repair protein hMre11 migrated to the sites of damage within 30 minutes. In contrast, hRad51, a human RecA homolog, did not localize at sites of DNA damage, a finding consistent with the distinct roles of these proteins in DNA repair.


Molecular profiling of lung carcinoma: identifying clinically useful tumor markers for diagnosis and prognosis.
The overall survival of patients with lung cancer is dismal despite extensive effort in improvement of diagnosis and treatment. A better understanding of the multistep genetic and epigenetic alterations in lung cancer pathogenesis and progression is necessary for development of improved diagnostic approaches and new targeted therapies. Identification of molecular alterations in the early lung carcinogenesis, together with advanced molecular techniques, may facilitate development of rapid and effective methods for early diagnosis and prognosis of lung carcinoma. In this review, we discuss current understanding of lung carcinogenesis and prospective molecular markers in lung cancer diagnosis. Although the impact of translating new technologies into clinical practice on survival has not been completely determined, they offer a new avenue of exciting novel approaches to early diagnosis of this deadly disease.


Hypopituitarism: A rare sequel of cerebral malaria - Presenting as delayed awakening from general anesthesia.
We report a case of delayed emergence from anesthesia in a 37-year-old male who came for emergency laparoscopic appendicectomy. This patient is hailing from one of the endemic zones of Malaria, Orissa State in India. Two months ago he had cerebral malaria and was treated in our intensive care unit. After recovering from cerebral malaria, he presented to us for acute abdomen, and he was taken for emergency laparoscopic appendicectomy. He had delayed emergence of around 2 h to extubate from the time of completion of surgery in spite of termination of anesthetic agents. Further investigations showed to have decreased serum levels of thyroid hormones and cortisol levels in the postoperative period. The Physician promptly diagnosed the condition as hypopituitarism a known sequel of cerebral malaria. The secondary thyroid insufficiency contributing to the delayed emergence from anesthesia. We also review the pertinent literature related to this rare sequelae of cerebral malaria and its perioperative implication to the anesthesiologist.


Survival and settlement success of coral planulae: independent and synergistic effects of macroalgae and microbes.
Restoration of degraded coral reef communities is dependent on successful recruitment and survival of new coral planulae. Degraded reefs are often characterized by high cover of fleshy algae and high microbial densities, complemented by low abundance of coral and coral recruits. Here, we investigated how the presence and abundance of macroalgae and microbes affected recruitment success of a common Hawaiian coral. We found that the presence of algae reduced survivorship and settlement success of planulae. With the addition of the broad-spectrum antibiotic, ampicillin, these negative effects were reversed, suggesting that algae indirectly cause planular mortality by enhancing microbial concentrations or by weakening the coral's resistance to microbial infections. Algae further reduced recruitment success of corals as planulae preferentially settled on algal surfaces, but later suffered 100% mortality. In contrast to survival, settlement was unsuccessful in treatments containing antibiotics, suggesting that benthic microbes may be necessary to induce settlement. These experiments highlight potential complex interactions that govern the relationships between microbes, algae and corals and emphasize the importance of microbial dynamics in coral reef ecology and restoration.


Functional Approach for Coronary Artery Disease: Filling the Gap Between Evidence and Practice.
The presence of myocardial ischemia is the most important prognostic factor in patients with coronary artery disease, and ischemia-directed revascularization has been a standard of care. Fractional flow reserve (FFR) is an invasive method used to detect the functionally significant epicardial coronary stenosis, and FFR-guided revascularization strategy has been proven to be superior to angiography-guided strategy. Recently, a hyperemia-free index, instantaneous wave free ratio (iFR), was developed and showed its non-inferiority for clinical outcomes compared with FFR-guided strategy. While evidence supporting the benefit of pressure wire assessment exists, there remain several unresolved issues, such as the mechanism of discordance between resting and hyperemic physiologic indices, clinical outcomes of patient/lesions with discordant results among the physiologic indices, role of physiologic indices beyond per-vessel decision tool, and the role of microvascular dysfunction in patient prognosis. The current article will review the recent studies performed to address these questions.


Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model.
Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for idiopathic pulmonary fibrosis and advanced Hepatocellular carcinoma, but has not been explored for liver fibrosis yet. In this study, we aimed to investigate the therapeutic effects and mechanism of BIBF1120 in liver fibrogenesis. The effects of BIBF1120 were evaluated in TGFβ-activated mouse 3T3 fibroblasts, LX2 cells, primary human hepatic stellate cells (HSCs) and CCl4-induced liver fibrogenesis mouse model. Fibroblasts-conditioned medium studies were performed to assess the paracrine effects on macrophages and endothelial cells. In-vitro in TGFβ-activated fibroblasts, BIBF1120 significantly inhibited expression of major fibrotic parameters, wound-healing and contractility. In vivo in CCl4-induced acute liver injury model, post-disease BIBF1120 administration significantly attenuated collagen accumulation and HSC activation. Interestingly, BIBF1120 drastically inhibited intrahepatic inflammation and angiogenesis. To further elucidate the mechanism of action, 3T3-conditioned medium studies demonstrated increased 3T3-mediated macrophage chemotaxis and endothelial cells tube formation and activation, which was significantly decreased by BIBF1120. These results suggests that BIBF1120 can be a potential therapeutic approach for the treatment of liver fibrosis.


SATVI - after 10 years closing in on a new and better vaccine to prevent tuberculosis.
The vision of the South African Tuberculosis Vaccine Initiative (SATVI) (www.satvi.uct.ac.za) is 'A World Without TB' and our mission is 'Innovative and high-quality TB vaccine research in Africa, to impact the global epidemic'. Over the last 10 years, our focus has been twofold: first, clinical trials of BCG and of new candidate vaccines, and second, complementary research that addresses critical questions in TB vaccine development. SATVI is now widely regarded as the leading TB vaccine clinical research site in the world.


The role of prospero homeobox 1 (PROX1) expression in follicular thyroid carcinoma cells.
The prospero homeobox 1 (Prox1) transcription factor is a key player during embryogenesis and lymphangiogenesis. Altered Prox1 expression has been found in a variety of human cancers, including papillary thyroid carcinoma (PTC). Interestingly, Prox1 may exert tumor suppressive or tumor promoting effect, depending on the tissue context. In this study, we have analyzed Prox1 expression in normal and malignant human thyroid carcinoma cell lines. Moreover, we determined the effect of Prox1 silencing and overexpression on the cellular processes associated with the metastatic potential of tumor cells: proliferation, migration, invasion, apoptosis and anchorage-independent growth, in the follicular thyroid carcinoma (FTC) FTC-133 cell line. We found that Prox1 expression was significantly higher in FTC-derived cells than in PTC-derived cells and normal thyroid, and it was associated with the PI3K/Akt signaling pathway. In the FTC-133 cells, it was associated with cell invasive potential, motility and wound closure capacities, but not with proliferation or apoptosis. Modifying Prox1 expression also induced substantial changes in the cytoskeleton structure and cell morphology. In conclusion, we have shown that Prox1 plays an important role in the development of FTC and that its suppression prevents, whereas its overexpression promotes, the malignant behavior of thyroid follicular cancer cells.


Polymer Composite with Improved Thermal Conductivity by Constructing a Hierarchically Ordered Three-Dimensional Interconnected Network of BN.
In this work, we report a fabrication of epoxy resin/ordered three-dimensional boron nitride (3D-BN) network composites through combination of ice-templating self-assembly and infiltration methods. The polymer composites possess much higher thermal conductivity up to 4.42 W m-1 K-1 at relatively low loading 34 vol % than that of random distribution composites (1.81 W m-1 K-1 for epoxy/random 3D-BN composites, 1.16 W m-1 K-1 for epoxy/random BN composites) and exhibit a high glass transition temperature (178.9-229.2 °C) and dimensional stability (22.7 ppm/K). We attribute the increased thermal conductivity to the unique oriented 3D-BN thermally conducive network, in which the much higher thermal conductivity along the in-plane direction of BN microplatelets is most useful. This study paves the way for thermally conductive polymer composites used as thermal interface materials for next-generation electronic packaging and 3D integration circuits.


Equal Distribution of Mating Type Alleles and the Presence of Strobilurin Resistance in Algerian Zymoseptoria tritici Field Populations.
Zymoseptoria tritici, the causal agent of septoria tritici blotch, is an important wheat pathogen responsible for high yield losses worldwide. The assessment of the distribution of both mating type idiomorphs was studied in several wheat-growing areas in North Algeria. Both mating types occurred at all spatial scales tested and showed an equal frequency distribution at the country level, with 53% for Mat1-1 and 47% for Mat1-2. At finer scales, co-occurrence of both mating types was found in 38% of leaves analyzed and 44% of the studied lesions. Additionally, efficacy reduction of strobilurin applications prompted us to study strobilurin resistance conferred by the G143A substitution in the mitochondrial cytochrome b gene, which was found for the first time in six strains. The results suggest that the Algerian Z. tritici population undergoes frequent sexual reproduction mirrored by co-occurrence of both mating types, which likely will rapidly increase the fraction of strobilurin-resistant isolates in the Algerian population, as has been shown in all other regions where strobilurin resistance surfaced.


The course of shipped livers used as full size, reduced or split grafts.
A total of 110 transplants, 66 in adults (8 retransplants) and 30 in children (6 retransplants) were analysed according to the origin of the graft (shipped n = 39-non-shipped i.e. self procured n = 71) and the way they were transplanted (as full size grafts (FS) n = 82, reduced size grafts (RED) n = 23 or split grafts (SG) n = 5). Twenty-nine transplants were performed for urgent and 81 for elective indications. There was a statistically higher incidence of 2 or more risk factors in the donors that were selfprocured (non shipped) than in donors from shipped livers (p = 0.025). The overall 3 months graft survival was 79.5% for shipped livers versus 69% for non-shipped livers and patients survival was 89.2% versus 79.0% respectively after 3 months and 82.9% versus 74.4% after 40 months. From these results that were analysed with risk factors of the donors, cold ischaemia time and liver function tests in recipients, transplanted for acute and elective indications, it is concluded that shipping of grafts is a practical and safe procedure even if size reduction or the use of SG is intended.


Mitochondrial carrier proteins can reversibly change their transport mode: the cases of the aspartate/glutamate and the phosphate carrier.
A number of mitochondrial carrier systems function both in homologous and in heterologous exchange mode, which, in the case of the phosphate carrier is a homologous Pi(-)-Pi- and a heterologous Pi(-)-OH- exchange. In addition, we showed that mitochondrial carriers, e.g. the aspartate/glutamate and the phosphate carrier, can undergo a functional shift from coupled antiport to uncoupled uniport after modification of cysteine residues. In this transport mode a mixture of carrier- and channel-type properties is observed. To address this question on the molecular level, the phosphate carrier from yeast (S. cerevisiae) mitochondria was expressed in E. coli, solubilized, purified and functionally reconstituted. From three cysteine residues present in the yeast phosphate carrier at positions 28, 134 and 300, only one single cysteine residue (C28) was found responsible for the functional switch from antiport to uniport. Upon replacement by a serine residue, this interconversion was blocked. After incorporation of the carrier into giant liposomes, electrophysiological methods (patch clamp) were applied. Under these conditions, a fourth transport mode of the phosphate carrier was observed, namely an action as anion-selective channel, which could be reversibly blocked by phosphate.


A method for the identification of Streptococcus mutans in gingival margin plaque by immunofluorescence.
A method was developed to identify Streptococcus mutans in natural dental plaque by indirect immunofluorescence staining, using a high-titred polyclonal antiserum raised against a serotype c strain of S. mutans followed by an FITC conjugate. Specificity was determined by staining 45 representative strains of plaque organisms, which demonstrated minimal cross-reactions. In vitro incubation of S. mutans NCTC 10449 films with a human serum containing antibodies to S. mutans and the presence of extracellular polysaccharide did not inhibit staining. The staining method enabled 98% of the streptococci to be detected in mixtures of S. mutans NCTC 10449 and Lactobacillus casei NCTC 10302. S. mutans was detected at a ratio of 1:100,000 in mixtures of pure cultures. In plaque samples, S. mutans could be distinguished from other organisms, including an unidentified cross-reacting bacillus found in some gingival plaque samples. The results suggest that immunofluorescence is a fast, practical method for identifying specific bacteria in plaque and, therefore, could be of use in microbiological studies of caries.


The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior.
The peptide hormone angiotensin II (ATII) plays a prominent role in regulating vasoconstriction and blood pressure. Its primary target is the angiotensin II receptor type 1 (AT1), the stimulation of which induces an increase in cytosolic [Ca2+] and calmodulin activation. Ca2+-bound (activated) calmodulin stimulates the activity of the Na+/ H+ exchanger isoform 1 (NHE1); and increased NHE1 activity is known to promote melanoma cell motility. The competitive AT1 receptor inhibitor losartan is often used to lower blood pressure in hypertensive patients. Since AT1 mediates ATII-stimulated NHE1 activity, we set out to investigate whether ATII and losartan have an impact on NHE1-dependent behavior of human melanoma (MV3) cells. ATII receptor expression was verified by PCR, F-actin was visualized using fluorescently labeled phalloidin, and cytosolic [Ca2+] and pH were determined ratiometrically using Fura-2 and BCECF, respectively. MV3 cell behavior was analyzed using migration, adhesion, invasion and proliferation assays. MV3 cells express both AT1 and the angiotensin II receptor type 2 (AT2). Stimulation of MV3 cells with ATII increased NHE1 activity which could be counteracted by both losartan and the Ca2+/ calmodulin inhibitor ophiobolin-A. ATII stimulation induced a decrease in MV3 cell migration and a more spherical cell morphology accompanied by an increase in the density of F-actin. Independently of the presence of ATII, both NHE1 and migratory activity were reduced when AT1 was blocked by losartan. On the other hand, losartan clearly increased cell adhesion to, and the invasion of, a collagen type I substrate. The AT2 inhibitor PD123319 did not affect NHE1 activity, proliferation and migration, but increased adhesion and invasion. Losartan inhibits NHE1 activity and the migration of human melanoma cells. At the same time, losartan promotes MV3 cell adhesion and invasion. The therapeutic use of AT1 antagonists (sartans) in hypertensive cancer patients should therefore be given critical consideration.


Expression of histamine H2 receptor in Chinese hamster ovary cells: a probe to study the desensitization mechanism.
Canine histamine H2 receptor DNA, cloned by polymenase chain reaction (PCR), was transfected into Chinese hamster ovary cells using an expression vector. The expression of H2 receptors was demonstrated by immunoblotting with specific antibodies and the binding of tiotidine, an H2 receptor antagonist. H2 receptor-specific cAMP production was observed only in cells expressing canine H2 receptors. Preincubation of transfected cells with 10 microM histamine for 10 or 60 min at 37 degrees C decreased both the maximal response and the sensitivity of the subsequent histamine-stimulated cAMP production, showing desensitization. Under these circumstances, decreases in tiotidine binding without changes in affinity in intact cells and also in the membrane were observed, whereas there was no decrease in total H2 receptor number. Thus, desensitization of histamine H2 receptor was associated with the sequetration of receptors.


Technology Literacy in Undergraduate Medical Education: Review and Survey of the US Medical School Innovation and Technology Programs.
Modern innovations, like machine learning, genomics, and digital health, are being integrated into medical practice at a rapid pace. Physicians in training receive little exposure to the implications, drawbacks, and methodologies of upcoming technologies prior to their deployment. As a result, there is an increasing need for the incorporation of innovation and technology (I&T) training, starting in medical school. We aimed to identify and describe curricular and extracurricular opportunities for innovation in medical technology in US undergraduate medical education to highlight challenges and develop insights for future directions of program development. A review of publicly available I&T program information on the official websites of US allopathic medical schools was conducted in June 2020. Programs were categorized by structure and implementation. The geographic distribution of these categories across US regions was analyzed. A survey was administered to school-affiliated student organizations with a focus on I&T and publicly available contact information. The data collected included the founding year, thematic focus, target audience, activities offered, and participant turnout rate. A total of 103 I&T opportunities at 69 distinct Liaison Committee on Medical Education-accredited medical schools were identified and characterized into the following six categories: (1) integrative 4-year curricula, (2) facilitated doctor of medicine/master of science dual degree programs in a related field, (3) interdisciplinary collaborations, (4) areas of concentration, (5) preclinical electives, and (6) student-run clubs. The presence of interdisciplinary collaboration is significantly associated with the presence of student-led initiatives (P=.001). "Starting and running a business in healthcare" and "medical devices" were the most popular thematic focuses of student-led I&T groups, representing 87% (13/15) and 80% (12/15) of respondents, respectively. "Career pathways exploration for students" was the only type of activity that was significantly associated with a high event turnout rate of >26 students per event (P=.03). Existing school-led and student-driven opportunities in medical I&T indicate growing national interest and reflect challenges in implementation. The greater visibility of opportunities, collaboration among schools, and development of a centralized network can be considered to better prepare students for the changing landscape of medical practice.


Effects of selected socio-demographic characteristics on nutrition knowledge and eating behavior of elementary students in two provinces in China.
National and international child health surveys have indicated an increase in childhood obesity in China. The increase has been attributed to a rising standard of living, increasing availability of unhealthy foods, and a lack of knowledge about healthy diet. The objective of this study was to assess the effect of selected socio-demographic characteristics on the BMI, nutrition knowledge, and eating behavior of elementary school children. Multistage stratified cluster sampling was used. Information on demographics, nutrition knowledge, and eating behavior was gathered by means of questionnaires. The schools' doctors provided the height and weight data. The study was set in one economically advantaged and one economically disadvantaged province in China. The participants were Grade 3 students, ages 8-10 years (N = 3922). A cluster analysis identified four socio-demographic variables distinguished by parental education and family living arrangement. A one-way ANOVA compared differences among the clusters in BMI, child nutrition knowledge, and child eating behavior. Students in the cluster with lowest parent education level had the lowest nutrition knowledge scores and eating behavior scores. There was no significant benefit from college education versus high school education of parents in the other three clusters. BMI was not affected by parent education level. The nutrition status of elementary school age children will benefit most by increasing the general level of education for those adults who are presently least educated.


In Vitro and In Vivo Characterization of an 18F-AlF-Labeled PSMA Ligand for Imaging of PSMA-Expressing Xenografts.
The aim was to compare the prostate-specific membrane antigen (PSMA)-targeting characteristics of PSMA-11, radiolabeled on the basis of chelation of 18F-AlF, with those of 68Ga-PSMA-11 to image PSMA-expressing xenografts. Methods: Labeling of 18F-AlF-PSMA-11 via 18F-AlF-complexation was performed as described by Boschi et al. and Malik et al. with minor modifications. Several conditions for the quality control of the labeling of 18F-AlF-PSMA-11 via 18F-AlF-complexation were evaluated to characterize the influence of ethanol, acetonitrile, and trifluoroacetic acid on the stability of the labeled product. Internalization kinetics of 18F-AlF-PSMA-11 were compared with those of 68Ga-PSMA-11 using PSMA-expressing LNCaP tumor cells. Biodistribution of 18F-AlF-PSMA-11 (0.26 nmol/mouse, 8-9 MBq/mouse) in male BALB/c nude mice with PSMA-expressing subcutaneous LS174T-PSMA tumors was compared with that of 68Ga-PSMA-11 at 1 and 2 h after injection. In addition, 18F-AlF-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/CT imaging were performed at 1 and 2 h after injection. Results: In contrast to 68Ga-PSMA-11, 18F-AlF-PSMA-11 was not stable in water (radiochemical purity was 64.5% immediately after purification and 52.7% at 120 min after purification). 18F-AlF-PSMA-11 remained relatively stable in 25 mM NH4OAc, pH 6.9, and radiochemical purity decreased from 98.5% at purification to 96.3%, 94.7%, and 92.5% at 60, 120, and 180 min after purification. In vitro, the 18F- and 68Ga-labeled compounds showed rapid internalization in LS174T-PSMA cells. The highest tumor uptake (percentage injected dose [%ID]) was observed at 2 h after injection (10.8 ± 2.3 %ID/g and 7.9 ± 1.3 %ID/g for 18F-AlF-PSMA-11 and 68Ga-PSMA-11, respectively [P > 0.05]). Renal tracer uptake peaked at 2 h after injection (43.5 ± 5.7 %ID/g and 105.8 ± 13.8 %ID/g for 18F-AlF-PSMA-11 and 68Ga-PSMA-11, respectively, P < 0.05). Bone uptake of 18F-AlF-PSMA-11 was 3.3 ± 0.6 at 1 h after injection and 5.0 ± 0.6 %ID/g at 2 h after injection and was dependent on the radiochemical purity at the time of injection. Bone uptake of 68Ga-PSMA-11 reached 0.1 ± 0.0 %ID/g at 1 and 2 h after injection. PSMA-expressing xenografts could be visualized using both 68Ga-PSMA-11- and 18F-AlF-PSMA-11 PET/CT. Conclusion: 18F-AlF-PSMA-11 using direct labeling with aluminum fluoride can be produced in NH4OAc, pH 6.9; shows a high internalization rate; and visualizes PSMA-expressing tumors with similar tumor uptake. Lower kidney uptake than with 68Ga-PSMA-11 may be advantageous for tumor detection. However, the limited instability and consequent Al18F uptake in bone might hamper the visualization of small PCa bone metastases.


Lifestyle Modification in Rheumatoid Arthritis: Dietary and Physical Activity Recommendations Based on Evidence.
Rheumatoid arthritis is a systemic autoimmune disease, considered the most common inflammatory articular disease among the general population. However, not only the joints are affected; rheumatoid arthritis also has an extra-articular manifestation. As for many other chronic diseases, rheumatoid arthritis may be exacerbated by poorer lifestyle choices. In fact, recent studies emphasize the role of nutrition and physical activity in this disease. In the current paper, we aim to describe lifestyle modifications based on diet and physical activity and other recommendations that seem to improve the clinical management and the disease outcome of Rheumatoid arthritis. A three-component lifestyle modification programme has been considered based on: (i) A low-fat low-sodium Mediterranean diet rich in fruits, vegetables, whole grains and nuts and poor in sugar-sweetened beverages, red and processed meat and trans fats, and the supplementation with omega-3 fatty acids, non-essential amino acids and probiotics, (ii) An appropriate physical activity programme based on an active daily lifestyle, aerobic exercise and resistance training and (iii) Adequate sleep hygiene and smoking reduction/cessation, that seems to have positive effects in terms of disease progression and related outcomes. Lifestyle modification programme should be considered as the basis of any treatment, (i.e., pharmacological treatment), in patients with rheumatoid arthritis.


[Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T cell lymphoma: report of one case].
Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T cell lymphoma, is an uncommon disease, with an aggressive clinical behavior. Differentiation with other types of cutaneous T-cell lymphoma (CTCL) that express a CD8+ cells, is based only on clinical grounds and in certain morphological characteristics, such as a marked epidermotropism with squamous cell necrosis. We report a 50-year-old male presenting with painless cutaneous lesions appearing in trunk, limbs, scalp and face, suggestive of cutaneous lymphoma. He was admitted to the hospital in bad conditions, with confluent papules and tumors, some of them ulcerated and with foul smelling honey-colored crusts, involving the complete body surface. Cutaneous biopsy demonstrated a CD8 positive epidermotropic cytotoxic T cell lymphoma. He was treated with chemotherapy with an excellent initial response, but cutaneous lesions reappeared after four cycles. He did not respond to rescue chemotherapy and died seven months after diagnosis.


Facile and cost-effective preparation of PVA/modified calcium carbonate nanocomposites via ultrasonic irradiation: Application in adsorption of heavy metal and oxygen permeation property.
This work is focused on the fabrication and determination of physicochemical behaviors of new poly(vinyl alcohol) (PVA) nanocomposites (NCs) containing various contents of calcium carbonate (CC) nanoparticles modified with γ-aminopropyl triethoxy silane (ATS) (henceforth designated as CC-ATS) which could be a crucial treatment for their application as gas barrier to O2 gas and uptake of metal ions in waste waters. Samples were produced through the solution casting method under ultrasound irradiation. Thermal and mechanical performances were also evaluated for all ultrasonically synthesized nanocomposites and the results indicated that thermal and mechanical stability are dramatically enhanced by addition of a small amount of modified CC-ATS within PVA up to 5wt% and higher amounts has low effect on the composite properties. The result of oxygen gas permeability of PVA showed a 25.44% reduction by adding of 5wt% of CC-ATS into polymer matrix. Experimental adsorption isotherm data indicated that PVA NC has more efficiency for Cu(II) adsorption relative to pure PVA and well simulated by Langmuir model with maximum adsorption capacity of 45.45mgg-1. Moreover, study of sorption kinetic indicated that the solute adsorption on PVA/CC-ATS NC 5wt% was well modeled using the pseudo-second-order.


Comparison of 4 commercial modified-live porcine reproductive and respiratory syndrome virus (PRRSV) vaccines against heterologous Korean PRRSV-1 and PRRSV-2 challenge.
The efficacy of 4 commercial porcine reproductive and respiratory syndrome virus (PRRSV) modified-live vaccines (MLV), against PRRSV-1 and PRRSV-2 was evaluated and compared in growing pigs. Two of the vaccines were based on PRRSV-1 and two on PRRSV-2. There were no significant differences between each of the two PRRSV-1 MLV vaccines and the two PRRSV-2 MLV vaccines respectively based on virology, immunological, and pathological evaluations. Vaccination with either of the PRRSV-1 MLV vaccines resulted in reduced PRRSV-1 but not PRRSV-2 viremia. Additionally, vaccination with either of the PRRSV-1 MLV vaccines resulted in reduction of lung lesions and PRRSV-1 positive cells in PRRSV-1 challenged pigs but had no significant effect in PRRSV-2 challenged pigs. In contrast, vaccination with either of the two PRRSV-2 MLV vaccines resulted in the reduction of both PRRSV-1 and PRRSV-2 viremia. The PRRSV-2 MLV vaccines were also able to effectively reduce lung lesions and PRRSV positive cells after challenge with either PRRSV-1 or PRRSV-2. Our data suggest that while vaccination with PRRSV-1 MLV vaccines can be effective against PRRSV-1, only PRRSV-2 MLV vaccines can protect against both Korean PRRSV-1 and PRRSV-2 challenges in this study.


Prevention of Infection: A Systematic Review of Evidence-Based Practice Interventions for Management in Patients With Cancer
Cancer-related infections lead to increases in mortality, antibiotic use, and hospital stays. Other adverse outcomes include dose delays and reductions, which can result in suboptimal treatment outcomes. Effective implementation of risk assessment and evidence-based interventions for the prevention and treatment of infection are essential to improve care and reduce costs related to infections in patients with cancer receiving immunosuppressive therapy. The Oncology Nursing Society (ONS) Putting Evidence Into Practice (PEP) prevention of infection resource have been developed and updated to identify and disseminate the best available scientific evidence. Pharmacologic and nonpharmacologic interventions were evaluated, resulting in recommended for practice rating for catheter care bundles, antimicrobial prophylaxis, vaccination for specific populations, and implementation of contact precautions for resistant organisms.


Effect of rofecoxib on the glomerular filtration rate, proteinuria and the renin-angiotensin-aldosterone system in elderly subjects with chronic renal impairment.
Considering the increasing popularity and prescribing of specific COX-2 inhibitors, a new class of NSAIDs lacking gastrointestinal side effects, the evaluation of their effects on renal function has become very important. The aim of the study was to evaluate the effect of rofecoxib on GFR, proteinuria and the renin-angiotensin-aldosterone system (RAAS) in elderly patients with chronic renal impairment under controlled conditions of water and salt intake. There were ten patients (average age 67 years, range 53 - 80 years) with analgesic or vascular nephropathy (average GFR 54 ml/min/1.73 m2, range 30 - 79 ml/min/ 1.73 m2) given 25 mg rofecoxib daily for seven days under balanced conditions of water and sodium metabolism (salt intake 6 - 8 g/24 hours). The effect of rofecoxib on GFR measured using inulin clearance (C(in)), creatinine clearance (C(Cr)) serum cystatin C concentration (S(cystatin)), tubular creatinine secretion (using the ratio C(Cr)/C(in)), 24-hour urinary excretion of albumin (U(alb)V) and prostaglandins (U(PGE2)V and U(PGF2alpha)V), basal and stimulated plasma renin activity (PRA) and serum aldosterone concentration S(aldosterone) was evaluated before and on Day 7 during rofecoxib treatment. Rofecoxib did not significantly change C(in), C(Cr), S(cystatin), C(Cr)/C(in) and U(alb)V. However, U(PGE2)V and U(PGF2alpha)V were decreased during rofecoxib administration (p = 0.059 and p = 0.024, respectively). Rofecoxib attenuated the stimulated rise of PRA and S(aldosterone) (p = 0.019 and p = 0.008, respectively). Short-term rofecoxib administration was not associated with significant change in GFR in elderly patients with moderate chronic renal impairment under conditions of balanced salt and water metabolism despite significant attenuation of RAAS activity. Since the C(Cr)/C(in) ratio did not change in our study, we assume rofecoxib to have no influence on creatinine tubular secretion.


Neuromodulation of cancer pain.
Managing cancer-related chronic pain is challenging to health care professionals as well as cancer patients and survivors. The management of cancer-related pain has largely consisted of pharmacological treatments, which has caused researchers to focus on neurotransmitter activity as a mediator of patients' perception of pain rather than the electrical activity during neurobiological processes of cancer-related pain. Consequently, brain-based pain treatment has focused mainly on neurotransmitters and not electrical neuromodulation. Neuroimaging research has revealed that brain activity is associated with patients' perceptions of symptoms across various diagnoses. The brain modulates internally generated neural activity and adjusts perceptions according to sensory input from the peripheral nervous system. Cancer-related pain may result not only from changes in the peripheral nervous system but also from changes in cortical activity over time. Thus, cortical reorganization by way of the brain's natural, plastic ability (neuroplasticity) may be used to manage pain symptoms. Physical and psychological distress could be modulated by giving patients tools to regulate neural activity in symptom-specific regions of interest. Initial research in nononcology populations suggests that encouraging neuroplasticity through a learning paradigm can be a useful technique to help treat chronic pain. Here we review evidence that indicates a measurable link between brain activity and patient-reported psychological and physical distress. We also summarize findings regarding both the neuroelectrical and neuroanatomical experience of symptoms, review research examining the mechanisms of the brain's ability to modify its own activity, and propose a brain-computer interface as a learning paradigm to augment neuroplasticity for pain management.


IGRNet: A Deep Learning Model for Non-Invasive, Real-Time Diagnosis of Prediabetes through Electrocardiograms.
The clinical symptoms of prediabetes are mild and easy to overlook, but prediabetes may develop into diabetes if early intervention is not performed. In this study, a deep learning model-referred to as IGRNet-is developed to effectively detect and diagnose prediabetes in a non-invasive, real-time manner using a 12-lead electrocardiogram (ECG) lasting 5 s. After searching for an appropriate activation function, we compared two mainstream deep neural networks (AlexNet and GoogLeNet) and three traditional machine learning algorithms to verify the superiority of our method. The diagnostic accuracy of IGRNet is 0.781, and the area under the receiver operating characteristic curve (AUC) is 0.777 after testing on the independent test set including mixed group. Furthermore, the accuracy and AUC are 0.856 and 0.825, respectively, in the normal-weight-range test set. The experimental results indicate that IGRNet diagnoses prediabetes with high accuracy using ECGs, outperforming existing other machine learning methods; this suggests its potential for application in clinical practice as a non-invasive, prediabetes diagnosis technology.


Fracture of S1-2 after L4-S1 decompression and fusion. Case report and review of the literature.
The author describes a woman in whom an S1-2 fracture developed after L4-S1 decompression and fusion. Osteoporosis was not present, but the lesion failed to respond to conservative therapy, necessitating surgical extension of the spinal fusion. Although biomechanical complications of lumbosacral fusion are uncommon, pseudarthrosis, degenerative spondylolisthesis, and stress fractures have been reported. To date, only four cases of sacral stress fracture appear in the literature, all involving female patients and reportedly associated with osteoporosis. Unlike the present case, the fracture resolved satisfactorily in all cases with conservative treatment.


Comfortable and maximum walking speed of adults aged 20-79 years: reference values and determinants.
to establish reference values for both comfortable and maximum gait speed and to describe the reliability of the gait speed measures and the correlation of selected variables with them. descriptive and cross-sectional. subjects were 230 healthy volunteers. Gait was timed over a 7.62 m expanse of floor. Actual and height normalized speed were determined. Lower extremity muscle strength was measured with a hand-held dynamometer. mean comfortable gait speed ranged from 127.2 cm/s for women in their seventies to 146.2 cm/s for men in their forties. Mean maximum gait speed ranged from 174.9 cm/s for women in their seventies to 253.3 cm/s for men in their twenties. Both gait speed measures were reliable (coefficients > or = 0.903) and correlated significantly with age (r > or = -0.210), height (r > or = 0.220) and the strengths of four measured lower extremity muscle actions (r = 0.190-0.500). The muscle action strengths most strongly correlated with gait speed were nondominant hip abduction (comfortable speed) and knee extension (maximum speed). these normative values should give clinicians a reference against which patient performance can be compared in a variety of settings. Gait speed can be expected to be reduced in individuals of greater age and of lesser height and lower extremity muscle strength.


Fluidized capacitive bioanode as a novel reactor concept for the microbial fuel cell.
The use of granular electrodes in Microbial Fuel Cells (MFCs) is attractive because granules provide a cost-effective way to create a high electrode surface area, which is essential to achieve high current and power densities. Here, we show a novel reactor design based on capacitive granules: the fluidized capacitive bioanode. Activated carbon (AC) granules are colonized by electrochemically active microorganisms, which extract electrons from acetate and store the electrons in the granule. Electricity is harvested from the AC granules in an external discharge cell. We show a proof-of-principle of the fluidized capacitive system with a total anode volume of 2 L. After a start-up period of 100 days, the current increased from 0.56 A/m(2) with 100 g AC granules, to 0.99 A/m(2) with 150 g AC granules, to 1.3 A/m(2) with 200 g AC granules. Contact between moving AC granules and current collector was confirmed in a control experiment without biofilm. Contribution of an electro-active biofilm to the current density with recirculation of AC granules was limited. SEM images confirmed that a biofilm was present on the AC granules after operation in the fluidized capacitive system. Although current densities reported here need further improvement, the high surface area of the AC granules in combination with external discharge offers new and promising opportunities for scaling up MFCs.


Tissue engineering: the current status of this futuristic modality in head neck reconstruction.
To define tissue engineering and describe the components that are involved in engineering tissue. To provide examples of the most recent developments in tissue engineering as they apply to the otolaryngologist. To provide a general overview of selected exciting advances outside the field of general otolaryngology but of general interest to the reconstructive community. Tissue engineering is a rapidly evolving field that can be defined as the regeneration of new tissues through the use of biologic mediators and matricis. The three components required are scaffolds, signaling molecules, and cells. A significant amount of work has been done to generate bone, cartilage, cornea, and vascular grafts. Tissue engineered bone is the only tissue type that has been evaluated in Phase III clinical trials and is in routine clinical use. Engineered bone from BMP-2 and BMP-7 is used in orthopedics for lumbar fusions and long bone nonunions. Clinical application of bone tissue engineering in the head and neck is limited to case reports. There has been success in tissue engineering with cartilage for the nose and ear in immune incompetent animal models but there has been difficulty with generating scaffolds that do not incite an immune reaction in an immune competent model. The most advanced organ engineered is a bladder that has been successful in a canine model. Tissue engineering holds the promise of "off the shelf" parts for reconstruction of tissues and organs. The widest clinical application is with bone in orthopedics. Applications in the head and neck are limited, at present, due to the immunogenicity of the scaffolds and the challenging wounds encountered in both cancer and cosmetic patients.


Discrepancy between self-awareness and actual diagnosis and treatment of the conditions among adolescent with scoliosis in middle-school age.
[Purpose] The purpose of this research was to determine the awareness of the actual conditions of the diagnosis and treatment of scoliosis by focusing on middle-school students in order to provide a basis for active education and treatment of scoliosis. [Subjects and Methods] The survey was conducted among 4,782 students. The students performed Adam's forward bend test, and some of the students who showed predictive features of scoliosis were further examined for the spine structure with rasterstereography. [Results] The proportion of students with awareness about scoliosis appeared to be 71.47%. Among the students, 50.84% knew the definition of scoliosis and 4.37% were diagnosed as having scoliosis, of whom 46.37% underwent treatment. It was a significant difference between to get a diagnosis and the predictive scoliosis or the scoliosis. [Conclusion] The results showed that the students in the second grade of middle school had high awareness levels, but about 50% of them did not know the definition of scoliosis. More than 50% of them did not receive treatment after diagnosed as having scoliosis. Therefore, active education and school screening for scoliosis should be provided to adolescent students.


The effects of material and experiential discretionary purchases on consumer happiness: moderators and mediators.
Experiential purchases are differentiated from material purchases in terms of objective; experiential purchases serve the purpose of acquiring a life experience, while material purchases serve the purpose of acquiring an object. Research has demonstrated that experiential purchases are associated with more happiness than material purchases. The current study investigated two explanations for this relationship that focused on the how the purchase influenced the self and how the purchase influenced interpersonal relationships. In addition, the study explored whether social economic status would influence the strength of the relationship between the type of purchase and happiness. Participants were required to recall either a recent experiential or material purchase and rate their happiness with the purchase. Then participants completed scales designed to measure the purchase's impact on the self and interpersonal relationships. Last, participants completed a scale to measure social economic status. It was found that Impacts on the Self mediated the relationship between purchase type and happiness and Socioeconomic Status moderated the relationship.


Viral vector strategy for glial cell line-derived neurotrophic factor therapy for stroke.
Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily. Over the last decade, GDNF has been shown to promote regenerative and restorative effects on dopaminergic neurons. Accumulating evidence also demonstrates that administration of GDNF to areas of ischemic brain injury limits cerebral infarction and reduces damage to motor functions in animal models of stroke. Neurotrophic factor and anti-apoptotic mechanisms, among others, have been proposed to underlie the therapeutic effects of GDNF. A major obstacle for GDNF therapy is the protein delivery to the brain, as well as its sustained bioavailability over time. Gene therapy and the use of viral vectors offer a technique for longevity of GDNF expression within the brain. In this review, we consider the risks and benefits of GDNF gene therapy as it relates to the treatment of stroke.


Immigration, Work, and Health: A Literature Review of Immigration Between Mexico and the United States.
Understanding the influence someone's job or career has on their health goes beyond the physical, emotional and social hazards, risks and conditions that they face at work. One's job or career also exerts a significant influence over other aspects of life that contribute or detract from their health and that of their family. Work is the major incentive for Latin American migration to the United States. Latino immigrants experience increasingly poorer outcomes for physical health and chronic diseases the longer they remain in the U.S. The strong link between work and immigration suggests that, for many Latin Americans, immigration can be understood as a career path which puts them, and their family members, in situations that can change their physical, emotional, and social health as a condition of their employment. Given the large number of Latin Americans who emigrate for work, it is essential that the unique physical, mental and social impacts of emigration are accounted for when working with clients impacted by emigration at the individual, family and community level as well as those social workers practicing at the system level. This paper is a literature review that explores the impact that emigrating for work has on the health of those that emigrate and their family members that stay behind.


Mapping of spinal projection of primary nociceptive neurones in the rat.
The FRAP (fluoride-resistant acid phosphatase) reaction was used to draw up the map of the somatotopic organization of the primary nociceptive neurones of the forelimb in the rat spinal cord. The disappearance of FRAP activity from the central terminals of primary sensory neurones in the substantia gelatinosa was studied after transection of the brachial plexus and the median nerve. A map of the central terminals of FRAP-reactive primary sensory neurones was drawn up by the recording of enzyme depletion. After complete transection of the brachial plexus, partial depletion of FRAP was seen in the lower cervical and upper thoracic cord; the degree of FRAP disappearance was striking in segments C5, C6 and C7, and slight between segments C5 and C6. After transection of the median nerve, the FRAP reaction was observed to disappear completely in the medial portion, but remained over approximately one-quarter of the width in the middle of the Rolando substance. The enzyme activity remained in a narrow strip about 2 segments long. The maps resulting from microscopic and geometric analysis of serial sections showed that the terminals of FRAP-reactive primary nociceptive neurones of the forelimb projected mostly to the medial portion of lamina II in the rat spinal cord, from segment C4 to T3. The findings are discussed in relation to the somatotopic organization of primary afferents.


[The neuroprotective effect of GABA-ergic substances in cerebral ischemia].
The GABA precursor progabide, the GABA-aminotransferase inhibitor valproate, and the GABA receptor agonist baclofen increased the resistance of mice and rats to ischemia of the brain in two different modes. Both time and dose curves of the neuroprotective and hypothermal effects correlated in individual animals within a group, but there was no correlation for different series. Probably hypothermia is just one of the components in the mechanism of the neuroprotective effect of GABAergic compounds.


The value of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein as a predictive marker for hepatitis C virus-related complications after systemic chemotherapy.
Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+)-M2BP) was developed recently as a predictive marker of progression to liver fibrosis and hepatocellular carcinoma (HCC) in patients seropositive for hepatitis C virus (HCV). We retrospectively analyzed 16 HCV-seropositive patients who received systemic chemotherapy for hematologic malignancies to evaluate the usefulness of WFA(+)-M2BP for predicting HCV-related complications. These were defined as the onset of significant liver damage (LD) with increased HCV RNA levels, leading to interrupted or discontinued chemotherapy or the occurrence of HCC after chemotherapy. Baseline WFA(+)-M2BP levels were determined using preserved serum samples. The median level of WFA(+)-M2BP was 1.59 [cutoff index (C.O.I.) value range 0.38-6.66]. With a median follow-up of 623 days (range 120-2404), LD and HCC were observed in three and two patients, respectively. Detectable HCV RNA and WFA(+)-M2BP ≥2.0 C.O.I. at baseline were identified as risk factors for these HCV-related complications (P = 0.034 and P = 0.005, respectively). The sensitivity, specificity, and positive and negative predictive values of the WFA(+)-M2BP level (cutoff point: 2.0 C.O.I.) for the occurrence of HCV-related complications were 100.0, 81.8, 71.4, and 100.0 %, respectively. WFA(+)-M2BP may be a useful marker for the prediction of HCV-related complications in HCV-seropositive patients following systemic chemotherapy.


Phosphorylation of the C-terminal domain of yeast topoisomerase II by casein kinase II affects DNA-protein interaction.
Eukaryotic DNA topoisomerase II is an abundant nuclear enzyme that is essential for cell proliferation. This homodimeric enzyme catalyzes the cleavage and re-ligation of double-stranded DNA required to separate replicated sister chromatids. Both biochemical and genetic studies show that its catalytic activity is required for chromosome condensation and segregation, and that its decatenation activity can be stimulated by a variety of protein kinases in vitro. In budding yeast, topoisomerase II is most highly phosphorylated in metaphase, and casein kinase II (CKII) was shown to be the major kinase modifying topoisomerase II. We have investigated the effects of phosphorylation of yeast topoisomerase II by CKII in vitro, by means of gel-retardation and filter binding assays. The phosphorylation of the C terminus of topoisomerase II by CKII appears to increase the stability of the complex formed with linear DNA fragments, while dephosphorylation has the opposite effect. Rephosphorylation of phosphatase-treated topoisomerase II by chicken casein kinase II restores a stable protein-DNA complex using a linear DNA fragment. The enhanced stability of the topoisomerase II-DNA complex is also observed with relaxed circular DNA, but not with supercoiled minicircles, in agreement with published results using topoisomerase II from Drosophila. Limited proteolysis and probing with domain-specific antibodies shows that, with the exception of a weakly modified residue between amino acid residues 660 and 1250, all residues modified by casein kinase II are in the last 180 amino acid residues of yeast topoisomerase II.


The significance of occlusion in restorative dentistry.
All occlusal therapy relates ultimately to the hinge position of the mandible. By consensus, the optimum hinge position is centric relation, the most anterosuperior position of the condyles in the glenoid fossae, articulating against the eminences, with the disks properly interposed. Also by consensus, the optimum occlusal scheme is mutual protection, in which the posterior teeth contact simultaneously and equally in centric occlusion, the canines disclude the posterior teeth in lateral excursions, and the anterior teeth disclude the posterior teeth in protrusion. Whenever CR cannot be used as the starting point of occlusal treatment, or when sufficient canine support is lacking, the clinician may have to prescribe a treatment condylar position other than CR or modify the occlusal scheme. Mutual protection occlusion is the simplest to develop and CR is the simplest starting point. Departures from these ideals create added complexities for the dentist. The greater the number of excursive contacts in the occlusal scheme, the more involved the equilibration of those contacts. A treatment condylar position other than CR may not be repeatable when needed, and two studies suggest that it may change over time. Without a stable, repeatable foundation supporting it, the occlusion may be in jeopardy. The removal of occlusal interferences, although not warranted as a routine prophylactic measure, is indicated under certain conditions. When beginning a significant amount of occlusal treatment, the clinicians may remove closing interference to achieve CR at the desired vertical dimension. They may remove excursive interferences that they do not want to perpetuate in the new scheme. Selective removal may alleviate the signs of trauma from occlusion. There may be periodontal justification for axializing and equilibrating occlusal forces. Nonaxial forces on teeth with cervical erosion should be reduced as a means of limiting further erosion and protecting cervical restorations. When occlusal disharmony has been shown to reactivate a TMD, an equilibration or a more extensive rehabilitation may be necessary in the second phase of TMD treatment. In the symptomatic phase of a TMD, however, only reversible measures are appropriate. In this time of fast-moving change in restorative techniques and products, all operative dentists should raise their consciousness of occlusal principles. Occlusal forces set limits on the selection of materials and often prescribe the design features needed for a successful outcome. With structurally or periodontally compromised teeth, the occlusal planning to minimize nonaxial forces lies at the heart of the restoration. Virtually all restorative dentistry is affected by the occlusal forces of the teeth in function.(ABSTRACT TRUNCATED AT 400 WORDS)


Rheumatic disease in childhood.
The autoimmune diseases, juvenile rheumatoid arthritis and systemic lupus erythematosus, are two of the more common acquired chronic diseases of childhood. In this article we will describe features of the diagnosis and treatment of these disorders. Particular emphasis is placed on the complications and how to anticipate them. The management of these diseases must include an appreciation of how chronic illness can affect family function and school relationships. With early attention to these nonmedicinal details, the majority of children can progress through childhood and adolescence with few physical or emotional handicaps.


Computer simulations of bioequivalence trials: selection of design and analyte in BCS drugs with first-pass hepatic metabolism: linear kinetics (I).
Modeling and simulation approaches are useful tools to assess the potential outcome of different scenarios in bioequivalence studies. The aim of this study is to propose a new and improved semi-physiological model for bioequivalence trial simulations and apply it for all BCS (Biopharmaceutic Classification System) drug classes with non-saturated first-pass hepatic metabolism. The semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Parent drug and metabolite levels for both reference and test were simulated. Eight types of drugs (with high or low permeability and high or low solubility (class I to IV) and high or low intrinsic clearance) were considered in two variability scenarios (high-low) and in six test products of decreasing biopharmaceutic quality. The scenarios were tested in single dose and steady state studies. In case of drugs with non-saturated hepatic first-pass effect (and no gut-wall metabolism) the parent drug is usually the most sensitive analyte and the single dose design is usually the most sensitive study design to detect the worsening of the biopharmaceutic quality of the test formulation. The only exception to this general conclusion was observed in class III drugs (high solubility, low permeability) with low intrinsic clearance for which the parent drug C(max) ratio in steady state shows higher sensitivity followed by the metabolite C(max) ratio in single dose. This exceptional behaviour is caused by a limited operative absorption time (or absorption window) in class III drugs that precludes complete absorption and produces a non-linear absorption. Therefore, it can be concluded that the metabolite does not need to be measured if the drug has no gut-wall metabolism and shows linear pharmacokinetics. Interestingly, a steady state study should be conducted in this exceptional case to compare with the highest possible sensitivity. Metabolite data in most of the scenarios either shows less sensitivity to the product characteristics (resulting in C(max) ratios passing the bioequivalence criteria when the products were not bioequivalent) or it gives the same information as the parent compound.


Liquid Transfer for Viscoelastic Solutions.
Viscoelastic liquid transfer from one surface to another is a process that finds applications in many technologies, primarily in printing. Here, cylindrical-shaped capillary bridges pinned between two parallel disks are considered. Specifically, the effects of polymer mass fraction, solution viscosity, disk diameter, initial aspect ratio, final aspect ratio, stretching velocity, and filling fraction (alike contact angle) are experimentally investigated in uniaxial extensional flow. Both Newtonian and viscoelastic polymer solutions are prepared using polyethylene glycol and polyethylene oxide, with a wide variety of mass fractions. The results show that the increase in polymer mass fraction and solvent viscosity reduces the liquid transfer to the top surface. Moreover, the increase in the initial and final stretching heights of the capillary bridge also decreases the liquid transfer for both Newtonian and viscoelastic solutions. Finally, the shape of the capillary bridge is varied by changing the liquid volume. Now, Newtonian and viscoelastic solutions exhibit opposite behaviors for the liquid transfer. These findings are discussed in terms of interfacial shape instability and gravitational drainage.