Surface-Modified Lyotropic Crystalline Nanoconstructs Bearing Doxorubicin and Buparvaquone Target Sigma Receptors through pH-Sensitive Charge Conversion to Improve Breast Cancer Therapy.
In the current study, we aimed to develop lyotropic crystalline nanoconstructs (LCNs) based on poly(l-glutamic acid) (PLG) with a two-tier strategy. The first objective was to confer pH-responsive charge conversion properties to facilitate the delivery of both doxorubicin (DOX) and buparvaquone (BPQ) in combination (B + D@LCNs) to harness their synergistic effects. The second goal was to achieve targeted delivery to sigma receptors within the tumor tissues. To achieve this, we designed a pH-responsive charge conversion system using a polymer consisting of poly(ethylenimine), poly(l-lysine), and poly(l-glutamic acid) (PLG), which was then covalently coupled with methoxybenzamide (MBA) for potential sigma receptor targeting. The resulting B + D@LCNs were further modified by surface functionalization with PLG-MBA to confer both sigma receptor targeting and pH-responsive charge conversion properties. Our observations indicated that at physiological pH 7.4, P/B + D-MBA@LCNs exhibited a negative charge, while under acidic conditions (pH 5.5, characteristic of the tumor microenvironment), they acquired a positive charge. The particle size of P/B + D-MBA@LCNs was determined to be 168.23 ± 2.66 nm at pH 7.4 and 201.23 ± 1.46 nm at pH 5.5. The crystalline structure of the LCNs was confirmed through small-angle X-ray scattering (SAXS) diffraction patterns. Receptor-mediated endocytosis, facilitated by P/B + D-MBA@LCNs, was confirmed using confocal laser scanning microscopy and flow cytometry. The P/B + D-MBA@LCNs formulation demonstrated a higher rate of G2/M phase arrest (55.20%) compared to free B + D (37.50%) and induced mitochondrial depolarization (59.39%) to a greater extent than P/B + D@LCNs (45.66%). Pharmacokinetic analysis revealed significantly improved area under the curve (AUC) values for both DOX and BPQ when administered as P/B + D-MBA@LCNs, along with enhanced tumor localization. Tumor regression studies exhibited a substantial reduction in tumor size, with P/B + D-MBA@LCNs leading to 3.2- and 1.27-fold reductions compared to B + D and nontargeted P/B + D@LCNs groups, respectively. In summary, this two-tier strategy demonstrates substantial promise for the delivery of a drug combination through the prototype formulation. It offers a potential chemotherapeutic option by minimizing toxic effects on healthy cells while maximizing therapeutic efficacy.


Tuberculosis and the risk of infection with other intracellular bacteria: a population-based study.
SUMMARY Persons who develop tuberculosis (TB) may have subtle immune defects that could predispose to other intracellular bacterial infections (ICBIs). We obtained data on TB and five ICBIs (Chlamydia trachomatis, Salmonella spp., Shigella spp., Yersinia spp., Listeria monocytogenes) reported to the Tennessee Department of Health, USA, 2000-2011. Incidence rate ratios (IRRs) comparing ICBIs in persons who developed TB and ICBIs in the Tennessee population, adjusted for age, sex, race and ethnicity were estimated. IRRs were not significantly elevated for all ICBIs combined [IRR 0.87, 95% confidence interval (CI) 0.71-1.06]. C. trachomatis rate was lowest in the year post-TB diagnosis (IRR 0.17, 95% CI 0.04-0.70). More Salmonella infections occurred in extrapulmonary TB compared to pulmonary TB patients (IRR 14.3, 95% CI 1.67-122); however, this appeared to be related to HIV co-infection. TB was not associated with an increased risk of other ICBIs. In fact, fewer C. trachomatis infections occurred after recent TB diagnosis. Reasons for this association, including reduced exposure, protection conferred by anti-TB drugs or macrophage activation by Mycobacterium tuberculosis infection warrant further investigation.


Conservation of a masked nuclear export activity of La proteins and its effects on tRNA maturation.
La is an RNA-processing-associated phosphoprotein so highly conserved that the human La protein (hLa) can replace the tRNA-processing function of the fission yeast La protein (Sla1p) in vivo. La proteins contain multiple trafficking elements that support interactions with RNAs in different subcellular locations. Prior data indicate that deletion of a nuclear retention element (NRE) causes nuclear export of La and dysfunctional processing of associated pre-tRNAs that are spliced but 5' and 3' unprocessed, with an accompanying decrease in tRNA-mediated suppression, in fission yeast. To further pursue these observations, we first identified conserved residues in the NREs of hLa and Sla1p that when substituted mimic the NRE deletion phenotype. NRE-defective La proteins then deleted of other motifs indicated that RNA recognition motif 1 (RRM1) is required for nuclear export. Mutations of conserved RRM1 residues restored nuclear accumulation of NRE-defective La proteins. Some RRM1 mutations restored nuclear accumulation, prevented disordered pre-tRNA processing, and restored suppression, indicating that the tRNA-related activity of RRM1 and its nuclear export activity could be functionally separated. When mapped onto an hLa structure, the export-sensitive residues comprised surfaces distinct from the RNA-binding surface of RRM1. The data indicate that the NRE has been conserved to mask or functionally override an equally conserved nuclear export activity of RRM1. The data suggest that conserved elements mediate nuclear retention, nuclear export, and RNA-binding activities of the multifunctional La protein and that their interrelationship contributes to the ability of La to engage its different classes of RNA ligands in different cellular locations.


Single-site model of the neuronal 5-hydroxytryptamine uptake and imipramine-binding site.
Recently, a high affinity [3H]imipramine-binding site of protein nature that appeared to be related to the 5-hydroxytryptamine (5-HT, serotonin) uptake mechanism was demonstrated. This binding site was only part of desipramine-displaceable [3H]imipramine binding, which contained a significant amount of additional binding not related to 5-HT uptake. The present study further investigates the [3H]imipramine-binding site of protein nature in the rat brain. Displacement by 5-HT and 6-methoxytetrahydro-beta-carboline (6-MeO-TH beta C) revealed monophasic displacement patterns with 60% displaceable binding. This binding fraction was abolished by protease treatment of the brain tissue prior to binding assay. Saturation studies of [3H]imipramine binding (1-30 nM) in rat cortex showed that the binding displaced by 30 microM 5-HT [Bmax 322 +/- 16 fmol/mg of protein, Kd 4.17 +/- 1.07 nM (means +/- SE)] was not different from the binding displaced by 1.0 microM norzimeldine (Bmax 349 +/- 15 fmol/mg of protein, Kd 4.47 +/- 1.07 nM) or 30 microM 6-MeO-TH beta C (Bmax 439 +/- 28 fmol/mg of protein, Kd 5.49 +/- 1.09 nM). When 100 microM desipramine was used in saturation studies, the binding was different from that displaced by 5-HT with Bmax 608 +/- 42 fmol/mg of protein and Kd 6.68 +/- 1.09 nM. Both displacement and saturation studies in which two displacing agents were combined indicated that most of the binding competed by 5-HT (30 microM) and norzimeldine (1.0 microM) is identical. Similarly, the binding displaced by 5-HT or norzimeldine is subsumed within 6-MeO-TH beta C (30 microM)-displaceable binding. Lesion studies with parachloroamphetamine, a selective toxin for 5-HT terminals, which resulted in a 83% reduction of [3H] 5-HT uptake ( [3H]noradrenaline uptake unaffected), abolished cortical [3H]imipramine binding displaced by 30 microM 5-HT or 1.0 microM norzimeldine. (greater than 80% reduction). However, with 100 microM desipramine as displacer, 40% of the binding remained in lesioned animals. The [3H]imipramine binding displaced by 30 microM 5-HT or 1.0 microM norzimeldine was sodium dependent, and an increase in NaCl concentration from 0 to 120 mM resulted in a 10-fold increase in affinity without effect on Bmax, whereas no change in binding was observed with increasing concentrations of LiCl.(ABSTRACT TRUNCATED AT 400 WORDS)


Spectral domain optical coherence tomography and angiographic findings in multifocal posterior pigment epitheliopathy treated with low-fluence photodynamic therapy.
The aim was to evaluate spectral domain optical coherence tomographic (SD-OCT), fluorescein angiography (FA) and indocyanine green angiography (ICGA) findings in multifocal posterior pigment epitheliopathy (MPPE) treated with low-fluence photodynamic therapy. A 54-year-old Japanese man with serous retinal detachment (SRD) and pigment epithelial detachment (PED) due to multifocal posterior pigment epitheliopathy in the right eye was managed with ICGA-guided low-fluence photodynamic therapy. Outcome measures included visual acuity, SD-OCT appearance and FA and ICGA findings. The patient received low-fluence photodynamic therapy within two weeks after the onset of symptoms. After treatment, serous retinal detachment and PED resolved in two weeks. Visual acuity returned to 1.0, the external limiting membrane and the photoreceptor inner and outer segment junction integrity were restored and the subfoveal choroidal thickness was greatly reduced. There has been no recurrence in six months. FA demonstrated stoppage of leakage and ICGA showed a marked decrease of choroidal venous dilation and vascular hyperpermeability. To our knowledge, this is the first report to examine photoreceptor integrity, foveal choroidal thickness and choroidal circulation in a case of MPPE treated with low-fluence photodynamic therapy. Early application of the photodynamic therapy led to restoration of photoreceptor integrity with improvement of choroidal thickness and circulation.


Benign extracerebral fluid collection in infancy as a risk factor for the development of de novo intracranial arachnoid cysts.
Intracranial arachnoid cysts are a relatively common benign intracranial pathology, accounting for as many as 0.75%-1% of nontraumatic CNS lesions. Although it has already been demonstrated that rupture of arachnoid cysts may lead to subdural hematomas/hygromas, no study to date has investigated benign extracerebral collection in infancy as a possible predisposing factor for further development of arachnoid cysts. The authors performed a retrospective imaging and chart review of macrocephalic infants 12 months old or younger who were referred to neurosurgical care at OSF St. Francis Medical Center from 2003 to 2010, and who were diagnosed with benign extracerebral fluid collection in infancy on thin-slice (1-mm) head CT scans. Special attention was given to the investigation of risk factors for further development of de novo arachnoid cysts. Several epidemiological factors in the infants and mothers were analyzed, including gestational age at delivery, mode of delivery, mother's age at delivery, delivery complications, birth weight, age of macrocephaly development, degree of macrocephaly, family history of macrocephaly, prenatal and postnatal history of infection, fontanel status, presence of papilledema, previous history of head trauma, and smoking status. Imaging characteristics of the initial scans, such as location of subdural collection (frontal vs frontoparietal and frontotemporal) and presence of ventriculomegaly, were also evaluated. For those patients in whom arachnoid cysts were identified on subsequent CT scans, the size and location of the cysts were also analyzed. The authors identified 44 children with benign extracerebral fluid collection in infancy. From this group, over a mean follow-up of 13 months (range 6-13 months), 18 children developed intracranial arachnoid cysts (a 40.9% incidence of de novo development of arachnoid cysts), with 27.8% presenting with bilateral cysts. In the multiple logistic regression analysis, infants who presented with an extracerebral collection restricted to the bilateral frontal region were more likely to develop intracranial arachnoid cysts (p = 0.035) than those with collections involving the frontotemporal and frontoparietal regions (odds ratio [OR] = 5.73). Additionally, children with benign extracerebral fluid collections and plagiocephaly were more likely to develop intracranial arachnoid cysts (p = 0.043) than those without plagiocephaly (OR = 4.96). This is the first report in the neurosurgical literature demonstrating that benign extracerebral fluid collections in infancy may constitute a significant risk factor for development of de novo arachnoid cysts. These findings support a 2-hit hypothesis for the development of arachnoid cysts, in which the combination of an embryological defect in arachnoid development followed by a second event leading to impairment of CSF fluid absorption in early childhood could lead to abnormal CSF dynamics and the consequent expansion of fluid collections in the intraarachnoid spaces.


Supporting patients facing difficult health care decisions: use of the Ottawa Decision Support Framework.
To investigate family physicians' views on factors that make health care decisions difficult for patients, interventions family physicians use to support patients making decisions, and interventions proposed by the Ottawa Decision Support Framework (ODSF). Thirteen group discussions. Five family practice units. One hundred twenty family physicians. The multifaceted implementation intervention consisted of feedback from participants, a reminder at point of care, and an interactive workshop. During the workshop, family physicians were asked about their views on 2 videos both showing the concluding phase of a simulated clinical encounter with a woman facing a decision about hormone therapy. One video showed usual care; the other showed use of the ODSF process and related tools. Content was analyzed using observations by non-participants, field notes, material collected from participants during workshops, evaluation forms completed at the end of workshops, and comments written on exit questionnaires from the implementation trial. Family physicians' views on the types of difficult decisions their patients face, the factors that make decisions difficult for patients, the interventions family physicians use to support patients' decisions, and the interventions proposed by the ODSF. The 2 most frequently cited factors making decisions difficult for patients were experiencing uncertainty and fears about adverse outcomes. Before being introduced to the ODSF, participants had used mostly information-related strategies to provide decision support. After learning about the ODSF, participants overwhelmingly identified assessing patients' values as a priority. At the end of the workshop, the 5 changes in practice participants most frequently intended to make were, in order of importance, to assess patients' values, to ask about patients' preferred role in decision making, to screen for decisional conflict, to assess support or undue pressure on patients, and to increase patients' involvement in decision making. The ODSF process and related tools have the potential to broaden family physicians' views on supporting patients facing difficult decisions.


SptP, a Salmonella typhimurium type III-secreted protein, inhibits the mitogen-activated protein kinase pathway by inhibiting Raf activation.
Salmonella has developed ways to modulate host cellular response in order to survive. Although the steps required for such modulation have been incompletely characterized, there is increasing evidence for a role for SptP, a type III secretion protein. In part, the actions of SptP are thought to be mediated through its reported inhibition of the extracellular-regulated kinase (ERK) MAP kinase pathway. In the present studies, a series of transfections were performed in which various constitutively activated components of the MAP kinase pathway were co-transfected with SptP in order to determine the mechanism by which SptP inhibits this MAP kinase activation. SptP was found to inhibit the activation of ERK stimulated by both a constitutively active form of Ras and a partially activated form of Raf-1 containing a phospho-mimetic mutation (Raf Y340D). In contrast, the activation of ERK by constitutively active forms of MAP kinase kinase (MEK) was not inhibited, suggesting that the actions of SptP were mediated by Raf-1. In order to determine how SptP might interfere with activation of Raf, we utilized a membrane-localized form of Raf. Constitutive membrane-localization of Raf (RafCAAX), resulting in partial activation, did not prevent inhibition by SptP. However, introduction of an additional, partially activating (Y340D) phospho-mimetic mutation, to RafCAAX, dramatically reduced the ability of SptP to inhibit Raf action. Comparison of SptP mutants, lacking either GTPase-activating protein (GAP) activity or tyrosine phosphatase activity, further suggested that SptP inhibits both the membrane localization and subsequent phosphorylation required for activation of Raf. Both tyrosine phosphatase activity and GAP activity were responsible for SptP inhibition of Raf(Y340D)-induced ERK activation, but only GAP activity was responsible for inhibition of the membrane localized forms of Raf-1. To assess the biological significance of SptP, we examined tumour necrosis factor (TNF)-alpha induction following Salmonella infection. SptP gene deletion enhanced the capacity of Salmonella to induce TNF-alpha secretion following infection of J774A.1 macrophage cells.


Blind multiuser detector for chaos-based CDMA using support vector machine.
The algorithm and the results of a blind multiuser detector using a machine learning technique called support vector machine (SVM) on a chaos-based code division multiple access system is presented in this paper. Simulation results showed that the performance achieved by using SVM is comparable to existing minimum mean square error (MMSE) detector under both additive white Gaussian noise (AWGN) and Rayleigh fading conditions. However, unlike the MMSE detector, the SVM detector does not require the knowledge of spreading codes of other users in the system or the estimate of the channel noise variance. The optimization of this algorithm is considered in this paper and its complexity is compared with the MMSE detector. This detector is much more suitable to work in the forward link than MMSE. In addition, original theoretical bit-error rate expressions for the SVM detector under both AWGN and Rayleigh fading are derived to verify the simulation results.


OBP100 binds remarkably degenerate octamer motifs through specific interactions with flanking sequences.
We have used the 100-kD HeLa cell octamer-binding protein OBP100 as a model to study flexible DNA sequence recognition by promoter-binding proteins. OBP100 binds to the conserved octamer motif ATGCAAAT found in numerous promoters and additionally to two degenerate octamer motifs (sites I and II) within the SV40 enhancer region. We show here that OBP100 binds the herpes simplex virus immediate early promoter TAATGARAT (R = purine) motif itself, extending the flexibility of OBP100 sequence recognition to sequences that bear very little resemblance (four matches over a 14-bp region). Nevertheless, a progression of OBP100-binding sites can be established that links the sequences of these two apparently unrelated binding sites by incremental steps. Mutational and chemical modification interference analyses of a degenerate octamer binding site (SV40 site II) show that specific sequences, which are not normally conserved but flank the degenerate octamer motif, can compensate for the degeneracy in the octamer core sequence. Thus, different regions of the binding site sequence (core or flanking) can diverge separately but not independently of one another. These results suggest that flexible DNA sequence recognition arises because there are few obligatory contact sites for OBP100 binding, but, rather, specific binding reflects the sum of many independent interactions.


Empirical Factors Affecting the Quality of Non-Negative Matrix Factorization of Mammalian Cell Raman Spectra.
Mammalian cells contain various macromolecules that can be investigated non-invasively with Raman spectroscopy. The particular mixture of major macromolecules present in a cell being probed are reflected in the measured Raman spectra. Determining macromolecular identities and estimating their concentrations from these mixture Raman spectra can distinguish cell types and otherwise enable biological research. However, the application of canonical multivariate methods, such as principal component analysis (PCA), to perform spectral unmixing yields mathematical solutions that can be difficult to interpret. Non-negative matrix factorization (NNMF) improves the interpretability of unmixed macromolecular components, but can be difficult to apply because ambiguities produced by overlapping Raman bands permit multiple solutions. Furthermore, theoretically sound methods can be difficult to implement in practice. Here we examined the effects of a number of empirical approaches on the quality of NNMF results. These approaches were evaluated on simulated mammalian cell Raman hyperspectra and the results were used to develop an enhanced procedure for implementing NNMF. We demonstrated the utility of this procedure using a Raman hyperspectral data set measured from human islet cells to recover the spectra of insulin and glucagon. This was compared to the relatively inferior PCA of these data.


Restrictive Breathing Mask Reduces Repetitions to Failure During a Session of Lower-Body Resistance Exercise.
Andre, TL, Gann, JJ, Hwang, PS, Ziperman, E, Magnussen, MJ, and Willoughby, DS. Restrictive breathing mask reduces repetitions to failure during a session of lower-body resistance exercise. J Strength Cond Res 32(8): 2103-2108, 2018-The purpose of this study was to determine the effect of restrictive breathing mask (RBM) on muscle performance, hemodynamic, and perceived stress variables during a session of lower-body resistance exercise. In a crossover design, 10 participants performed 2 separate testing sessions, RBM and no mask, consisting of squat, leg press, and leg extension. The paired-samples t-test was used for session rating of perceived exertion (S-RPE), perceived stress before and after, heart rate (HR), pulse oximetry, and a 2 × 4 (session [mask, no mask] × time [squat exercise, leg press exercise, leg extension exercise, total resistance exercise session]) factorial analysis of variance with repeated measures (p ≤ 0.05). A significant decrease was found in total repetitions during the RBM condition (p < 0.01). A majority of the decrease in repetitions to failure occurred in the squat (p < 0.05) and in the leg press (p < 0.01), whereas no difference was observed in leg extension (p = 0.214). A significant increase was observed in S-RPE during the RBM session (p < 0.01). A significant increase was found in prestress (p < 0.01) and poststress (p = 0.01) in the RBM session. No significant difference existed for HR between exercise sessions (p = 0.08). A significant decrease existed in pulse oximetry during the RBM session (p < 0.01). The use of an RBM had a negative effect on the number of repetitions completed during an acute session of lower-body resistance training.


A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling.
The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E2 and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H2 receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling.


Geographic social vulnerability is associated with the alpha diversity of the human microbiome.
As a risk factor for conditions related to the microbiome, understanding the role of SVI on microbiome diversity may assist in identifying public health implications for microbiome research. Here we found, using a sub-sample of the Human Microbiome Project phase 1 cohort, that SVI was linked to microbiome diversity across body sites and that SVI may influence race/ethnicity-based differences in diversity. Our findings, build on the current knowledge regarding the role of human geography in microbiome research, suggest that measures of geographic social vulnerability be considered as additional contextual factors when exploring microbiome alpha diversity.


Salience of Somatosensory Stimulus Modulating External-to-Internal Orienting Attention.
Shifting between one's external and internal environments involves orienting attention. Studies on differentiating subprocesses associated with external-to-internal orienting attention are limited. This study aimed to reveal the characteristics of the disengagement, shifting and reengagement subprocesses by using somatosensory external stimuli and internally generated images. Study participants were to perceive nociceptive external stimuli (External Low (EL) or External High (EH)) induced by electrical stimulations (50 ms) followed by mentally rehearsing learned subnociceptive images (Internal Low (IL) and Internal High (IH)). Behavioral responses and EEG signals of the participants were recorded. The three significant components elicited were: fronto-central negativity (FCN; 128-180 ms), fronto-central P2 (200-260 ms), and central P3 (320-380 ms), which reflected the three subprocesses, respectively. Differences in the FCN and P2 amplitudes during the orienting to the subnociceptive images revealed only in the EH but not EL stimulus condition that are new findings. The results indicated that modulations of the disengagement and shifting processes only happened if the external nociceptive stimuli were of high salience and the external-to-internal incongruence was large. The reengaging process reflected from the amplitude of P3 correlated significantly with attenuation of the pain intensity felt from the external nociceptive stimuli. These findings suggested that the subprocesses underlying external-to-internal orienting attention serve different roles. Disengagement subprocess tends to be stimulus dependent, which is bottom-up in nature. Shifting and reengagement tend to be top-down subprocesses, which taps on cognitive control. This subprocess may account for the attenuation effects on perceived pain intensity after orienting attention.


Point-tracked quantitative analysis of left ventricular surface motion from 3-D image sequences.
We propose and validate the hypothesis that we can use differential shape properties of the myocardial surfaces to recover dense field motion from standard three-dimensional (3-D) image sequences (MRI and CT). Quantitative measures of left ventricular regional function can be further inferred from the point correspondence maps. The noninvasive, algorithm-derived results are validated on two levels. First, the motion trajectories are compared to those of implanted imaging-opaque markers of a canine model in two imaging modalities, where subpixel accuracy is achieved. Second, the validity of using motion parameters (path length and thickness changes) for detecting myocardial injury area is tested by comparing algorithms derived results to postmortem analysis TTC staining of myocardial tissue, where the achieved Pearson product-moment correlation value is 0.968.


Mosquitofish (Gambusia affinis) preference and behavioral response to animated images of conspecifics altered in their color, aspect ratio, and swimming depth.
Mosquitofish (Gambusia affinis) is an example of a freshwater fish species whose remarkable diffusion outside its native range has led to it being placed on the list of the world's hundred worst invasive alien species (International Union for Conservation of Nature). Here, we investigate mosquitofish shoaling tendency using a dichotomous choice test in which computer-animated images of their conspecifics are altered in color, aspect ratio, and swimming level in the water column. Pairs of virtual stimuli are systematically presented to focal subjects to evaluate their attractiveness and the effect on fish behavior. Mosquitofish respond differentially to some of these stimuli showing preference for conspecifics with enhanced yellow pigmentation while exhibiting highly varying locomotory patterns. Our results suggest that computer-animated images can be used to understand the factors that regulate the social dynamics of shoals of Gambusia affinis. Such knowledge may inform the design of control plans and open new avenues in conservation and protection of endangered animal species.


Unidentified cachexia patients in the oncologic setting: Cachexia UFOs do exist.
Cachexia is an important outcome-modulating parameter in patients with cancer. In the context of a randomized controlled trial on cachexia and nutritional therapy, the TiCaCONCO (Tight Caloric Control in the Cachectic Oncologic Patient) trial, the contacts between patients with cancer and health care practitioners and oncologists were screened. The aim of this retrospective study was to identify in the charts the input of data on body weight (necessary to identify cachexia stage), relevant nutritional data, and nutritional interventions triggered or implemented by oncologists and dietitians. In a tertiary, university oncology setting, over a time span of 8 mo (34 wk), the charts of patients admitted to an oncology, gastroenterology, or abdominal surgery unit were screened for the presence of information contributing to a cancer cachexia diagnosis. Data (patient characteristics, tumor type, and location) was gathered. We analyzed 9694 files. Data on body weight was present for >90% of patients. Of the 9694 screening, 118 new diagnoses of cancer were present (1.22% of patient contacts). Information on weight evolution or nutritional status was absent for 54 patients (46%). In contacts between oncologists and patients with cancer, at the time of diagnosis, cachexia was present in 50 patients (42%). In 7 of these patients (14%), no nutritional information was present in the notes. Of the 50 patients with cachexia, only 8 (16%) had a nutritional intervention initiated by the physician. Nutritional interventions were documented in the medical note in 11 patients (9%) in the overall study population. Dietitians made notes regarding nutrition and weight for 49 patients (42%). We could not demonstrate a difference in mortality between cachectic and non-cachectic patients, although numbers are small for analysis. Patients newly diagnosed with cancer are not systematically identified as being cachectic and if they are, interventions in the field of nutrition therapy are largely lacking. Important barriers exist between oncologists and dietitians, the former being mandatory to the success of a nutrition trial in cancer.


Investigation on NMR relaxivity of nano-sized cyano-bridged coordination polymers.
We present the first comparative investigation of the Nuclear Magnetic Resonance (NMR) relaxivity of a series of nanosized cyano-bridged coordination networks stabilized in aqueous solution. These Ln(3+)/[Fe(CN)6](3-) (Ln = Gd, Tb, Y) and M(2+)/[Fe(CN)6](3-) (M = Ni, Cu, Fe) nanoparticles with sizes ranging from 1.4 to 5.5 nm are stabilized by polyethylene glycols (MW = 400 or 1000), polyethylene glycol functionalized with amine groups (MW = 1500), or by N-acetyl-D-glucosamine. The evaluation of NMR relaxivity allowed estimation of the Magnetic Resonance Imaging (MRI) contrast efficiency of our systems. The results demonstrate that Gd(3+)/[Fe(CN)6](3-) nanoparticles have r1p and r2p relaxivities about four times higher than the values observed in the same conditions for the commercial Contrast Agents (CAs) ProHance or Omniscan, regardless of the stabilizing agent used, while nanoparticles of Prussian blue and its analogues M(2+)/[Fe(CN)6](3-) (M = Ni, Cu, Fe) present relatively modest values. The influence of the chemical composition of the nanoparticles, their crystal structure, spin values of lanthanide and transition metal ions, and stabilizing agent on the relaxivity values are investigated and discussed.


HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly.
Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 signaling also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD.


Identification of cell surface dipeptidylpeptidase IV in human fibroblasts.
An antigen with dipeptidylpeptidase IV activity was identified at the surface of normal human fibroblasts. Hydrophobic interaction electrophoresis in phenyl-Sepharose revealed that the enzyme contained a hydrophobic domain, while lactoperoxidase-catalysed iodination with 125I of living cells indicated that the protein was located at the cell surface. Crossed immunoelectrophoresis with specific antibodies of acid-extracted or papain-treated cells showed a shift of the dipeptidylpeptidase IV peak to a faster mobility. The molecular properties of the fibroblast enzyme were clearly different from those described for dipeptidylpeptidase IV from other tissues and species. Fibroblast dipeptidylpeptidase IV contained two different disulphide-linked subunits, of apparent Mr values 125000 and 135000 (denatured and reduced). In gel filtration, an Mr of about 400000 was observed for the unreduced molecule. The enzymic properties of fibroblast dipeptidylpeptidase IV were very similar to those of the well-characterized pig kidney enzyme. Activity towards glycyl-L-prolyl-beta-naphthylamide was inhibited 50% by 0.023 mM-di-isopropylphosphorofluoridate. L-Alanyl-L-alanyl-beta-naphthylamide was hydrolysed ten times more slowly than glycyl-L-prolyl-beta-naphthylamide.


Dissolved core alginate microspheres as "smart-tattoo" glucose sensors.
The feasibility of multilayer thin film coated dissolved-core alginate-templated microsphere sensors based on fluorescence resonance energy transfer and competitive binding, was explored in simulated interstitial fluid, using glucose as a model analyte. The glucose sensitivity was observed to be 0.89%/mM glucose with a linear response in the range of 0-50 mM glucose. The sensor response was observed to be completely reversible in nature with a response time of 120 seconds. The system was further demonstrated to respond similarly using near-infrared dyes (Alexa Fluor-647-labeled dextran as donor and QSY-21-conjugated apo-GOx as acceptor) which exhibited a sensitivity of 0.94%/mM glucose with a linear response in range of 0-50 mM glucose, making the sensor more amenable to in vivo use, when implanted in scattering tissue.


Mono-(2-ethylhexyl) phthalate (MEHP) reversibly disrupts the blood-testis barrier (BTB) in pubertal rats.
The blood-testis barrier (BTB) is constituted by tight junctions between adjacent Sertoli cells (SC) that create a specialized adluminal microenvironment to foster the development of spermatocytes and spermatids. The BTB is a well-studied target of numerous environmental toxicants, including di-(2-ethylhexyl) phthalate (DEHP), a compound widely used in various consumer products. MEHP is the active toxic metabolite of DEHP that has long been recognized in postnatal rodents to disrupt SC function. This study evaluates the impact of MEHP on the integrity of the BTB in both pubertal and adult rats and the signal transduction pathways known to be involved in the disruption of the BTB. Treatment of prepubertal rats with 700 mg/kg MEHP for 24 hours functionally disrupted the BTB integrity. A similar treatment of adult rats with MEHP did not disrupt the integrity of the BTB. The observed disruption of the BTB integrity in the MEHP-treated prepubertal rats occurred concomitantly with a decreased expression and mislocalization of both the ZO1 and occludin tight junction-associated proteins, as well as sloughing of spermatocytes and spermatids. At this same time, MEHP treatment induced a transient surge of p44/42 mitogen-activated protein kinase (MAPK) pathway. Interestingly, after a recovery period of 5 weeks, the BTB recovered and was functionally intact. This is the first report to indicate that acute MEHP exposure of prepubertal rats, but not adult rats, disrupts the functional integrity of the BTB and that this effect on the BTB is reversible.


Bleaching of browned water yam (Dioscorea alata) with African oil bean seed lipoxygenase (Part 2).
Purified African oil bean seed lipoxygenase was used to bleach water yam tubers that were browned by exposing their cut surfaces to air. The enzyme solution destroyed the polyphenols extracted from the browned water yams and the polyphenols at the browned yam tubers which resulted in the bleaching of the browned yam tubers to their original white colour. The destruction of the polyphenol extract and the bleaching of the browned yam tubers were found to be dependent on the enzyme concentration of the enzyme.


Correlates of lactation in mothers of very low birth weight infants.
We sought to determine the correlates of intent to breastfeed and of successful lactation and nursing at the breast in mothers of very low birth weight (VLBW; <1.5 kg) infants. We conducted a prospective observational study of 119 mothers of singleton VLBW infants (mean birth weight: 1056 g; mean gestational age: 28 weeks), 87 (73%) of whom intended to breastfeed. Mothers completed questionnaires at 3 weeks' postnatal age and at 35 and 40 weeks' (term) and 4 months' corrected ages (CAs). Of the 87 mothers who intended to breastfeed, 30 mothers (34%) continued lactation beyond 40 weeks' CA (postmenstrual plus postnatal age). Compared with mothers who discontinued lactation before this time, those who continued were older (31 vs 26 years), more were married (80% vs 39%), they had more than a high school education (70% vs 42%), and they were white (63% vs 35%). There were no significant differences in their infants' birth data or rates of neonatal morbidity. Significant correlates of lactation beyond 40 weeks' CA included beginning milk expression before 6 hours postdelivery, expressing milk > or =5 times per day, and kangaroo care. These correlates remained significant after controlling for maternal age, race, marital status, and education beyond high school. At 4 months' CA, 14 mothers (16%) were still lactating, 12 of whom were nursing at the breast. Increased maternal support specifically directed toward behavioral factors, including early and more frequent milk expression and kangaroo care, may improve the rates of successful lactation among mothers of VLBW infants who choose to breastfeed.


Acquired comitant esotropias - comparison of surgical outcomes of accommodative vs non-accommodative types.
Purpose: To compare the motor and sensory outcomes of strabismus surgery and the factors affecting surgical success in acquired acute non-accomodative esotropia (ANAET) and partially accommodative refractive esotropia (pARET). Methods: A retrospective chart review of patients with ANAET and pARET who underwent unilateral or bilateral horizontal rectus muscle surgery between January 2020 and December 2021 was conducted. Patients with postoperative follow-up of at least six weeks were included. Patients with pattern deviation, lateral incomitance, and near-distance disparity were excluded. Motor success was defined as a postoperative deviation within eight prism diopters of orthophoria. Sensory success was defined as presence of binocular single vision (BSV) for both distance and near (Worth four dot test). The effect of factors like age at onset, age at surgery, amblyopia before surgery, duration of squint before treatment, presence or absence and magnitude of vertical deviation, preoperative angle of deviation, and spherical equivalent on the motor and sensory success in each group were analyzed and compared. Results: 38 patients with ANAET and 33 patients with pARET were included. The mean age of onset of esotropia was 8.55 ± 4.65 years and 4.39 ± 2.27 years (p < .001) and the mean age at surgery was 10.62 ± 4.99 years and 7.89 ± 2.84 years (p = .006) in the ANAET and the pARET group respectively. The mean duration of the final follow-up was 38.51 weeks in the ANAET and 48.68 weeks in the pARET group (p = .089). Patients were successfully aligned for both distance and near in 81.5% of patients in the ANAET and 78.9% of patients in the pARET group at the final follow-up (p. 0.775). A BSV for both distance and near at the final follow-up was seen in 81.2% vs 66.6% of patients in the ANAET and the pARET group respectively (p = .25). A good near stereoacuity (<120 arcsecs) was seen in 60.6% and 41.9% of the ANAET and the pARET groups respectively (p = .175). The percentage of patients in the ANAET group who had orthophoria, any esodeviation, and any exodeviation for distance at the final follow-up was 63.1%, 34.2% and, 2.6%. The percentage of patients in the pARET group in similar categories was 36.3%, 42.4% and, 21.2%. None of the demographic and preoperative factors were found to affect the surgical outcomes in the two groups. Conclusions: The motor and sensory outcomes were similar in the two groups. A higher proportion of ANAET patients remained orthophoric during the follow-up. The patients in the pARET group showed a tendency toward exodrift.


The evolution of speech: vision, rhythm, cooperation.
A full account of human speech evolution must consider its multisensory, rhythmic, and cooperative characteristics. Humans, apes, and monkeys recognize the correspondence between vocalizations and their associated facial postures, and gain behavioral benefits from them. Some monkey vocalizations even have a speech-like acoustic rhythmicity but lack the concomitant rhythmic facial motion that speech exhibits. We review data showing that rhythmic facial expressions such as lip-smacking may have been linked to vocal output to produce an ancestral form of rhythmic audiovisual speech. Finally, we argue that human vocal cooperation (turn-taking) may have arisen through a combination of volubility and prosociality, and provide comparative evidence from one species to support this hypothesis.


Biomechanical differences between two different shapes of oblique lumbar interbody fusion cages on whether to add posterior internal fixation system: a finite element analysis.
Oblique lateral lumbar fusion (OLIF) is widely used in spinal degeneration, deformity and other diseases. The purpose of this study was to investigate the biomechanical differences between two different shapes of OLIF cages on whether to add posterior internal fixation system, using finite element analysis. A complete three-dimensional finite element model is established and verified for L3-L5. Surgical simulation was performed on the verified model, and the L4-L5 was the surgical segment. A total of the stand-alone group (Model A1, Model B1) and the BPSF group (Model A2, Model B2) were constructed. The four OLIF surgical models were: A1. Stand-alone OLIF with a kidney-shaped Cage; B1. Stand-alone OLIF with a straight cage; A2. OLIF with a kidney-shaped cage + BPSF; B2. Stand-alone OLIF with a straight cage + BPSF, respectively. The differences in the range of motion of the surgical segment (ROM), equivalent stress peak of the cage (ESPC), the maximum equivalent stress of the endplate (MESE) and the maximum stress of the internal fixation (MSIF) were compared between different models. All OLIF surgical models showed that ROM declines between 74.87 and 96.77% at L4-L5 operative levels. The decreasing order of ROM was Model A2 > Model B2 > Model A1 > Model A2. In addition, the ESPC and MESE of Model A2 are smaller than those of other OLIF models. Except for the left-bending position, the MSIF of Model B2 increased by 1.51-16.69% compared with Model A2 in each position. The maximum value of MESE was 124.4 Mpa for Model B1 in the backward extension position, and the minimum value was 7.91 Mpa for Model A2 in the right rotation. Stand-alone group showed significantly higher ROMs and ESPCs than the BPSF group, with maximum values of 66.66% and 70.59%. For MESE, the BPSF group model can be reduced by 89.88% compared to the stand-alone group model. Compared with the traditional straight OLIF cage, the kidney-shaped OLIF cage can further improve the stability of the surgical segment, reduce ESPC, MESE and MSIF, and help to reduce the risk of cage subsidence.


Photosynthetic electron sinks in transgenic tobacco with reduced amounts of Rubisco: little evidence for significant Mehler reaction.
Transgenic tobacco (Nicotiana tabacum L. cv. W38) plants with an antisense gene directed against the mRNA of the small subunit of Rubisco were used to investigate the role of O2 as an electron acceptor during photosynthesis. The reduction in Rubisco has reduced the capacity for CO2-fixation in these plants without a similar reduction in electron transport capacity. Concurrent measurements of chlorophyll fluorescence and CO2 assimilation at different CO2 and O2 partial pressures showed close linear relationships between chloroplast electron transport rates calculated from chlorophyll fluorescence and those calculated from CO2-fixation. These relationships were similar for wild-type and transgenic plants, indicating that the reduced capacity for CO2 fixation in the transgenic plants did not result in extra electron transport not associated with the photosynthetic carbon reduction (PCR) or photorespiratory carbon oxidation (PCO) cycle. This was further investigated with mass spectrometric measurements of 16O2 and 18O2 exchange made concurrently with measurements of chlorophyll fluorescence. In all tobacco lines the rates of 18O2 uptake in the dark were similar to the 18O2 uptake rates at very high CO2 partial pressures in the light. Rates of oxygenase activity calculated from 18O2 uptake at the compensation point were linearly related to the Rubisco content of leaves. The ratios of oxygenase to carboxylase rates were calculated from measurements of 16O2 evolution and 18O2 uptake at the compensation point. These ratios were lower in the transgenic plants, consistent with their higher CO2 compensation points. It is concluded that although there may be some electron transport to O2 to balance conflicting demands of NADPH to ATP requirements, this flux must decrease in proportion with the reduced demand for ATP and NADPH consumption in the transgenic lines. The altered balance between electron transport and Rubisco capacity, however, does not result in rampant electron transport to O2 or other electron transport acceptors in the absence of PCR and PCO cycle activity.


Factors influencing condom use in a sample of homosexually active men.
A sample of 502 homosexually active men were recruited from genitourinary medicine clinics and non clinic sources and interviewed in relation to their sexual behaviour and factors that might influence their use of condoms. Three hundred and eighty three men (76%) reported penetrative anal sex in the previous year. Ninety four (25%) had not used condoms in penetrative sex. Failure to use condoms was associated with unfavourable attitudes to them, not knowing close friends or partners who had HIV-related health problems, having fewer sexual partners and being in a closed monogamous relationship. On the other hand levels of awareness about the risks of unprotected anal sex and involvement in gay networks and social groups were not predictors of condom use.


Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial.
To evaluate whether placental transfusion influences brain myelination at 4 months of age. A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC, <20 seconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed. In the DCC and ICC groups, clamping time was 172 ± 188 seconds vs 28 ± 76 seconds (P < .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P < .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing. At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development. ClinicalTrials.gov: NCT01620008.


Effects of Cerebral Blood Flow and Vessel Conditions on Speech Recognition in Patients With Postlingual Adult Cochlear Implant: Predictable Factors for the Efficacy of Cochlear Implant.
Cochlear implantation (CI) has been the most successful procedure for restoring hearing in a patient with severe and profound hearing loss. However, possibly owing to the variable brain functions of each patient, its performance and the associated patient satisfaction are widely variable. The authors hypothesize that peripheral and cerebral circulation can be assessed by noninvasive and globally available methods, yielding superior presurgical predictive factors of the performance of CI in adult patients with postlingual hearing loss who are scheduled to undergo CI. Twenty-two adult patients with cochlear implants for postlingual hearing loss were evaluated using Doppler sonography measurement of the cervical arteries (reflecting cerebral blood flow), flow-mediated dilation (FMD; reflecting the condition of cerebral arteries), and their pre-/post-CI best score on a monosyllabic discrimination test (pre-/post-CI best monosyllabic discrimination [BMD] score). Correlations between post-CI BMD score and the other factors were examined using univariate analysis and stepwise multiple linear regression analysis. The prediction factors were calculated by examining the receiver-operating characteristic curve between post-CI BMD score and the significantly positively correlated factors. Age and duration of deafness had a moderately negative correlation. The mean velocity of the internal carotid arteries and FMD had a moderate-to-strong positive correlation with the post-CI BMD score in univariate analysis. Stepwise multiple linear regression analysis revealed that only FMD was significantly positively correlated with post-CI BMD score. Analysis of the receiver-operating characteristic curve showed that a FMD cutoff score of 1.8 significantly predicted post-CI BMD score. These data suggest that FMD is a convenient, noninvasive, and widely available tool for predicting the efficacy of cochlear implants. An FMD cutoff score of 1.8 could be a good index for determining whether patients will hear well with cochlear implants. It could also be used to predict whether cochlear implants will provide good speech recognition benefits to candidates, even if their speech discrimination is poor. This FMD index could become a useful predictive tool for candidates with poor speech discrimination to determine the efficacy of CI before surgery.


Strength gains following different combined concentric and eccentric exercise regimens.
Loss of muscle strength and cross-sectional area is a well-recognized consequence of spaceflight. Existing countermeasures have not been fully effective in preventing muscle weakness and atrophy in microgravity. Resistance exercise programs that consist of both eccentric and concentric actions have resulted in strength and muscle mass gains in ground-based studies. 1) A concentric/eccentric combination exercise regimen (with a bias of either concentric or eccentric exercise) will result in a greater strength gain than concentric exercise alone; and 2) an eccentrically biased regimen will result in the greatest strength gain of all. The 31 subjects were randomly assigned to one of three isokinetic exercise groups (CON-ECC: 75% concentric and 25% eccentric; ECC-CON: 75% eccentric and 25% concentric; CON: 100% concentric); each subject trained the right leg 3 d per week for 5 wk. Pre- and post-training isokinetic concentric/ eccentric strength tests and DEXA scans assessed changes in muscle strength and/or mass. All three groups showed an increase in eccentric muscle strength with the CON group showing the smallest gain (10.1%). Significantly larger gains were noted in the two combination groups (19.5%, 18.1%; p < 0.042), with the largest gains in eccentric strength. No significant change was noted in muscle mass. A resistance exercise protocol which includes eccentric as well as concentric exercise, particularly when the eccentric exercise is emphasized, appears to result in greater strength gains than concentric exercise alone. Findings suggest eccentric exercise may be an important component of the in-flight resistance exercise protocol for long-duration spaceflight.


Estimation of covariate effects on net survivals in the relative survival progressive illness-death model.
Recently, there has been a lot of development in relative survival field. In the absence of data on the cause of death, the research has tended to focus on the estimation of survival probability of a cancer (as a disease of interest). In many cancers, one nonfatal event that decreases the survival probability can occur. There are a few methods that assess the role of prognostic factors for multiple types of clinical events while dealing with uncertainty about the cause of death. However, these methods require proportional hazard or Markov assumptions. In practice, one or both of these assumptions might be violated. Violation of the proportional hazard assumption can lead to estimates that are biased, and difficult to interpret and violation of Markov assumption results in inconsistent estimators. In this work, we propose a semi-parametric approach to estimate the possibly time-varying regression coefficients in the likely non-Markov relative survival progressive illness-death model. The performance of the proposed estimator is investigated through simulations. We illustrate our approach using data from a study on rectal cancer resected for cure conducted in two French population-based digestive cancer registries.


Investigation of the sensitivity and specificity of radiological signs for diagnosis of periapical infection of equine cheek teeth.
Radiography is commonly used for the diagnosis of equine cheek teeth (CT) infection but, to our knowledge, no study to date has evaluated the relative values of individual specific radiographic signs when making a diagnosis. To investigate the sensitivity and specificity of individual radiographic signs identified from the literature for the diagnosis of CT apical infection using a retrospective case-control study. Cropped radiographs taken using computed radiography of 41 apically infected CT and 41 control CT were independently blindly evaluated by 3 clinicians for the presence of 12 predetermined radiographic signs associated with CT apical infection. A final diagnosis of either noninfected or infected was made. Sensitivity and specificity were calculated for the presence or absence of each radiographic sign for each clinician. Uni- and multivariable conditional logistic regression were used to determine strength of association of the 12 radiographic signs with apical infection. Median sensitivity and specificity for the diagnosis of CT apical infection were 76 and 90%, respectively. Periapical sclerosis, clubbing of one or 2 roots, degree of clubbing and periapical halo formation had the highest sensitivities (73-90%), with moderate specificity (61-63%). Multivariable conditional logistic regression revealed that severity of periapical sclerosis and extensive periapical halo were strongly associated with CT apical infection. The presence of periapical sclerosis and formation of a periapical halo were strongly associated with CT apical infection. Computed radiography appears to have a higher sensitivity but similar specificity to previously published results using film radiography to detect CT apical infection. These findings may aid practitioners when interpreting radiographs of equine CT as to the relative significance of their findings.


Label-free Screening of common urinary system tumors from blood plasma based on surface-enhanced Raman spectroscopy.
The incidence of common urinary system tumors has been rising rapidly in recent years, and most urinary system-derived tumors lack specific biomarkers. To explore the efficacy of Surface-enhanced Raman spectroscopy (SERS) of blood plasma in screening three common urinary system tumors, including bladder cancer (BC), prostate cancer (PCa), and renal cell carcinoma (RCC). SERS plasma spectra from 125 plasma samples, including 25 PCa, 38 RCC, 24 BC patients, and 38 normal volunteers, were collected. All candidates had no other comorbidities. The Diagnosis was based on the combination of Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA), and the effectiveness of the diagnostic algorithms was verified using the Receiver Operating Characteristic Curve (ROC). There are significant differences in SERS signals between PCa, BC, RCC, and normal plasma, especially at 639, 889, 1010, 1136, and 1205 cm-1. The PCA-LDA results show that high sensitivity (100%), specificity (100%), and accuracy (100%) could be achieved for screening the PCa, RCC, BC group vs. the normal group, the PCa group vs. the BC and RCC group, respectively. The diagnostic sensitivity, specificity, and accuracy for the BC group vs. the RCC group are 79.2%, 71.1%, and 75.15%, respectively. The integrated area under the ROC curve (AUC) is 1.0, 1.0, and 1.0 for the PCa, RCC, and BC group vs. the normal group, respectively. The AUC of the PCa group vs. the BC group and RCC group and the BC group vs. the RCC group are 1.0, 1.0, and 0.842, respectively. Label-free plasma-SERS technology with PCA-LDA analysis could be a useful screening method for detecting urinary system tumors (PCa, RCC, and BC) in this exploratory study.


Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes.
Vitiligo is a skin depigmentation disorder with an increasing prevalence. Among recognized mechanisms is the oxidative stress that affects melanocytes which are responsible for skin pigmentation. Studies have shown that high concentration of hydrogen peroxide, or H2O2, induces apoptotic activities. Few studies have been done with lower doses of H2O2. Using human skin melanocytes, we investigated the effect of moderate concentration of H2O2 on melanocyte dendrites. Confocal data show that H2O2 at 250 µM induces loss of dendrites, as indicated by cytoskeletal proteins. α-melanocyte stimulating hormone or α-MSH pretreatment protects against H2O2-induced loss of dendrites, while α-MSH alone enhances dendrites. PI3K/AKT inhibitor LY294002 and mTORC1 inhibitor Rapamycin inhibit α-MSH-induced dendrites. In this study, we also investigated the effect of TNFα on cultured human skin melanocytes, since TNFα plays important roles in vitiligo. Confocal data demonstrate that TNFα induces NFκB activation. Western blot analysis shows that TNFα induces IκB phosphorylation and degradation. Interestingly, α-MSH does not have any effect of TNFα-induced IκB degradation and NF-κB activation. α-MSH, however, activates mTORC1 pathway. TNFα induces p38 but not AMPKα activation. Collectively, our data suggest that modulation of mTOR and NF-κB pathways may be a novel approach for better clinical management of vitiligo.


A Retrospective Study of Success, Failure, and Time Needed to Perform Awake Intubation.
Awake intubation is the standard of care for management of the anticipated difficult airway. The performance of awake intubation may be perceived as complex and time-consuming, potentially leading clinicians to avoid this technique of airway management. This retrospective review of awake intubations at a large academic medical center was performed to determine the average time taken to perform awake intubation, its effects on hemodynamics, and the incidence and characteristics of complications and failure. Anesthetic records from 2007 to 2014 were queried for the performance of an awake intubation. Of the 1,085 awake intubations included for analysis, 1,055 involved the use of a flexible bronchoscope. Each awake intubation case was propensity matched with two controls (1:2 ratio), with similar comorbidities and intubations performed after the induction of anesthesia (n = 2,170). The time from entry into the operating room until intubation was compared between groups. The anesthetic records of all patients undergoing awake intubation were also reviewed for failure and complications. The median time to intubation for patients intubated post induction was 16.0 min (interquartile range: 13 to 22) from entrance into the operating room. The median time to intubation for awake patients was 24.0 min (interquartile range: 19 to 31). The complication rate was 1.6% (17 of 1,085 cases). The most frequent complications observed were mucous plug, endotracheal tube cuff leak, and inadvertent extubation. The failure rate for attempted awake intubation was 1% (n = 10). Awake intubations have a high rate of success and low rate of serious complications and failure. Awake intubations can be performed safely and rapidly.


Mercury in cetaceans: Exposure, bioaccumulation and toxicity.
The fate and transportation of mercury in the marine environment are driven by a combination of anthropogenic atmospheric and aquatic sources, as well as natural geological inputs. Mercury biomagnifies up the food chain, resulting in the bioaccumulation of toxic concentrations in higher trophic organisms even when concentrations in their habitat remain below the threshold level for direct toxicity. As a result, mercury exposure has been recognised as a health concern for both humans and top marine predators, including cetaceans. There appears to be no overall trend in the global measured concentrations reported in cetaceans between 1975 and 2010, although differences between areas show that the highest concentrations in recent decades have been measured in the tissues of Mediterranean odontocetes. There is increasing concern for the impacts of mercury on the Arctic marine ecosystem with changes in water temperatures, ocean currents, and prey availability, all predicted to affect exposure. The accumulation of mercury in various tissues has been linked to renal and hepatic damage as well as reported neurotoxic, genotoxic, and immunotoxic effects. These effects have been documented through studies on stranded and by-caught cetaceans as well as in vitro cell culture experiments. Demethylation of methylmercury and protection by selenium have been suggested as possible mercury detoxification mechanisms in cetaceans that may explain the very high concentrations measured in tissues of some species with no apparent acute toxicity. Thus, the ratio of selenium to mercury is of importance when aiming to determine the impact of the contaminant load at an individual level. The long-term population level effects of mercury exposure are unknown, and continued monitoring of odontocete populations in particular is advised in order to predict the consequences of mercury uptake on marine food chains in the future.


Inhibitory deficits in reading disability depend on subtype: guessers but not spellers.
In this study, children with the guessing subtype of dyslexia (who read fast and inaccurately) were compared with children with the spelling subtype (who read slowly and accurately) on three aspects of executive functioning (EF): response inhibition, susceptibility to interference from irrelevant information, and planning. It was found that guessers were impaired in their ability to inhibit inappropriate responding on all tasks used to assess EF (the stop signal task, the Stroop task, and the Tower of London task). This raises the question of whether the specific reading disorder of guessers may be linked to the same executive deficits which underlie ADHD. In order to unite a fast/inaccurate reading style with executive deficiencies, an attempt is made to incorporate the concept of executive control into models of lexical activation.


Global Prostate Cancer Incidence and Mortality Rates According to the Human Development Index.
Prostate cancer (PC) is one of the leading causes of death, especially in developed countries. The human development index (HDI) and its dimensions seem correlated with incidence and mortality rates of PC. This study aimed to assess the association of the specific components of HDI (life expectancy at birth, education, gross national income per 1000 capita, health, and living standards) with burden indicators of PC worldwide. Information of the incidence and mortality rates of PC was obtained from the GLOBOCAN cancer project in year 2012 and data about the HDI 2013 were obtained from the World Bank database. The correlation between incidence, mortality rates, and the HDI parameters were assessed using STATA software. A significant inequality of PC incidence rates was observed according to concentration indexes=0.25 with 95% CI (0.22, 0.34) and a negative mortality concentration index of -0.04 with 95% CI (-0.09, 0.01) was observed. A positive significant correlation was detected between the incidence rates of PC and the HDI and its dimensions including life expectancy at birth, education, income, urbanization level and obesity. However, there was a negative significant correlation between the standardized mortality rates and the life expectancy, income and HDI.


The combined impact of plant-derived dietary ingredients and acute stress on the intestinal arachidonic acid cascade in Atlantic salmon (Salmo salar).
A study was conducted to assess the effect of substituting high levels of dietary fish oil (FO) and fishmeal (FM) for vegetable oil (VO) and plant protein (PP) on the intestinal arachidonic acid (AA) cascade in the carnivorous fish species Atlantic salmon. Four diets were fed to salmon over a period of 12 months, including a control FMFO diet, with varying replacements of plant-derived ingredients: 80 % PP and 35 % VO; 40 % PP and 70 % VO; 80 % PP and 70 %VO. Subsequently, fish were examined pre- (0 h) and post- (1 h) acute stress for blood parameters and intestinal bioactive lipidic mediators of inflammation (prostaglandins). Plasma cortisol responses were greatest in the FMFO group, while 80 % PP and 70 % VO fish exhibited increased plasma chloride concentrations. The n-3:n-6 PUFA ratio in intestinal glycerophospholipids from 70 % VO groups significantly decreased in both proximal and distal regions due to elevated levels of 18 : 2n-6 and the elongation/desaturation products 20 : 2n-6 and 20 : 3n-6. Increases in n-6 PUFA were not concomitant with increased AA, although the AA:EPA ratio did vary significantly. The 40 % PP and 70 % VO diet produced the highest intestinal AA:EPA ratio proximally, which coincided with a trend in elevated levels of PGF2alpha, PGE2 and 6-keto-PGF1alpha in response to stress. PGE2 predominated over PGF2alpha and 6-keto-PGF1alpha (stable metabolite of PGI2) with comparable concentrations in both intestinal regions. Cyclo-oxygenase-2 (COX-2) mRNA expression was an order of magnitude higher in distal intestine, compared with proximal, and was significantly up-regulated following stress. Furthermore, the 80 % PP and 70 % VO diet significantly amplified proximal COX-2 induction post-stress. Results demonstrate that high replacements with plant-derived dietary ingredients can enhance COX-2 induction and synthesis of pro-inflammatory eicosanoids in the intestine of salmon in response to acute physiological stress.


Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS.
Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~100× average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL.


Effect of temporary closure of oronasal fistulae on levator veli palatini muscle activity.
The objective of this study was to clarify electromyographically the effects of closing an oronasal fistula on levator muscle activity and oral air pressure in patients with velopharyngeal incompetence and in those with adequate velopharyngeal function. Five patients with adequate velopharyngeal function and six patients with velopharyngeal incompetence were studied. All subjects had an oronasal fistula at the anterior third portion of the hard palate in spite of primary palatal closure using palatal push-back operation. The smoothed electromyographic activity of the levator veli palatini muscle was measured with the fistula closed with a cotton swab dipped in saline and with the fistula left open. Under the closed fistula condition, oral air pressure was greater than that observed under the open fistula condition irrespective of velopharyngeal function. Levator veli palatini muscle activity was significantly lower in magnitude under the condition of closure than under the open condition in the patients with adequate velopharyngeal function, whereas in those with velopharyngeal incompetence, it was not significantly changed. The results suggest that velopharyngeal function is affected by temporary closure of an oronasal fistula, and that the magnitude of the effect is greater for subjects with adequate velopharyngeal function than for subjects with velopharyngeal incompetence.


Amantadine-resistant influenza A in a nursing facility.
Rapid index case treatment and amantadine prophylaxis were implemented in two nursing homes exposed to influenza A. Facility A had no isolation of cases, and 18 of 22 cases occurred after amantadine hydrochloride therapy was initiated. Three patients exhibited amantadine-resistant virus. Facility B had day 1 isolation of the index case. A facility-wide outbreak did not occur. The experience of these facilities suggests that concurrent amantadine treatment and prophylaxis without adequate case isolation may promote further influenza A infection in a nursing facility.


Polymorphism in the 5'-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction.
Human glutamate-cysteine ligase (GCL) is a rate-limiting enzyme for the synthesis of glutathione that plays a crucial role in antioxidant defense mechanisms in most mammalian cells, including vascular cells. Oxidants transcriptionally upregulate GCL genes for glutathione synthesis, providing a protective mechanism against oxidative stress-induced cellular dysfunction. This study examined the hypothesis that variation in the GCL genes may be associated with coronary artery disease in which oxidative stress plays a pathogenetic role. We searched for the common variants in the 5'-flanking region of the GCL modifier subunit (GCLM) gene in patients with myocardial infarction (MI). We found a polymorphism (-588C/T) in which the T allele showed lower promoter activity (40% to 50% of C allele) in response to oxidants in the luciferase reporter gene assay. Allele frequencies were determined by polymerase chain reaction-based analysis of restriction fragment length polymorphism in 429 patients with MI and 428 control subjects (as defined by angiography) in Kumamoto Prefecture, Japan. The frequency of the T polymorphism was significantly higher in the MI group than in the control group (CT and TT genotypes: 31.5% in MI group versus 19.2% in control group; P<0.001). In multiple logistic regression analysis, the T polymorphism was a risk factor for MI independent of traditional coronary artery disease risk factors (odds ratio, 1.98; 95% confidence interval, 1.38 to 2.83; P<0.001). These findings suggest that the -588T polymorphism of the GCLM gene may suppress GCLM gene induction in response to oxidants and that it is a genetic risk factor for MI.


Fungi and bacteria in the beds of rural and urban infants correlate with later risk of atopic diseases.
Rural children have a lower risk of asthma and atopic diseases than urban children. However, whether indoor microbiota in non-farming rural homes provides protection is unclear. Here, we examine if microbes in the beds of rural and urban infants are associated with later development of atopic diseases. We studied fungi and bacteria in the beds of 6-month-old infants (n = 514) in association with the risk of asthma, allergic rhinitis, eczema and aeroallergen sensitization at 6 years of age in the prospective COPSAC2010 cohort. Both fungal and bacterial diversity were lower in the beds of children, who later developed allergic rhinitis (-0.22 [-0.43,-0.01], padj = .04 and -.24 [-0.42,-0.05], padj = .01 respectively) and lower bacterial richness was discovered in beds of children later developing asthma (-41.34 [-76.95,-5.73], padj = .02) or allergic rhinitis (-45.65 [-81.19,-10.10], padj = .01). Interestingly, higher fungal diversity and richness were discovered in the beds of children developing eczema (0.23 [0.02,0.43], padj = .03 and 29.21 [1.59,56.83], padj = .04 respectively). We defined a limited set of fungal and bacterial genera that predicted rural/urban environment. Some rural-associated bacterial genera such as Romboutsia and Bacillus and fungal genera Spegazzinia and Physcia were also associated with reduced risk of diseases, including eczema. These fungal and bacterial fingerprints predicting the living environment were associated with asthma and allergic rhinitis, but not eczema, with rural compositions being protective. The bed dust bacteria mediated 27% of the protective association of a rural living environment for allergic rhinitis (p = .04). Bed dust microbes can be differentially associated with airway- and skin-related diseases. The differing bed dust microbiota between rural and urban infants may influence their later risk of asthma and allergic rhinitis.


Efficacy of pulse methylprednisolone in a pediatric case of postinfectious bronchiolitis obliterans.
Postinfectious bronchiolitis obliterans is a chronic incapacitating disease with persistent airway inflammation. However, the efficacy of systemic corticosteroids has never been studied systematically. In the presented case, serial spirometry, plethysmography measurements, and nocturnal oximetry demonstrated progressive decline in lung hyperinflation and air-trapping and improvement in expiratory function and nocturnal oxygenation during and after six three-day courses of high-dose methylprednisolone (30 mg/kg/day). At four months post treatment, most gain in lung function was lost suggesting the need for sustained immunosuppression. Randomized, controlled trials using serial plethysmography measurements, spirometry, and nocturnal oximetry could provide evidence for the management of postinfectious bronchiolitis obliterans.


Ciprofloxacin-induced crystal nephropathy.
Ciprofloxacin is a commonly used antibiotic. Renal side effects are rare and are usually immune mediated. Clinical and experimental studies have suggested that crystalluria and crystal nephropathy occur in alkaline urine. Preexisting kidney function impairment, high dose of the medication, and advanced age predispose to this complication. We report a case of crystal nephropathy in a young woman treated with ciprofloxacin and a nonsteroidal anti-inflammatory drug.


Meal-induced hormone responses in a rat model of Roux-en-Y gastric bypass surgery.
Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for morbid obesity and remission of associated type 2 diabetes, but the mechanisms involved are poorly understood. The aim of the present study was to develop and validate a rat model for RYGB surgery that allows repeated measurement of meal-induced changes in gut and pancreatic hormones via chronic venous catheters. Male Sprague Dawley rats made obese on a palatable high-fat diet were subjected to RYGB or sham surgery and compared with chow-fed, lean controls. Hormonal responses to a mixed-liquid test meal were examined by frequent blood sampling through chronically implanted jugular catheters in freely behaving rats, 3-4 months after surgery, when RYGB rats had significantly reduced body weight and fat mass compared with sham-operated rats. Hyperleptinemia, basal hyperinsulinemia, and hyperglycemia as well as postprandial glucose intolerance seen in sham-operated, obese rats were completely reversed by RYGB and no longer different from lean controls. Postprandial increases in glucagon-like peptide-1, peptide YY, and amylin as well as suppression of ghrelin levels were all significantly augmented in RYGB rats compared with both sham-operated obese and lean control rats. Thus, our rat model replicates most of the salient hormonal and glycemic changes reported in obese patients after RYGB, with the addition of amylin to the list of potential candidate hormones involved in hypophagia, weight loss, and remission of diabetes. The model will be useful for elucidating the specific peripheral and central mechanisms involved in the suppression of appetite, loss of body weight, and remission of type 2 diabetes.


Platelet inhibitors in non-ST-segment elevation acute coronary syndromes and percutaneous coronary intervention: glycoprotein IIb/IIIa inhibitors, clopidogrel, or both?
The role of glycoprotein (Gp) IIb/IIIa receptor antagonists remains controversial and these agents are infrequently utilized during non-ST-segment elevation acute coronary syndromes (NSTE-ACS) despite American Heart Association/American College of Cardiology guidelines. Despite recommendations, the NRMI-4 (National Registry of Myocardial Infarction 4) and CRUSADE (Can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines?) registries observed that only 25%-32% of eligible patients received early Gp IIb/IIIa therapy, despite a 6.3% absolute mortality reduction in NRMI-4 and a 2% absolute mortality reduction in CRUSADE. A pooled analysis of Gp IIb/IIIa data from these registries suggest a major reduction in mortality (Odds Ratio = 0.43, 95% Confidence Index 0.25-0.74, p = 0.002) with early Gp IIb/IIIa therapy, yet clinicians fail to utilize this option in NSTE-ACS. The evidence-based approach to NSTE-ACS involves aspirin, clopidogrel, low-molecular weight heparins, or unfractionated heparin in concert with Gp IIb/Ila receptor antagonists, however, newer percutaneous coronary intervention (PCI)-based trials challenge current recommendations. Novel strategies emerging in NSTE-ACS include omitting Gp IIb/Ila inhibitors altogether or using Gp IIb/IIIa inhibitors with higher doses of clopidogrel in selected patients. The ISAR-REACT (Intracoronary stenting and antithrombotic regimen-Rapid early action for coronary treatment) and ISAR-SWEET (ISAR-Is abciximab a superior way to eliminate elevated thrombotic risk in diabetics) trials question the value of abciximab when 600 mg of clopidogrel concurrently administered during PCI. The CLEAR-PLATELETS (Clopidogrel loading with eptifibatide to arrest the reactivity of platelets) and PEACE (Platelet activity extinction in non-Q-wave MI with ASA, clopidogrel, and eptifibatide) trials suggest more durable platelet inhibition when Gp IIb/IIIa inhibitors are used with higher doses clopidogrel. The ISAR-COOL (ISAR: Cooling off strategy) trial found no difference in ischemic outcomes when Gp IIb/IIIa inhibitors were excluded and ARMYDA-2 (Antiplatelet therapy for reduction of myocardial damage during angioplasty) suggested higher doses of clopidogrel are more appropriate during PCI when Gp IIb/IIIa inhibitors are not utilized. This constellation of new trials forces reconsideration of current recommendations in regards to patient risk stratification, choice of antithrombotic therapy, doses, and timing. These new data will impact emerging guidelines and updates are currently in progress.


Corticosteroids as adjuvant therapy for ocular toxoplasmosis.
Ocular infection caused by Toxoplasma gondii, a parasite, may result in inflammation in the retina, choroid, and uvea, and consequently lead to complications such as glaucoma, cataract, and posterior synechiae. The objective of this systematic review was to assess the effects of adjunctive use of corticosteroids to anti-parasitic therapy versus anti-parasitic therapy alone for ocular toxoplasmosis. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register (2016; Issue 11)), MEDLINE Ovid, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, MEDLINE Ovid Daily (January 1946 to December 2016), Embase (January 1980 to December 2016), Latin American and Caribbean Literature on Health Sciences (LILACS (January 1982 to December 2016)), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 7 December 2016. We had planned to include randomized and quasi-randomized controlled trials. Eligible trials would have enrolled participants of any age who were immunocompetent and were diagnosed with acute ocular toxoplasmosis. Included trials would have compared anti-parasitic therapy plus corticosteroids versus anti-parasitic therapy alone, different doses or times of initiation of corticosteroids. Two authors independently screened titles and abstracts retrieved through the electronic searches. We retrieved full-text reports of studies categorized as 'unsure' or 'include' after we reviewed the abstracts. Two authors independently reviewed each full-text report for eligibility. Discrepancies were resolved through discussion. We identified no completed or ongoing trial that was eligible for this Cochrane review. Although research has identified a wide variation in practice regarding the use of corticosteroids, our review did not identify any evidence from randomized controlled trials for or against the role of corticosteroids in the management of ocular toxoplasmosis. Several questions remain unanswered by well-conducted randomized trials in this context, including whether the use of corticosteroids as an adjunctive agent is more effective than the use of anti-parasitic therapy alone; if so, when corticosteroids should be initiated in the treatment regimen (early versus late course of treatment), and what would be the best dose and duration of steroid use.


Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer.
We investigate whether the prognosis of patients with differentiated thyroid cancer is improved by maintaining a greater level of TSH suppression. One hundred and forty-one patients who underwent hormone therapy after thyroidectomy were followed up from 1970 to 1993 (mean, 95 months). Patients received levothyroxine (L-T4; mean dose, 2.6 micrograms/kg-day). TSH suppression was evaluated by TRH stimulation test until 1986 and thereafter by a second generation immunoradiometric assay. As TSH underwent fluctuation over time in most patients, we focused on subgroups of patients with relatively constant TSH levels during the follow-up. The relapse-free survival (RFS) was longer in the group with constantly suppressed TSH (all TSH values, < or = 0.05 mU/L; n = 18) than in the group with nonsuppressed TSH (all TSH values, > or = 1 mU/L; n = 15; P < 0.01). Age, sex, tumor node metastasis stage, and initial therapy were not different between the suppressed and nonsuppressed TSH groups. In the overall population, we analyzed the level of TSH suppression by studying the percentage of undetectable TSH values (< or = 0.05 mU/L) during the follow-up. The patients with a greater degree of TSH suppression (> 90% of undetectable TSH values; n = 19) had a trend toward a longer RFS than the remaining population (n = 102; P = 0.14). The patients with a lesser degree of TSH suppression (< 10% of undetectable TSH values; n = 27) had a shorter RFS than the remaining patients (n = 94; P < 0.01). In multivariate analysis that included TSH suppression, age, sex, histology, and tumor node metastasis stage, the degree of TSH suppression predicted RFS independently of other factors (P = 0.02). This study shows that a lesser degree of TSH suppression is associated with an increased incidence of relapse, supporting the hypothesis that a high level of TSH suppression is required for the endocrine management of thyroid cancer.


Reducing wandering by persons with dementia using differential reinforcement.
Wandering behavior of 4 geriatric patients with dementia residing in a long-term care facility was assessed using direct behavioral observations. The consequences identified during the observations as maintaining wandering for each patient were then applied for the absence of wandering using differential reinforcement of other behavior (DRO). The effectiveness of the DRO procedure was evaluated using an ABAB design. Results indicated significant reductions in wandering during treatment.


Influence of N-terminal sequence variation on the sorting of major adenylate kinase to the mitochondrial intermembrane space in yeast.
Major adenylate kinase (Aky2p) from yeast has no cleavable presequence and occurs in identical form in the mitochondrial intermembrane space (6-8%) and in the cytoplasm (approx. 90%). To identify the signal(s) on Aky2p that might be required for mitochondrial import, the N-terminal region was examined. The N-terminus of Aky2p can guide at least two cytoplasmic passengers, dihydrofolate reductase from mouse and UMP kinase (Ura6p) from yeast, to the intermembrane space in vivo, showing that the N-terminus harbours import information. In contrast, deletion of the eight N-terminal amino acid residues or the introduction of two compensating frameshifts into this segment does not abolish translocation into the organelle's intermembrane space. Thus internal targeting and sorting information must be present in Aky2p as well. Neither a pronounced amphiphilic alpha-helical moment nor positive charges in the N-terminal region is a necessary prerequisite for Aky2p to reach the intermembrane space. Even a surplus of negative charges in mutant N-termini does not impede basal import into the correct submitochondrial compartment. The potential to form an amphipathic alpha-helical structure of five to eight residues close to the N-terminus significantly improves import efficiency, whereas extension of this amphipathic structure, e.g. by replacing it with the homologous segment of Aky3p, a mitochondrial matrix protein from yeast, leads to misdirection of the chimaera to the matrix compartment. This shows that the topogenic N-terminal signal of Aky3p is dominant over the presumptive internal intermembrane space-targeting signal of Aky2p and argues that the sorting of wild-type Aky2p to the intermembrane space is not due to the presence in the protein of a specific sorting sequence for the intermembrane space, but rather is the consequence of being imported but not being sorted to the inner compartment. Some Aky2 mutant proteins are susceptible to proteolysis in the cytoplasm, indicating incorrect folding. They are nevertheless efficiently rescued by uptake into mitochondria, suggesting a negative correlation between folding velocity (or folding stability) and efficiency of import.


Forebrain structures specifically activated by conditioned taste aversion.
This study investigates which forebrain structures show Fos protein expression during conditioned taste aversion (CTA) acquisition and whether Fos expression depends on the aversion strength. A novel taste paired with an intraperitoneal injection of a low dose of the malaise-inducing agent lithium chloride (LiCl) induced a weak CTA, whereas associating this novel taste with a high dose of LiCl induced a strong CTA. Increasing the strength of the gastric malaise alone enhanced Fos expression in central, basal, and lateral amygdala nuclei and decreased Fos expression in the nucleus accumbens core. Taste-malaise association induced specific Fos activation in the insular cortex (with both the low and the high doses of LiCl) and the nucleus accumbens shell (with the high LiCl dose only). No significant variation of Fos expression was measured in the perirhinal cortex. Several forebrain areas may be sites of taste-malaise convergence during CTA acquisition depending on the strength of the aversion.


Ginger and 6-shogaol protect intestinal tight junction and enteric dopaminergic neurons against 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine in mice.
Objective: Ginger and its compound, 6-shogaol, have been known for improving gastrointestinal (GI) function and reducing inflammatory responses in GI tract. Recently, the treatment of GI dysfunction has been recognized as an important part of the management of neurodegenerative diseases, especially for Parkinson's disease (PD). In this study, we investigated whether ginger and 6-shogaol attenuate disruptions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the intestinal barrier and the enteric dopaminergic neurons.Methods: C57BL/6J mice received MPTP (30 mg/kg) for 5 days to induce GI alterations. Ginger (30, 100, 300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 15 days including the period of MPTP injection.Results: Ginger and 6-shogaol protected intestinal tight junction proteins disrupted by MPTP in mouse colon. In addition, ginger and 6-shogaol suppressed the increase of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α and IL-1β activated by macrophage. Moreover, ginger and 6-shogaol suppressed the MPTP-induced enteric dopaminergic neuronal damage via increasing the cell survival signaling pathway.Conclusion: These results indicate that ginger and 6-shogaol restore the disruption of intestinal integrity and enteric dopaminergic neurons in an MPTP-injected mouse PD model by inhibiting the processes of inflammation and apoptosis, suggesting that they may attenuate the GI dysfunction in PD patients.


Role of 15-hydroxyeicosatetraenoic acid in hemozoin-induced lysozyme release from human adherent monocytes.
Natural hemozoin (nHZ), a lipid-bound ferriprotoporphyrin IX crystal produced by Plasmodium parasites after hemoglobin catabolism, seriously compromises the functions of human monocytes, and 15-hydroxyeicosatetraenoic acid (15-HETE) and 4-hydroxynonenal (4-HNE), two nHZ lipoperoxidation products, have been related to such a functional impairment. nHZ was recently shown to promote inflammation-mediated lysozyme release from human monocytes through p38 mitogen-activated protein kinase- (MAPK)- and nuclear factor (NF)-κB-dependent mechanisms. This study aimed at identifying the molecule of nHZ lipid moiety that was responsible for these effects. Results showed that 15-HETE mimicked nHZ effects on lysozyme release, whereas 4-HNE did not. 15-HETE-enhanced lysozyme release was abrogated by anti-TNF-α and anti-IL-1β-blocking antibodies and mimicked by recombinant cytokines; on the contrary, MIP-1α/CCL3 was not involved as a soluble mediator of 15-HETE effects. Moreover, 15-HETE early activated p38 MAPK and NF-κB pathways by inducing p38 MAPK phosphorylation; cytosolic I-κBα phosphorylation and degradation; NF-κB nuclear translocation and DNA-binding. Inhibition of both routes through chemical inhibitors (SB203580, quercetin, artemisinin, and parthenolide) prevented 15-HETE-dependent lysozyme release. Collectively, these data suggest that 15-HETE plays a major role in nHZ-enhanced monocyte degranulation.


Analysis of the interplay of physiological response to food intake and drug properties in food-drug interactions.
The effect of food on oral drug absorption is determined by the complex interplay among gut physiological factors and drug properties. The currently used dissolution testing and classification systems (biopharmaceutics classification system, BCS or biopharmaceutics drug disposition classification system, BDDCS) do not account for dynamic changes in gastrointestinal physiology caused by food intake. This study aimed to identify key drug properties that influence food effect (FE) using supervised machine learning approaches. The analysis showed that drugs with high logP, dose number, and extraction ratio have a higher probability of positive FE, while drugs with low permeability and high efflux saturation index have a greater likelihood of negative FE. Weakly acidic drugs also showed a greater probability of positive FE, particularly at pKa >4.3. The importance of drug properties in predicting FE was ranked as logP, dose number, extraction ratio, pKa, and permeability. The accuracy of FE prediction using the models was compared with BCS and extended clearance classification system (ECCS). Overall, the likelihood or magnitude of FE depends on physiological changes to food intake such as altered bile acid secretion rate, intestinal metabolism, transport kinetics, and gastric emptying time, which should be considered along with drug properties (e.g., solubility, logP, and ionization) in predicting FE of orally administered drugs.