Dry Eye Related to Commonly Used New Antidepressants.
Antidepressants may have an impact on the course of eye dryness. The aim of this study was to investigate the effects of commonly used new antidepressants on eye wetting. Fifty-four patients using new antidepressants and 57 controls were recruited. The Beck Depression Scale and Beck Anxiety Scale questionnaires were completed by the patients, and drug use time and dosages were recorded. The Schirmer test was performed without prior instillation of topical anesthesia to the ocular surface, and the wetting result was recorded for each eye. Escitalopram, duloxetine, and venlafaxine were used by 27, 13, and 14 patients, respectively. The Schirmer test results in the patients were significantly lower than in the controls (P < 0.001). The patients using selective serotonin reuptake inhibitors (SSRIs) displayed lower wetting measurements (≤5 mm) compared with those using serotonin-norepinephrine reuptake inhibitors, which was independent of the duration of antidepressant usage (P < 0.05). Although SSRIs do not have anticholinergic adverse effects except paroxetine, we found that both SSRIs and serotonin-norepinephrine reuptake inhibitors increased the risk for eye dryness. The lower Schirmer test results of the SSRIs may be associated with a mechanism other than the anticholinergic system. An awareness of the drugs that contribute to dry eye will allow ophthalmologists, optometrists, and other physicians to better manage patients who have this problem.


Distribution of NHS resources for children's dental care in general dental practice in England.
To determine the relationship between the distribution of NHS resources in general dental practice and dental need and access to services for the population in England under the age of 18 in different socio-economic areas. A proxy for the oral health of under 18 year olds was made from prevalence surveys undertaken on five year old children in each health authority area in 1999/2000. The level of spending per head of the population was ascertained from Dental Practice Board data. Health authorities were grouped according to the eleven United Kingdom Office of National Statistics socio-economic groups. Access was measured by using registration levels of children. General dental practices providing National Health Service treatment for children aged 0-18 in England. There was no correlation (r = -0.03) between increasing need for dental care using mean dmft as a proxy and increasing spending per head of the population for each health authority. There was a correlation (r = 0.38) between increasing registration rates and increased spending per head. The populations under 18 had more spent on their oral health care living in areas classified as Mixed Economies, Services and Education and Most Prosperous. Those in Inner London, Manufacturing, Ports and Industry had proportionately the least. The difference between the highest and lowest group was 33%. The groups of Authorities were not homogenous in their level of resources with variations between Authorities in the same groups. The distribution of NHS resources to general dental practice for people under 18 does not reflect population need. The higher the registration rate for children the greater the amount resources deployed in an area.


Unlocking the microbial diversity and the chemical changes throughout the fermentation process of "hákarl", Greenland shark.
Hákarl is a unique traditional Icelandic product and is obtained by fermenting and drying Greenland shark (Somniosus microcephalus). However, little is known about the chemical and microbial changes occurring during the process. In this small-scale industrial study, fresh and frozen shark meat was fermented for eight and seven weeks, respectively, and then dried for five weeks. During the fermentation, trimethylamine N-oxide levels decreased to below the limit of detection within five weeks and pH increased from about 6 to 9. Simultaneously, trimethylamine and dimethylamine levels increased significantly. Total viable plate counts, and specific spoilage organisms increased during the first weeks of the fermentation period but decreased during drying. Culture-independent analyses (16S rRNA) revealed gradual shifts in the bacterial community structure as fermentation progressed, dividing the fermentation process into three distinct phases but stayed rather similar throughout the drying process. During the first three weeks of fermentation, Photobacterium was dominant in the fresh group, compared to Pseudoalteromonas in the frozen group. However, as the fermentation progressed, the groups became more alike with Atopostipes, Pseudomonas and Tissierella being dominant. The PCA analysis done on the chemical variables and 16S rRNA analysis variables confirmed the correlation between high concentrations of TMAO and Pseudoalteromonas, and Photobacterium at the initial fermentation phase. During the final fermentation phase, correlation was detected between high concentrations of TMA/DMA and Atopostipes, Pseudomonas and Tissierella. The results indicate the possibility to shortening the fermentation period and it is suggested that the microbial community can potentially be standardized with starter cultures to gain an optimal fermentation procedure.


Surface functionalized barium sulfate nanoparticles: controlled in situ synthesis and application in bone cement.
The controlled synthesis of surface functionalized BaSO4 nanoparticles with a diameter below 50 nm is achieved by combining the in situ generation of SO4 2- and the use of a difunctional surface modification agent, (2-(methacryloyloxy)ethyldimethyl-(3-sulfopropyl)ammoniumhydroxide (MSAH). Particularly, a pre-decomposition process of the SO4 2- precursor (S2O8 2-) is applied to decouple the in situ generation of SO4 2- and precipitation of BaSO4. As a result, the nucleation and growth of the BaSO4 particles is manipulated, which significantly reduces the particle size. Different combinations of the pre-decomposition time and MSAH/BaCl2 molar ratios showed a remarkable influence on the morphology and surface functionality of the BaSO4 particles. Furthermore, the morphology control by using other difunctional surface modification agents e.g. 3-sulfopropylmethacrylate potassium salt (SMPS) and 2-acrylamido-2-methylpropane sulfonic acid (AMSA) is examined. The MSAH-functionalized BaSO4 nanoparticles, used as s filler in bone cements, effectively improved the bending modulus and compressive strength of the poly (methyl methacrylate), PMMA, bone cements. The bone cement with MSAH-functionalized BaSO4 nanoparticles exhibited good radiopacity. Moreover, in vitro cell culture experiments demonstrated an improved biocompatibility compared to the bare BaSO4 particles. The MSAH-functionalized BaSO4 nanoparticles may be an ideal candidate material as a bone cement filler.


Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study.
In people with velo-cardio-facial syndrome [or 22q11.2 deletion syndrome (22qDS)], a single interstitial deletion of chromosome 22q11.2 causes a wide spectrum of cognitive deficits ranging from global learning difficulties to specific cognitive deficits. People with 22qDS are also at high risk of developing attention-deficit/hyperactivity disorder and autism spectrum disorders in childhood, and schizophrenia in adolescence or adult life. However, the neurobiology of 22qDS, and the relationship between abnormalities in brain anatomy and behaviour, is poorly understood. Thus, we studied the neuroanatomy of 22qDS children using fully automated voxel-based morphometry (VBM) and manually traced single region-of-interest (ROI) analysis. Also, we investigated whether those brain regions that differed significantly between groups were related to behavioural differences within children with 22qDS. We compared the brain morphometry of 39 children and adolescents with 22qDS (mean age: 11 years, SD +/-3, IQ = 67, SD +/-10) and 26 sibling controls (mean age: 11 years, SD +/-3, IQ = 102, SD +/-12). Using VBM, we found, after correction for IQ, that individuals with 22qDS compared with controls had a significant reduction in cerebellar grey matter, and white matter reductions in the frontal lobe, cerebellum and internal capsule. Using single ROI analysis, we found that people with 22qDS had a significant (P < 0.05) reduction in bulk volume bilaterally in the occipital-parietal lobes, but a larger right caudate nucleus and lateral ventricles. Further, within people with 22qDS, there was a significant positive correlation between severity of (i) schizotypy score and grey matter volume of the temporo-occipital regions and the corpus striatum; (ii) emotional problems and grey matter volume of frontostriatal regions; and (iii) social behavioural difficulties and grey matter in frontostriatal regions. Thus, subjects with 22qDS have widespread changes in brain anatomy, particularly affecting white matter, basal ganglia and cerebellum. Also, within 22qDS, regionally specific differences in brain development may partially underpin behavioural differences. We suggest that there is preliminary evidence for specific vulnerability of the frontostriatal and cerebellar-cortical networks in 22qDS.


A penalized regression approach to haplotype reconstruction of viral populations arising in early HIV/SIV infection.
Next generation sequencing (NGS) has been increasingly applied to characterize viral evolution during HIV and SIV infections. In particular, NGS datasets sampled during the initial months of infection are characterized by relatively low levels of diversity as well as convergent evolution at multiple loci dispersed across the viral genome. Consequently, fully characterizing viral evolution from NGS datasets requires haplotype reconstruction across large regions of the viral genome. Existing haplotype reconstruction algorithms have not been developed with the particular characteristics of early HIV/SIV infection in mind, raising the possibility that better performance could be achieved through a specifically designed algorithm. Here, we introduce a haplotype reconstruction algorithm, RegressHaplo, specifically designed for low diversity and convergent evolution regimes. The algorithm uses a penalized regression that balances a data fitting term with a penalty term that encourages solutions with few haplotypes. The regression covariates are a large set of potential haplotypes and fitting the regression is made computationally feasible by the low diversity setting. Using simulated and in vivo datasets, we compare RegressHaplo to PredictHaplo and QuRe, two existing haplotype reconstruction algorithms. RegressHaplo performs better than these algorithms on simulated datasets with relatively low diversity levels. We suggest RegressHaplo as a novel tool for the investigation of early infection HIV/SIV datasets and, more generally, low diversity viral NGS datasets. firstname.lastname@example.com. https://github.com/SLeviyang/RegressHaplo.


Long-Term Physical Exercise and Mindfulness Practice in an Aging Population.
Previous studies have shown that physical exercise and mindfulness meditation can both lead to improvement in physical and mental health. However, it is unclear whether these two forms of training share the same underlying mechanisms. We compared two groups of older adults with 10 years of mindfulness meditation (integrative body-mind training, IBMT) or physical exercise (PE) experience to demonstrate their effects on brain, physiology and behavior. Healthy older adults were randomly selected from a large community health project and the groups were compared on measures of quality of life, autonomic activity (heart rate, heart rate variability, skin conductance response, respiratory amplitude/rate), immune function (secretory Immunoglobulin A, sIgA), stress hormone (cortisol) and brain imaging (resting state functional connectivity, structural differences). In comparison with PE, we found significantly higher ratings for the IBMT group on dimensions of life quality. Parasympathetic activity indexed by skin conductance response and high-frequency heart rate variability also showed more favorable outcomes in the IBMT group. However, the PE group showed lower basal heart rate and greater chest respiratory amplitude. Basal sIgA level was significantly higher and cortisol concentration was lower in the IBMT group. Lastly, the IBMT group had stronger brain connectivity between the dorsal anterior cingulate cortex (dACC) and the striatum at resting state, as well as greater volume of gray matter in the striatum. Our results indicate that mindfulness meditation and physical exercise function in part by different mechanisms, with PE increasing physical fitness and IBMT inducing plasticity in the central nervous systems. These findings suggest combining physical and mental training may achieve better health and quality of life results for an aging population.


Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI.
To compare the natural history of individuals classified with mild cognitive impairment (MCI) in accordance with original criteria to the natural history of individuals classified with revised MCI criteria. The authors compared the rates of progression in 32 individuals with amnestic MCI and in 90 people with MCI according to revised criteria that allow nonamnestic deficits with progression in 276 individuals who were too minimally impaired (pre-MCI) to meet either MCI criteria. All individuals in this study were determined clinically to be very mildly cognitively impaired with a Clinical Dementia Rating (CDR) of 0.5. Rates of progression for the two MCI groups were similar with a decline of almost 0.50 SD per year on a psychometric composite. Decline was less (0.23 SD) in the pre-MCI group. Median survival time to CDR 1 (mild dementia) was comparable for the original (95% CI: 3.79 to 4.07 years) and revised (95% CI: 3.29 to 5.40) criteria MCI groups but approximately twice as long in the pre-MCI group (95% CI: 6.72 to 8.93). All cases from the amnestic MCI criteria group with neuropathologic diagnoses met criteria for Alzheimer disease as did more than 90% in the other two groups. Mild cognitive impairment as originally and currently defined is usually early stage Alzheimer disease, which can begin with a cognitive deficit other than memory. It is possible to identify Alzheimer disease at an even earlier stage than mild cognitive impairment by focusing on intraindividual change rather than comparison with group norms.


Measuring headache day severity using multiple features in daily diary designs.
Though migraine is thought of as a symptom complex, symptoms are typically assessed one at a time. For use in clinical research, we developed a composite measure of headache day severity by combining eight well-known symptoms captured in daily diaries. Data came from adults with a self-reported diagnosis of migraine (n = 4380) who provided daily diary information assessed using a novel digital platform. Nine observed features theoretically linked to headache day severity were analyzed using latent variable modeling to create a psychometrically robust headache day severity score. Logistic regression was used to assess the cross-sectional relationships of headache day severity scores against an array of clinically-relevant outcomes. Participants were largely females (90%), approaching middle age (mean age of 37.3) and living in the United States (49%) or United Kingdom (23%). Findings supported a single latent headache day severity construct based on eight observed headache features. Headache day severity scores were associated with an increased odds of physician visits (Odds ratio[95% CI]: 1.71[1.32-2.21]), emergency department visits (4.12[2.23-7.60]), missed school/work (2.90[2.56-3.29]), missed household work (3.37[3.06-3.72]), and missed other activities (3.29[2.97-3.64]) (p < .0001 for all). Modern measurement techniques support a single headache day severity construct that reflects migraine is a symptom complex. The headache day severity scores were associated with external validators and initial visualizations showed how headache day severity scores can be applied broadly in clinical practice and research.


Altered expression of basement membrane-related molecules in rat brain pericyte, endothelial, and astrocyte cell lines after transforming growth factor-beta1 treatment.
The basement membrane at the blood-brain barrier (BBB) plays important roles in maintaining the structure and function of capillary vessels. The BBB is constructed from endothelial cells, astrocytes and pericytes, but their interactions in the formation or maintenance of basement membrane have not been established. Transforming growth factor-beta1 (TGF-beta1) is known to increase fibronectin in brain capillary basement membrane with deposition of beta-amyloid. We previously reported that the mRNA level of alpha-smooth muscle actin in a brain capillary pericyte cell line TR-PCT1 was increased by treatment with TGF-beta1. In this study, expression of mRNAs encoding basement membrane-related molecules in TR-PCT1, a rat endothelial cell line TR-BBB13, and a type 2 astrocyte cell line TR-AST4 was evaluated by RT-PCR. The effects of TGF-beta1 on expression of basement membrane-related genes in these cell lines were also examined. Fibronectin, MMP-9, tPA, TIMP-1, and PAI-l in TR-PCT1 were higher than in TR-BBB13 and TR-AST4. In TR-PCT1 treated with TGF-beta1, collagen type IV, PAI-1, and MMP-9 were increased, and TIMP-2 was reduced. The change in PAI-1 mRNA was faster than those in MMP-9, TIMP-2, collagen type IV mRNAs. These results suggest that pericytes may be key cells in the maintenance of the basement membrane at the BBB.


Region-specific phosphorylation of rabphilin in mossy fiber nerve terminals of the hippocampus.
In mossy fiber synapses of the CA3 region of the hippocampus, long-term potentiation (LTP) is induced presynaptically by activation of cAMP-dependent protein kinase A (PKA). Rab3A is a synaptic vesicle protein that regulates vesicle fusion and is essential for mossy fiber LTP. Rab3A probably acts via two effector proteins, rabphilin and RIM, of which rabphilin is an in vitro substrate for PKA. To test if rabphilin is phosphorylated in nerve terminals and if its PKA-dependent phosphorylation correlates with the PKA-dependent induction of LTP in mossy fiber terminals, we have studied the phosphorylation of rabphilin in synaptosomes isolated from the CA1 and CA3 regions of the hippocampus. Rabphilin was phosphorylated in both CA1 and CA3 synaptosomes. However, when we treated the CA1 and CA3 synaptosomes with forskolin (an agent that enhances PKA activity) or induced Ca2+ influx into synaptosomes with high K+, rabphilin phosphorylation was increased selectively in mossy fiber CA3 synaptosomes, but not in CA1 synaptosomes. In contrast, the phosphorylation of synapsin, studied as a control for the specificity of the region-specific phosphorylation of rabphilin, was augmented similarly by both treatments in CA1 and CA3 synaptosomes. These results reveal that the phosphorylation states of two synaptic substrates for PKA and CaM KII, rabphilin and synapsin, are regulated differentially in a region-specific manner, an unexpected finding because rabphilin and synapsin are similarly present in CA1 and CA3 synaptosomes and are colocalized on the same synaptic vesicles. The region-specific phosphorylation of rabphilin agrees well with the restricted induction of LTP by presynaptic PKA activation in mossy fiber, but not CA1, nerve terminals.


[Treatment of imported tropical malaria caused by chloroquine-resistant strains of P. falciparum].
The chloroquine-resistant strains P. falciparum are widely spread in the countries of South-East Asia, Latin America. Since the middle of the 70s the strains also occurred in Eastern Africa. The given paper is concerned with 4 patients suffering from imported chloroquine-resistant tropical malaria. Of these, 3 patients come from Africa, and one from Vietnam. In the latter patient, the disease ran a grave course and was attended by coma, acute renal insufficiency, hepatitis, and hemolytic anemia. The patient was registered as having grade III resistance of P. falciparum to chloroquine. The schedules of the disease treatment including quinine with fansidar, metakelphin (or with sulphalene and chloridine), mafloquine or tetracycline are presented.


Fourier transform infrared spectroscopy of milk samples as a tool to estimate energy balance, energy- and dry matter intake in lactating dairy cows.
The objective of the study was to evaluate the potential of Fourier transform infrared spectroscopy (FTIR) analysis of milk samples to predict body energy status and related traits (energy balance (EB), dry matter intake (DMI) and efficient energy intake (EEI)) in lactating dairy cows. The data included 2371 milk samples from 63 Norwegian Red dairy cows collected during the first 105 days in milk (DIM). To predict the body energy status traits, calibration models were developed using Partial Least Squares Regression (PLSR). Calibration models were established using split-sample (leave-one cow-out) cross-validation approach and validated using an external test set. The PLSR method was implemented using just the FTIR spectra or using the FTIR together with milk yield (MY) or concentrate intake (CONCTR) as predictors of traits. Analyses were conducted for the entire first 105 DIM and separately for the two lactation periods: 5 ≤ DIM ≤ 55 and 55 < DIM ≤ 105. To test the models, an external validation using an independent test set was performed. Predictions depending on the parity (1st, 2nd and 3rd-to 6th parities) in early lactation were also investigated. Accuracy of prediction (r) for both cross-validation and external test set was defined as the correlation between the predicted and observed values for body energy status traits. Analyzing FTIR in combination with MY by PLSR, resulted in relatively high r-values to estimate EB (r = 0.63), DMI (r = 0.83), EEI (r = 0.84) using an external validation. Only moderate correlations between FTIR spectra and traits like EB, EEI and dry matter intake (DMI) have so far been published. Our hypothesis was that improvements in the FTIR predictions of EB, EEI and DMI can be obtained by (1) stratification into different stages of lactations and different parities, or (2) by adding additional information on milking and feeding traits. Stratification of the lactation stages improved predictions compared with the analyses including all data 5 ≤ DIM ≤105. The accuracy was improved if additional data (MY or CONCTR) were included in the prediction model. Furthermore, stratification into parity groups, improved the predictions of body energy status. Our results show that FTIR spectral data combined with MY or CONCTR can be used to obtain improved estimation of body energy status compared to only using the FTIR spectra in Norwegian Red dairy cattle. The best prediction results were achieved using FTIR spectra together with MY for early lactation. The results obtained in the study suggest that the modeling approach used in this paper can be considered as a viable method for predicting an individual cow's energy status.


Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease.
Actin-myosin interactions provide the driving force underlying each heartbeat. The current view is that actin-bound regulatory proteins play a dominant role in the activation of calcium-dependent cardiac muscle contraction. In contrast, the relevance and nature of regulation by myosin regulatory proteins (for example, myosin light chain-2 [MLC2]) in cardiac muscle remain poorly understood. By integrating gene-targeted mouse and computational models, we have identified an indispensable role for ventricular Mlc2 (Mlc2v) phosphorylation in regulating cardiac muscle contraction. Cardiac myosin cycling kinetics, which directly control actin-myosin interactions, were directly affected, but surprisingly, Mlc2v phosphorylation also fed back to cooperatively influence calcium-dependent activation of the thin filament. Loss of these mechanisms produced early defects in the rate of cardiac muscle twitch relaxation and ventricular torsion. Strikingly, these defects preceded the left ventricular dysfunction of heart disease and failure in a mouse model with nonphosphorylatable Mlc2v. Thus, there is a direct and early role for Mlc2 phosphorylation in regulating actin-myosin interactions in striated muscle contraction, and dephosphorylation of Mlc2 or loss of these mechanisms can play a critical role in heart failure.


Resting-state beta and gamma activity in Internet addiction.
Internet addiction is the inability to control one's use of the Internet and is related to impulsivity. Although a few studies have examined neurophysiological activity as individuals with Internet addiction engage in cognitive processing, no information on spontaneous EEG activity in the eyes-closed resting-state is available. We investigated resting-state EEG activities in beta and gamma bands and examined their relationships with impulsivity among individuals with Internet addiction and healthy controls. Twenty-one drug-naïve patients with Internet addiction (age: 23.33 ± 3.50 years) and 20 age-, sex-, and IQ-matched healthy controls (age: 22.40 ± 2.33 years) were enrolled in this study. Severity of Internet addiction was identified by the total score on Young's Internet Addiction Test. Impulsivity was measured with the Barratt Impulsiveness Scale-11 and a stop-signal task. Resting-state EEG during eyes closed was recorded, and the absolute/relative power of beta and gamma bands was analyzed. The Internet addiction group showed high impulsivity and impaired inhibitory control. The generalized estimating equation showed that the Internet-addiction group showed lower absolute power on the beta band than did the control group (estimate = -3.370, p < 0.01). On the other hand, the Internet-addiction group showed higher absolute power on the gamma band than did the control group (estimate = 0.434, p < 0.01). These EEG activities were significantly associated with the severity of Internet addiction as well as with the extent of impulsivity. The present study suggests that resting-state fast-wave brain activity is related to the impulsivity characterizing Internet addiction. These differences may be neurobiological markers for the pathophysiology of Internet addiction.


BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes.
The adaptor protein (AP)-3 complex is a component of the cellular machinery that controls protein sorting from endosomes to lysosomes and specialized related organelles such as melanosomes. Mutations in an AP-3 subunit underlie a form of Hermansky-Pudlak syndrome (HPS), a disorder characterized by abnormalities in lysosome-related organelles. HPS in humans can also be caused by mutations in genes encoding subunits of three complexes of unclear function, named biogenesis of lysosome-related organelles complex (BLOC)-1, -2, and -3. Here, we report that BLOC-1 interacts physically and functionally with AP-3 to facilitate the trafficking of a known AP-3 cargo, CD63, and of tyrosinase-related protein 1 (Tyrp1), a melanosomal membrane protein previously thought to traffic only independently of AP-3. BLOC-1 also interacts with BLOC-2 to facilitate Tyrp1 trafficking by a mechanism apparently independent of AP-3 function. Both BLOC-1 and -2 localize mainly to early endosome-associated tubules as determined by immunoelectron microscopy. These findings support the idea that BLOC-1 and -2 represent hitherto unknown components of the endosomal protein trafficking machinery.


Comparative effectiveness of monotherapies and combination therapies for patients with hypertension: protocol for a systematic review with network meta-analyses.
Hypertension has been cited as the most common attributable risk factor for death worldwide, and in Canada more than one of every five adults had this diagnosis in 2007. In addition to different lifestyle modifications, such as diet and exercise, there exist many pharmaco-therapies from different drug classes which can be used to lower blood pressure, thereby reducing the risk of serious clinical outcomes. In moderate and severe cases, more than one agent may be used. The optimal mono- and combination therapies for mild hypertension and moderate/severe hypertension are unclear, and clinical guidelines provide different recommendations for first line therapy. The objective of this review is to explore the relative benefits and safety of different pharmacotherapies for management of non-diabetic patients with hypertension, whether of a mild or moderate to severe nature. Searches involving MEDLINE and the Cochrane Database of Systematic Reviews will be used to identify related systematic reviews and relevant randomized trials. The outcomes of interest include myocardial infarction, stroke, incident diabetes, heart failure, overall and cardiovascular related death, and important side effects (cancers, depression, syncopal episodes/falls and sexual dysfunction). Randomized controlled trials will be sought. Two reviewers will independently screen relevant reviews, titles and abstracts resulting from the literature search, and also potentially relevant full-text articles in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion. Random effect pairwise meta-analyses and network meta-analyses will be conducted where deemed appropriate. Analyses will be geared toward studying treatment of mild hypertension and moderate/severe hypertension separately. Our systematic review results will assess the extent of currently available evidence for single agent and multi-agent pharmacotherapies in patients with mild, moderate and severe hypertension, and will provide a rigorous and updated synthesis of a range of important clinical outcomes for clinicians, decision makers and patients. PROSPERO Registration Number: CRD42013004459.


Mortality in a cohort of men expressing the glucose-6-phosphate dehydrogenase deficiency.
The objective of this study was to test the hypothesis of a lower mortality from cancer and cardiovascular diseases among men expressing glucose-6-phosphate dehydrogenase (G6PD) deficiency. We designed a mortality study based on death certificates from January 1, 1982 through December 31, 1992 in a cohort of G6PD-deficient men. Cohort members were 1,756 men, identified as expressing the G6PD-deficient phenotype during a 1981 population screening of the G6PD polymorphism. The setting was the island of Sardinia, Italy. Outcome measures were cause-specific standardized mortality ratios (SMRs), which were computed as 100 times the observed/expected ratio, with the general Sardinian male population as the reference. Deaths from all causes were significantly less than expected due to decreased SMRs for ischemic heart disease (SMR, 28; 95% confidence interval [CI], 10 to 62), cerebrovascular disease (SMR, 22; 95% CI, 6 to 55), and liver cirrhosis (SMR, 12; 95% CI, 0 to 66), which explained 95.6% of the deficit in total mortality. All cancer mortality was close to the expectation, with a significant increase in the SMR for non-Hodgkin's lymphoma (SMR, 545; 95% CI, 147 to 1,395). A decrease in mortality from cardiovascular diseases was one of the study hypotheses, based on an earlier human report and experimental evidence. However, selection bias is also a likely explanation. Further analytic studies are warranted to confirm whether subjects expressing the G6PD-deficient phenotype are protected against ischemic heart disease and cerebrovascular disease. This cohort study is consistent with more recent case-control studies in rejecting the hypothesis of a decreased cancer risk among G6PD-deficient subjects. The observed increase in mortality from non-Hodgkin's lymphoma and decrease in mortality from liver cirrhosis were not previously reported.


The effects of a pool of dispersers on host-parasitoid systems.
When individuals migrate in a multi-patch environment, a considerable proportion of their lifetime might be spent in transit between patches. We investigate the effects such a pool of dispersers can have on local stability and dynamics for a variety of multi-patch host-parasitoid models. When an arbitrary number of patches with internal Lotka-Volterra dynamics is coupled via a global pool of dispersers, the equilibrium is globally stable. The global pool is stabilising if dispersal is by hosts only, by parasitoids only, or by both hosts and parasitoids. If dispersal is local such that individuals first enter a pool close to the patch where they originate and then disperse to adjacent pools, the equilibrium is locally stable. We also analyse the situation where the functional response of parasitoids within a patch is Holling type II which is known to destabilise host-parasitoid systems. Coupling this single patch to a pool of dispersers can produce a locally stable interaction, provided the handling time of hosts is not too long. However, the pool provides a biologically realistic example of an interaction that is locally stable but not permanent. The longer the handling time, the smaller the region of population densities within which populations converge to the equilibrium state. In a multi-patch environment with a global disperser pool, the dynamics of the system are not qualitatively different from the single patch case (i.e. the equilibrium can be locally stable but the system is not permanent). In a multi-patch environment with local disperser pools, true spatial interactions between patches can develop. In contrast to the global pool, local pools can destabilise the stable equilibrium of the single patch case. Limit cycles develop around this unstable equilibrium that lead to extremely complicated dynamics. In contrast to the global pool, a system of local pools can exhibit bounded fluctuations so that populations do not go extinct.


Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: A randomized controlled trial.
Innovative non-pharmacological lifestyle strategies to treat non-alcoholic fatty liver disease (NAFLD) are critically needed. This study compared the effects of alternate day fasting (ADF) combined with exercise to fasting alone, or exercise alone, on intrahepatic triglyceride (IHTG) content. Adults with obesity and NAFLD (n = 80, 81% female, age: 23-65 years) were randomized to 1 of 4 groups for 3 months: combination of ADF (600 kcal/2,500 kJ "fast day" alternated with an ad libitum intake "feast day") and moderate-intensity aerobic exercise (5 session per week, 60 min/session); ADF alone; exercise alone; or a no-intervention control group. By month 3, IHTG content was significantly reduced in the combination group (-5.48%; 95% CI, -7.77% to -3.18%), compared with the exercise group (-1.30%; 95% CI, -3.80% to 1.20%; p = 0.02) and the control group (-0.17%; 95% CI, -2.17% to 1.83%; p < 0.01) but was not significantly different versus the ADF group (-2.25%; 95% CI, -4.46% to -0.04%; p = 0.05). Body weight, fat mass, waist circumference, and alanine transaminase (ALT) levels significantly decreased, while insulin sensitivity significantly increased in the combination group compared with the control group. Lean mass, aspartate transaminase (AST), HbA1c, blood pressure, plasma lipids, liver fibrosis score, and hepatokines (fetuin-A, FGF-21, and selenoprotein P) did not differ between groups. Combining intermittent fasting with exercise is effective for reducing hepatic steatosis in patients with NAFLD but may offer no additional benefit versus fasting alone.


Reversing UVB-induced photoaging with Hibiscus sabdariffa calyx aqueous extract.
Hibiscus sabdariffa is commonly used in daily life and its extract is applied widely in food and cosmetics. However, it has not been evaluated for its anti-aging effects. Hibiscus sabdariffa calyx aqueous extract (HSCAE) has shown potential collagenase activity suppression effects, together with tyrosinase activity inhibition, and anti-oxidation as a free radical scavenger. The current investigation demonstrated that HSCAE was not cytotoxic in skin fibroblasts, and it significantly decreased ultraviolet B (UVB)-induced reactive oxygen species (ROS) on a flow cytometry assay. Moreover, HSCAE reduced matrix metalloproteinase (MMP) expression, increased tissue inhibition of metalloproteinase (TIMP)-1 level, and enhanced collagen content by inhibiting collagenase activity. It also blocked mRNA and protein expressions of melanin production pathway key factors, including the microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and dopachrome tautomerase-2 (TRP-2). These results demonstrated, for the first time, the potential of HSCAE as a natural antioxidant with the ability to maintain collagen production and to decrease melanin syntheses under UVB radiation, for anti-aging effects. © 2019 Society of Chemical Industry.


Dual-channel functional electrical stimulation improvements in speed-based gait classifications.
Functional electrical stimulation (FES) is becoming an accepted treatment method for enhancing gait performance in patients who present with gait difficulties resulting from hemiparesis. The purpose of this study was to test whether individuals with hemiparesis who have varied gait speeds, which place them in different functional categories, benefit to the same extent from the application of FES. Thirty-six subjects with chronic hemiparesis demonstrating foot-drop and deficits in knee and/or hip control were fitted with a dual-channel FES system activating the dorsiflexors and hamstring muscles. Gait was assessed during a 2-minute walk test with and without stimulation. A second assessment was conducted after 6 weeks of daily use. Analysis was performed with the subjects stratified into three functional ambulation classes according to their initial gait categories. The dual-channel FES improved the gait velocity of all three subgroups. No minimal gait velocity was required in order to gain benefits from FES. For example, subjects with limited household ambulation capabilities improved their gait speed by 63.3% (from 0.30 ± 0.09 m/sec to 0.49 ± 0.20 m/sec; P < 0.01), while subjects with functional community ambulation capabilities improved their gait speed by 25.5% (from 0.90 ± 0.11 m/sec to 1.13 ± 0.22 m/sec; P < 0.01). Dual-channel FES positively affects gait velocity in patients with chronic hemiparesis, regardless of their initial gait velocity. Furthermore, gait velocity gains may be large enough to change an individual's ambulation status to a higher functional category.


Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Combined With Adrenocortical Carcinoma on 18F-FDG PET/CT.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a recognized distinct phenotypic variant of multiple cutaneous and uterine leiomyomatosis. The present case reports an extremely rare case of HLRCC syndrome combined with adrenocortical carcinoma. The case suggests that HLRCC should be considered in any young patient with bulky uterine leiomyomas and renal cell cancer, and F-FDG PET/CT can help detect unexpected additional primary malignancy in a patient with known cancer.


Exposure to environmental endocrine disruptors and child development.
Exposure to exogenous chemicals can affect endocrine function at multiple sites and through numerous specific modes of action, which may have far-reaching effects on human health and development. Widespread human exposure to known or suspected endocrine disrupting chemicals (EDCs) has been documented in the United States and worldwide, as have trends for increased rates of endocrine-related diseases and disorders among children. While human epidemiology studies of exposure to EDCs and children's health remain extremely limited, a growing body of evidence shows that exposure to a number of chemicals commonly found in consumer goods, personal care products, food, drinking water, and other sources may adversely affect child development through altered endocrine function. This narrative review provides a brief introduction to several common EDCs (with a specific focus on persistent organic pollutants, phthalates, bisphenol A, and contemporary-use pesticides, which represent only a small number of all known or suspected EDCs), an overview of the state of the human evidence for adverse effects of EDCs on child development (fetal growth, early reproductive tract development, pubertal development, neurodevelopment, and obesity), guidance for health care providers based on current knowledge, and recommendations for future research.


Cloning and characterisation of PGA1 and PGA2: two G protein alpha-subunits from pea that promote growth in the yeast Saccharomyces cerevisiae.
We report here on the cloning and characterization of two G protein alpha-subunits from pea: PGA1 and PGA2. Based on DNA gel blot analysis, PGA1 and PGA2 are the only Galpha homologous sequences in pea. RT-PCR analysis reveals that PGA1 and PGA2 transcripts are present in a variety of adult pea tissues. However, PGA2 mRNA is consistently detected at a lower level than PGA1 and demonstrates some degree of tissue specificity relative to PGA1. In the apical bud of pea seedlings, PGA1 and PGA2 transcripts decrease in response to 24 h of white light following growth for 6 days in darkness. The G protein mediated, yeast mating pathway was used to analyse the function of PGA1 and PGA2 in vivo. PGA1 downregulates the mating pathway, but through a mechanism that is independent of Gbetagamma sequestration. Unexpectedly, both PGA1 and PGA2 promote growth through a mating pathway independent mechanism.


The nephropathy of non-insulin-dependent diabetes: predictors of outcome relative to diverse patterns of renal injury.
Nephropathy of non-insulin-dependent diabetes mellitus (NIDDM) is the most common cause of end-stage renal failure (ESRF) in Western countries. This study investigates the clinical and histologic putative predictors of disease progression, with the final goal to identify patients at risk who may benefit from early diagnosis and intervention. It examines by repeated measurements of BP, blood glucose, serum creatinine, and urinary protein excretion rate 65 consecutive NIDDM patients with clinical, persistent proteinuria and biopsy-documented typical diabetic glomerulopathy (class I; n = 30), predominant nephroangiosclerosis (class II; n = 23), or nondiabetic type glomerulopathy (class III; n = 12), whose severity of renal tissue involvement was precisely quantified by a global histologic score. Baseline parameters and progression to renal end points, i.e., doubling of baseline serum creatinine, dialysis, or transplantation, were univariately and multivariately correlated by proportional hazards regression models. The median kidney survival time in the overall study population was 3.07 yr. Thirty-seven percent of patients reached an end point during a median (range) follow-up of 1.8 yr (0.4 to 5.7 yr). By univariate and multivariate analysis, kidney survival significantly correlated with baseline urinary protein excretion rate (P = 0.04 and P = 0.04, respectively) and renal tissue injury score (P = 0.0001 and P = 0.02, respectively), but not with the histologic classes. Patients with a urinary protein excretion rate < or = 2 g/24 h, or > 2 g/24 h with a histologic score < 7, never reached an end point. All patients with urinary protein excretion > 2 g/24 h and a histologic score > 13 progressed to ESRF over a median of 1.6 yr. No differences in other baseline parameters or in BP and diabetes control during follow-up accounted for these different outcomes. In NIDDM as well as in nondiabetic chronic renal disease, quantification of urinary protein excretion rate--independent of the pattern of underlying glomerular involvement--reliably discriminates progressors from nonprogressors and, combined with precise quantification of renal tissue injury, reliably predicts risk of ESRF. This information may be used to set guidelines for early diagnosis and appropriate intervention to reduce the number of diabetic patients who will need renal replacement therapy in years to come.


Does providing more accessible primary care psychology services lower the clinical threshold for referrals?
The growing number of specialist services being provided within primary care has lead to the argument that this will reduce the clinical threshold for referrals to these clinics. The possibility that increasing the accessibility of primary care psychology services will reduce the threshold for referral was examined by comparing levels of psychological disturbance among patients seen by practice-based clinical psychologists with those attending outpatient clinics. Psychological symptoms, distress, disruption in daily life and satisfaction with life were assessed using a questionnaire-based methodology. A consecutive series of 177 patients, assessed in a local general practice or an outpatient department across a wide range of urban locations, was studied over a fixed period. The study revealed equivalent levels of psychopathology within both specialist and primary care clinics. Of the overall sample, 79% were likely to merit a formal psychiatric diagnosis, relating primarily to mood disorder. Levels of subjective distress and life satisfaction were also equivalent at both service locations. The lack of evidence for a reduction in clinical threshold for referral within the primary care sample suggests that general practitioners' referral rates are similar regardless of whether practice-based clinical psychology services are available. This has implications for primary-care-led commissioning of mental health services.


Dynamic Epidemiology and Virulence Characteristics of Carbapenem-Resistant Klebsiella pneumoniae in Wenzhou, China from 2003 to 2016.
To investigate transitions in resistance mechanisms, virulence characteristics and molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae (CRKP) during 2003-2016 in a major Eastern Chinese medical center. From a total of 2299 K. pneumoniae clinical strains collected from 2003 to 2016, 214 were found to be CRKP isolates and were selected for further study. Characterization of these was conducted by molecular detection of antibiotic resistance markers and virulence determinants, modified carbapenem inactivation method and multilocus sequence typing (MLST). In this study, the prevalence of CRKP was increasing over the 14-year period, mirroring a national trend. These CRKP strains were resistant to most of the tested, clinically relevant drugs. The majority of these CRKP strains were positive for carbapenemases, with the Klebsiella pneumoniae carbapenemase (KPC) found to be the dominant type (207/210, 98.6%). The carrier rates of virulence genes uge, entB, fimH, mrkD and ureA increased in 2016, while the ybtA, iucA and irp2 showed a relatively constant trend. From MLST data, ST11 (88.8%, 190/214) was the preponderant sequence type (ST), followed by ST15 (1.9%, 4/214) and ST656 (1.4%, 3/214). Several strains with less common STs (ST690, ST895, ST1823 and ST1384) were also detected, and these too showed high levels of antimicrobial resistance. The average national rise in CRKP across China is mirrored in this in-depth analysis of a single hospital, while the prevalence of hypervirulent CRKP (such as ST15) was relatively low as of 2016. Continuous monitoring is necessary to keep track of CRKP and should include the prospect of newly emerging strains with less common STs and the prospect of detecting carbapenem-resistant, carbapenemase-negative Klebsiella pneumoniae.


The relationship between subjective and objective measurements of strength *.
Manual muscle testing is utilized by physicians and physical therapists to aid in the diagnosis and evaluation of pathology.' The basis of a diagnosis or the modification of a treatment program is dependent upon the clinician's perception of a patient's strength. This inherent subjectivity of manual muscle testing often leads to questionable findings in a medical examination. Factors such as sex, age, height, and weight serve only to increase the subjectivity of this evaluation This study demonstrates the use of a new manual muscle testing unit (MMTU) to quantify muscle strength objectively. The results of the MMTU were compared to a clinician's subjective evaluation of the stronger limb. In addition, the data obtained with the MMTU were analyzed to investigate further what constitutes a significant strength deficit. The MMTU's ability to differentiate strength differences and deficits demonstrates how manual muscle testing can assume a refined role in the evaluation of muscle strength. J Orthop Sports Phys Ther 1980;2(1):15-19.


Clinicopathologic study of thyroid carcinoma infiltrating the trachea.
Eighteen patients (10 women and 8 men), ranging in age from 37 to 80 years, with thyroid carcinoma infiltrating the trachea comprised this series. Eleven had primary and 7 had recurrent cases. Total laryngectomy was performed in 4 patients, and tracheal resection was carried out followed by end-to-end anastomosis in 13 patients. In one patient, reconstruction was done with Naville's artificial trachea after tracheal resection. Eleven patients were alive after 1 year and 8 months to 6 years and 7 months after the operation. This result was significantly better than that of a group of ten patients without resection of the infiltrated trachea (seven patients died within 6 months). Thus, combined resection of the upper airway improved the prognosis of advanced thyroid carcinoma with tracheal infiltration. Histologic examination of surgical specimens demonstrated well-differentiated carcinoma in seven patients, poorly differentiated carcinoma in seven patients, undifferentiated carcinoma in three patients, and squamous cell carcinoma in one patient. The result showed a higher frequency of poorly differentiated carcinoma than in the control group of 70 patients without tracheal infiltration.


Setting positive end-expiratory pressure: role in diaphragm-protective ventilation.
With mechanical ventilation, positive end-expiratory pressure (PEEP) is applied to improve oxygenation and lung homogeneity. However, PEEP setting has been hypothesized to contribute to critical illness associated diaphragm dysfunction via several mechanisms. Here, we discuss the impact of PEEP on diaphragm function, activity and geometry. PEEP affects diaphragm geometry: it induces a caudal movement of the diaphragm dome and shortening of the zone of apposition. This results in reduced diaphragm neuromechanical efficiency. After prolonged PEEP application, the zone of apposition adapts by reducing muscle fiber length, so-called longitudinal muscle atrophy. When PEEP is withdrawn, for instance during a spontaneous breathing trial, the shortened diaphragm muscle fibers may over-stretch which may lead to (additional) diaphragm myotrauma. Furthermore, PEEP may either increase or decrease respiratory drive and resulting respiratory effort, probably depending on lung recruitability. Finally, the level of PEEP can also influence diaphragm activity in the expiratory phase, which may be an additional mechanism for diaphragm myotrauma. Setting PEEP could play an important role in both lung and diaphragm protective ventilation. Both high and low PEEP levels could potentially introduce or exacerbate diaphragm myotrauma. Today, the impact of PEEP setting on diaphragm structure and function is in its infancy, and clinical implications are largely unknown.


Is the Distance Worth It? Patients With Rectal Cancer Traveling to High-Volume Centers Experience Improved Outcomes.
It is unclear whether traveling long distances to high-volume centers would compensate for travel burden among patients undergoing rectal cancer resection. The purpose of this study was to determine whether operative volume outweighs the advantages of being treated locally by comparing the outcomes of patients with rectal cancer treated at local, low-volume centers versus far, high-volume centers. This was a population-based study. The National Cancer Database was queried for patients with rectal cancer. Patients with stage II or III rectal cancer who underwent surgical resection between 2006 and 2012 were included. The outcomes of interest were margins, lymph node yield, receipt of neoadjuvant chemoradiation, adjuvant chemotherapy, readmission within 30 days, 30-day and 90-day mortality, and 5-year overall survival. A total of 18,605 patients met inclusion criteria; 2067 patients were in the long-distance/high-volume group and 1362 in the short-distance/low-volume group. The median travel distance was 62.6 miles for the long-distance/high-volume group and 2.3 miles for the short-distance/low-volume group. Patients who were younger, white, privately insured, and stage III were more likely to have traveled to a high-volume center. When controlled for patient factors, stage, and hospital factors, patients in the short-distance/low-volume group had lower odds of a lymph node yield ≥12 (OR = 0.51) and neoadjuvant chemoradiation (OR = 0.67) and higher 30-day (OR = 3.38) and 90-day mortality (OR = 2.07) compared with those in the long-distance/high-volume group. The short-distance/low-volume group had a 34% high risk of overall mortality at 5 years compared with the long-distance/high-volume group. We lacked data regarding patient and physician decision making and surgeon-specific factors. Our results indicate that when controlled for patient, tumor, and hospital factors, patients who traveled a long distance to a high-volume center had improved lymph node yield, neoadjuvant chemoradiation receipt, and 30- and 90-day mortality compared with those who traveled a short distance to a low-volume center. They also had improved 5-year survival. See Video Abstract at http://links.lww.com/DCR/A446.


Escape response kinematics in two species of tropical shark: short escape latencies and high turning performance.
Accelerative manoeuvres, such as fast-starts, are crucial for fish to avoid predation. Escape responses are fast-starts that include fundamental survival traits for prey that experience high predation pressure. However, no previous study has assessed escape performance in neonate tropical sharks. We quantitatively evaluated vulnerability traits of neonate tropical sharks by testing predictions on their fast-start escape performance. We predicted (1) high manoeuvrability, given their high flexibility, but (2) low propulsive locomotion owing to the drag costs associated with pectoral fin extension during escape responses. Further, based on previous work on dogfish, Squalus suckleyi, we predicted (3) long reaction times (as latencies longer than teleosts, >20 ms). We used two-dimensional, high-speed videography analysis of mechano-acoustically stimulated neonate blacktip reef shark, Carcharhinus melanopterus (n=12), and sicklefin lemon shark, Negaprion acutidens (n=8). Both species performed a characteristic C-start double-bend response (i.e. two body bends), but single-bend responses were only observed in N. acutidens. As predicted, neonate sharks showed high manoeuvrability with high turning rates and tight turning radii (3-11% of body length) but low propulsive performance (i.e. speed, acceleration and velocity) when compared with similar-sized teleosts and S. suckleyi. Contrary to expectations, escape latencies were <20 ms in both species, suggesting that the neurophysiological system of sharks when reacting to a predatory attack may not be limited to long response times. These results provide a quantitative assessment of survival traits in neonate tropical sharks that will be crucial for future studies that consider the vulnerability of these sharks to predation.


Trends in global protected area governance, 1992-2002.
Governance refers to the interactions among structures, processes, and traditions that determine direction, how power is exercised, and how the views of citizens or stakeholders are incorporated into decision-making. Governance is now recognized as a critical aspect of effective conservation and is a prominent part of the Convention on Biological Diversity's work program on protected areas. This study reports on a global survey to assess changes in governance of protected area systems between 1992 and 2002 based on responses from 41 countries. Results indicate that substantial changes have taken place with overall trends towards increased participation of more stakeholders, greater use of formal accountability mechanisms, and a wider range of participatory techniques. Many of these changes are supported by legislative and policy requirements and 75% of respondents reported changes in legislation over the past decade. Protected areas are becoming more influenced by global forces. A majority of respondents reported increased involvement of the private sector. Funding is coming from a broader range of sources, with a smaller proportion of income coming from government sources in 2002. Absolute funding amounts have increased, but almost two-thirds report that budgets fall short of requirements. Almost 90% of respondents felt that protected area governance had improved over the last decade; 67% felt that this had also led to improved management effectiveness. Respondents felt that secure funding, capacity building, and increased community involvement were the main governance needs for the future.


Minimum variance control for mitigation of vibrations in adaptive optics systems.
In this paper, we address the design of a minimum variance controller (MVC) for the mitigation of vibrations in modern telescope adaptive optics (AO) systems. It is widely accepted that a main source of non-turbulent perturbations is the mechanical resonance induced by the wind or the instrumentation systems, such as fans and cooling pumps. To adequately mitigate vibrations, the application of frequency-based controllers has been considered in the past decade. In this work, we express the system model in terms of the tracking of a zero-input signal via the MVC. We show that the MVC is an equivalent representation of the linear quadratic Gaussian (LQG) controller for the AO system. We also show that by developing the MVC, we can obtain different expressions, in terms of transfer functions, that offer insights into the behavior and expected performance of the controller in the frequency domain. In addition, we analyze the impact of the accuracy of the system and perturbations model on the mitigation of vibrations.


Expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in acute and chronic inflammation.
The objective of this study was to quantify, in vivo, constitutive and tumor necrosis factor alpha (TNF-alpha)-enhanced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in different tissues from healthy wild-type mice (C57BL/6) as well as interleukin-10 (IL-10)-deficient mice with and without active colitis. Using the dual radiolabel monoclonal antibody technique, we found substantial constitutive expression of MAdCAM-1 in the intestine, colon, and mesenteric lymph nodes. MAdCAM-1 expression in these tissues was significantly enhanced, in a time-dependent manner, by systemic administration of TNF-alpha. Maximum surface expression was observed at 18 h after TNF-alpha administration and remained significantly elevated at 48 h post-TNF-alpha injection. No significant constitutive nor TNF-alpha-induced expression of MAdCAM-1 was detected in skeletal muscle, brain, or heart. In IL-10-deficient (IL-10 k/o) mice with no clinical or histological evidence of colitis, constitutive and TNF-alpha-induced expression of MAdCAM-1 in the intestine, cecum, and colon was not different from those values obtained with healthy wild-type controls. IL-10-deficient mice with active colitis exhibited a four- to fivefold greater expression of MAdCAM-1 in the cecum and colon compared with their healthy controls or to IL-10 k/o mice with no evidence of colitis. Taken together, these data demonstrate that TNF-alpha enhances surface expression of MAdCAM-1 in intestinal and colonic tissues to the same extent in both wild-type and IL-10 k/o mice with no colonic inflammation, whereas IL-10 k/o mice with active colitis exhibited a profound up-regulation of MAdCAM-1 in the colon.


Characteristic brain magnetic resonance imaging abnormalities in central nervous system aquaporin-4 autoimmunity.
Although neuromyelitis optica has been traditionally regarded as a disease without brain involvement, brain abnormalities are not uncommon in patients with neuromyelitis optica-related disorders. We aimed to characterize the brain magnetic resonance imaging (MRI) abnormalities in neuromyelitis optica spectrum disorder patients who are seropositive for anti-aquaporin-4 autoantibody (AQP4 Ab). Of 236 consecutive patients with inflammatory demyelinating central nervous system diseases, we retrospectively analyzed MRI characteristics of 78 patients who were seropositive for AQP4 Ab. For an average observational period of 6.3 years, 62 patients (79%) had brain lesions on MRI. Twenty-four patients (31%) had brain MRI abnormalities at the onset of disease, and 35 (45%) had symptomatic brain involvement. Characteristic brain MRI abnormalities were classified into five categories: (1) lesions involving corticospinal tracts (e.g. posterior limb of internal capsule and cerebral peduncle (44%); (2) extensive hemispheric lesions likely due to vasogenic edema (29%); (3) periependymal lesions surrounding aqueduct and the third and fourth ventricles (22%); (4) periependymal lesions surrounding lateral ventricles (40%); and (5) medullary lesions, often contiguous with cervical lesions (31%). Fifty-four patients (69%) showed at least one kind of brain abnormality among the five characteristic MRI lesions. Ten patients showed gadolinium-enhancing lesions, which were characterized by multiple patchy enhancing patterns with blurred margins. In central nervous system AQP4 autoimmunity, brain MRI abnormalities were more common than is generally appreciated and were characterized by their unique localization and configuration.


Time series prediction of lung cancer patients' breathing pattern based on nonlinear dynamics.
This study focuses on predicting breathing pattern, which is crucial to deal with system latency in the treatments of moving lung tumors. Predicting respiratory motion in real-time is challenging, due to the inherent chaotic nature of breathing patterns, i.e. sensitive dependence on initial conditions. In this work, nonlinear prediction methods are used to predict the short-term evolution of the respiratory system for 62 patients, whose breathing time series was acquired using respiratory position management (RPM) system. Single step and N-point multi step prediction are performed for sampling rates of 5 Hz and 10 Hz. We compare the employed non-linear prediction methods with respect to prediction accuracy to Adaptive Infinite Impulse Response (IIR) prediction filters. A Local Average Model (LAM) and local linear models (LLMs) combined with a set of linear regularization techniques to solve ill-posed regression problems are implemented. For all sampling frequencies both single step and N-point multi step prediction results obtained using LAM and LLM with regularization methods perform better than IIR prediction filters for the selected sample patients. Moreover, since the simple LAM model performs as well as the more complicated LLM models in our patient sample, its use for non-linear prediction is recommended.


Perspectives on obesity and its treatment: health care providers and the general public in rural West Virginia and urban Baltimore.
To determine and compare the perspectives of the general public and health care providers (HCPs) on obesity and its treatment in rural West Virginia (WV) and Baltimore, MD. Surveys were completed in both locations by the general public (WV: n = 200; Baltimore: n = 171) and HCPs (WV: n = 25; Baltimore: n = 15). BMI (body mass index) ≥ 30 (WV: n = 94; Baltimore: n = 58) was associated with a stronger belief in the heritability of obesity and with the ability to control obesity by controlling food cost, compared with those with normal BMI (WV: n = 42; Baltimore: n = 57). Those with a high school education (WV: n = 112; Baltimore: n = 113) were less likely to agree that obesity is a problem in the community and that proper diet and exercise are realistic expectations, compared with those with at least some higher education. Perspectives of HCPs differed significantly from the general public in both locations. Many differences in perspective on obesity exist between WV and Baltimore, within both populations, and between HCPs and the general public in both settings. A better understanding of patient views is important for effective obesity management. HCPs must consider each patient's level of understanding when discussing management and consequences of obesity. More time spent with patients who have less insight into their obesity may improve patient adherence with treatment and overall patient outcomes.


Histidine-proline-rich glycoprotein as a plasma pH sensor. Modulation of its interaction with glycosaminoglycans by ph and metals.
The middle domain of plasma histidine-proline-rich glycoprotein (HPRG) contains unusual tandem pentapeptide repeats (consensus G(H/P)(H/P)PH) and binds heparin and transition metals. Unlike other proteins that interact with heparin via lysine or arginine residues, HPRG relies exclusively on histidine residues for this interaction. To assess the consequences of this unusual requirement, we have studied the interaction between human plasma HPRG and immobilized glycosaminoglycans (GAGs) using resonant mirror biosensor techniques. HPRG binding to immobilized heparin was strikingly pH-sensitive, producing a titration curve with a midpoint at pH 6.8. There was little binding of HPRG to heparin at physiological pH in the absence of metals, but the interaction was promoted by nanomolar concentrations of free zinc and copper, and its pH dependence was shifted toward alkaline pH by zinc. The affinity of HPRG for various GAGs measured in a competition assay decreased in the following order: heparin > dermatan sulfate > heparan sulfate > chondroitin sulfate A. Binding of HPRG to immobilized dermatan sulfate had a midpoint at pH 6.5, was less influenced by zinc, and exhibited cooperativity. Importantly, plasminogen interacted specifically with GAG-bound HPRG. We propose that HPRG is a physiological pH sensor, interacting with negatively charged GAGs on cell surfaces only when it acquires a net positive charge by protonation and/or metal binding. This provides a mechanism to regulate the function of HPRG (the local pH) and rationalizes the role of its unique, conserved histidine-proline-rich domain. Thus, under conditions of local acidosis (e.g. ischemia or hypoxia), HPRG can co-immobilize plasminogen at the cell surface as well as compete for heparin with other proteins such as antithrombin.


Bacteriologic and vaccination studies in a field epizootic of infectious bovine keratoconjunctivitis in calves.
Infectious bovine keratoconjunctivitis (IBK) was enzootic in the beef cattle herds at Dixon Springs Agricultural Center, University of Illinois. The development of nonhemolytic and hemolytic Moraxella bovis flora in the eyes of 48 calves in a closed cow-calf herd was monitored from late May to October, 1972. The incidence of clinical IBK was recorded each week. In late May, nonhemolytic M bovis was isolated from 26% of calf eyes. The peak incidence of IBK was observed in early September, with 26% of the eyes affected. At that time, nonhemolytic M bovis was isolated from 10% of the eyes, and hemolytic M bovis from 58%. By late October, nonhemolytic M bovis was isolated from 25% of the eyes, and hemolytic M bovis from only 4%. In an attempt to increase the resistance of ocular tissue, 19 calves were vaccinated in each third eyelid with 0.5 ml of an autogenous M bovis bacterin in late May. Vaccination did not provide practical protection against the establishment of hemolytic M bovis in the eyes nor the development of clinical IBK. However, at the peak incidence of IBK, hemolytic M bovis was isolated from the eyes of 48% of vaccinated calves and 73% of nonvaccinated calves; clinical IBK was present in 21% of the eyes of vaccinated calves and 29% of nonvaccinated calves. In evaluating the in vitro proteolytic potential of M bovis isolates, 83 hemolytic and 5 nonhemolytic isolates peptonized litmus milk; 176 nonhemolytic isolates did not peptonize litmus milk. Hemolytic M bovis isolates were more pathogenic for mice than were nonhemolytic isolates. Of 60 mice, 53 (88%) died in 1 to 3 hours after intraperitoneal inoculation of hemolytic isolates; 8 of 32 (25%) mice died in 5 to 15 hours after inoculation of nonhemolytic isolates. Hemolytic M bovis isolates produced testicular swelling and scrotal necrosis after inoculation into the scrotal sac of rabbits; nonhemolytic isolates produced only mild transient testicular swelling.


Joint power generation differentiates young and adult sprinters during the transition from block start into acceleration: a cross-sectional study.
The aim of this study was to investigate differences in joint power generation between well-trained adult athletes and young sprinters from block clearance to initial contact of second stance. Eleven under 16 (U16) and 18 under 18 (U18) promising sprinters executed an explosive start action. Fourteen well-trained adult sprinters completed the exact same protocol. All athletes were equipped with 74 spherical reflective markers, while an opto-electronic motion analysis system consisting of 12 infrared cameras (250 Hz, MX3, Vicon, Oxford Metrics, UK) and 2 Kistler force plates (1,000 Hz) was used to collect the three-dimensional marker trajectories and ground reaction forces (Nexus, Vicon). Three-dimensional kinematics, kinetics, and power were calculated (Opensim) and time normalised from the first action after gunshot until initial contact of second stance after block clearance. This study showed that adult athletes rely on higher knee power generation during the first stance to induce longer step length and therefore higher velocity. In younger athletes, power generation of hip was more dominant.


Is there any future for T-cell depleted bone marrow transplantation in chronic myeloid leukaemia?
There is no doubt that the poor reputation of T-cell depleted bone marrow transplant arises from its use in CML patients, where an increase in graft rejection and, above all, in leukaemia relapse has been reported by almost all centres. Evidence suggests that the standard conditioning regimen (once thought to be sufficiently immunosuppressive and myeloablative in unmanipulated transplants) should no longer be considered adequate when the immunological balance has shifted in favour of unopposed host-versus-graft reactivity and the GvL effect is lacking. Since GvHD remains the major problem in BMT, we suggest T-cell depletion should be considered the most effective method for GvHD prophylaxis but the cytoreductive effect of the conditioning regimens and the anti-leukaemia immune reactivity should be enhanced.


[The sensitivity to landomycins A and E of streptomycetes, producers of polyketide antibiotics].
Streptomycetes, which are the producers of different polyketide antibiotics, can be divided into 4 groups as to their sensitivity to landomycins A and E: 1) S. glaucescens Tü49, producer of tetracenomycin and S. aureofaciens 019, producer of chlortetracycline belong to the most landomycin-sensitive strains. 2) S. cyanogenus S136, producer of landomycin A, and S. lividans TK24, producer of actinorhodin, were sensitive to mean and high doses of landomycin E (more than 60-80 ug/ml). 3) S. globisporus 1912 (producer of landomycin E), S. cyanogenus S136, S. fradiae Tü2717, producer of urdamycins and S. coelicolor A3(2), producer of actinorhodin have moderate sensitivity to all doses of the both antibiotics but strain S136 only to low doses. 4) Resistance to landomycins A and E was observed in strain S. olivaceus Tü2353, producer of elloramycin. In all the experiments landomycin E showed the 1-2 orders higher lethal activity in comparison with landomycin A which molecule is composed of the same aglycon landomycenone A but a longer polysaccharide chain which probably hampers the penetration of antibiotic through the cell membrane.


Endocytic pathway inhibition attenuates extracellular vesicle-induced reduction of chemosensitivity to bortezomib in multiple myeloma cells.
Extracellular vesicles (EVs), including exosomes and microvesicles, derived from bone marrow stromal cells (BMSCs) have been demonstrated as key factors in the progression and drug resistance of multiple myeloma (MM). EV uptake involves a variety of mechanisms which largely depend on the vesicle origin and recipient cell type. The aim of the present study was to identify the mechanisms involved in the uptake of BMSC-derived small EVs (sEVs) by MM cells, and to evaluate the anti-MM effect of targeting this process. Methods: Human BMSC-derived sEVs were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. The effects of chemical inhibitors and shRNA-mediated knockdown of endocytosis-associated genes on sEV uptake and cell apoptosis were analyzed by flow cytometry. The anti-MM effect of blocking sEV uptake was evaluated in vitro and in a xenograft MM mouse model. Results: sEVs derived from BMSC were taken up by MM cells in a time- and dose-dependent manner, and subsequently promoted MM cell cycling and reduced their chemosensitivity to bortezomib. Chemical endocytosis inhibitors targeting heparin sulphate proteoglycans, actin, tyrosine kinase, dynamin-2, sodium/proton exchangers, or phosphoinositide 3-kinases significantly reduced MM cell internalization of BMSC-derived sEVs. Moreover, shRNA-mediated knockdown of endocytosis-associated proteins, including caveolin-1, flotillin-1, clathrin heavy chain, and dynamin-2 in MM cells suppressed sEV uptake. Furthermore, an endocytosis inhibitor targeting dynamin-2 preferentially suppressed the uptake of sEV by primary MM cells ex vivo and enhanced the anti-MM effects of bortezomib in vitro and in a mouse model. Conclusion: Clathrin- and caveolin-dependent endocytosis and macropinocytosis are the predominant routes of sEV-mediated communication between BMSCs and MM cells, and inhibiting endocytosis attenuates sEV-induced reduction of chemosensitivity to bortezomib, and thus enhances its anti-MM properties.


Sustained thrombolysis with DNA-recombinant tissue type plasminogen activator in rabbits.
Tissue type plasminogen activator (t-PA) is an effective thrombolytic agent in experimental animals. The duration of the thrombolytic effect of infused t-PA is unknown. We compared the duration of the thrombolytic effect of t-PA with streptokinase by measuring the lysis of 125I-fibrin-labeled thrombi in rabbit jugular veins at different times after a bolus injection of the fibrinolytic agents. The pharmacodynamics of both thrombolytic agents were determined in rabbits using a sensitive ex vivo fibrinolytic assay. Streptokinase and t-PA were given as a bolus dose of 15,000 U/kg. There was no detectable circulating fibrinolytic activity 30 minutes after the bolus dose of t-PA and 120 minutes after the bolus dose of streptokinase. The t-PA injection produced 34% thrombolysis at 30 minutes, 90% thrombolysis at 120 minutes, and 96% thrombolysis at 240 minutes. The streptokinase injection produced 17% thrombolysis at 30 minutes, 34% at 120 minutes, and 34% at 240 minutes. These observations indicate that the thrombolytic effect of t-PA is sustained beyond its time of clearance from the circulation whereas the thrombolytic effect of streptokinase closely parallels its activity in the circulation.


Recommendations for Selection and Characterization of Protein Biomarker Assay Calibrator Material.
As biomarkers continue to become an integral part of drug development and decision-making, there are increased expectations for reliable and quantitative assays. Protein biomarker assay results are directly influenced by the calibrator material. The selection of calibrator material presents many challenges that impact the relative accuracy and performance of the assay. There is an industry-wide challenge finding reliable and well-characterized calibrator material with good documentation. Several case studies are presented that demonstrate some of the challenges involved in selecting appropriate calibrators along with the resolutions that were ultimately applied. From these experiences, we present here a set of recommendations for selecting and characterizing calibrator material based on the intended purpose of the assay. Finally, we introduce a commutability approach, based on common clinical chemistry practices, which can be used to demonstrate inter-changeability with calibrator materials across multiple lots and technology platforms for all types of protein biomarker assays.


Towards a better testicular sperm extraction: novel sperm sorting technologies for non-motile sperm extracted by microdissection TESE.
Non-obstructive azoospermia (NOA) is the most severe form of male factor infertility. It is characterized by a lack of spermatogenesis in the seminiferous tubules. Microdissection testicular sperm extraction (microTESE) has significantly improved testicular sperm retrieval rates compared to conventional techniques for NOA. Following testicular biopsy, the sperm is usually non-motile and contained within seminiferous tubules requiring extensive laboratory processing to find individual sperm sufficient for artificial reproductive technologies (ART). Current techniques include mechanical and enzymatic processing which is time-consuming and often damaging to sperm. We review novel techniques that may help improve sperm retrieval rates after microTESE including microfluidics (dielectrophoretic cell sorting, spiral channel sorting, and pinched flow fractionation), fluorescence-activated cell sorting (FACS), and magnetic-activated cell sorting (MACS).


Interleukin-8 gene silencing on pancreatic cancer cells using biodegradable polymer nanoplexes.
Pancreatic cancer is one of the deadliest cancers throughout the world with rarely efficient therapies currently available. Gene therapy on pancreatic cancer through small interfering RNA (siRNA)-based RNA interference (RNAi) has shown great potential and attracted much attention. However, due to the fragile nature of nucleic acid, the application of RNAi as a safe and efficient carrier faces great challenges. In this contribution, a self-assembly regime, which is based on well-defined cationic polylactides (CPLAs) with tertiary amine groups, has been used to encapsulate and protect siRNAs from fast degradation. CPLA is a safe and degradable formulation that allowed us to deliver siRNAs targeting the proangiogenic chemokine interleukin-8 (IL-8) to pancreatic cancer cells for gene therapy. Stable IL-8 siRNA-CPLA nanoplexes were successfully formed by electrostatic force and high gene transfection efficiencies were shown on two pancreatic cancer cell lines. We did not observe any cytotoxicity from these CPLAs over a large concentration range via cell viability evaluations. More importantly, the silencing of IL-8 gene expression significantly attenuated the proliferation of pancreatic cancer cells. Our preliminary results support the future development of gene therapy that might provide an effective and safe treatment approach towards pancreatic cancer.


Tapentadol at medium to high doses in patients previously receiving strong opioids for the management of cancer pain.
The aim of this study was to assess the efficacy and tolerability of tapentadol (TP) for a period of 4 weeks in patients who were already treated by opioids. A convenience sample of 30 patients was selected for a prospective observational cohort study. Cancer patients who were receiving at least 60 mg of oral morphine equivalents were selected. Patients discontinued their previous opioid analgesics before starting TP, in doses calculated according the previous opioid consumption (1:3.3 ratio with oral morphine equivalents). The subsequent doses were changed according to the patients' needs for a period of 4 weeks. Oral morphine was offered as a breakthrough pain medication. Pain and symptom intensity were recorded at weekly intervals. Distress score (DS) was calculated from the sum of symptom intensities. TP opioid escalation indexes (TPEI) for the study period were calculated. Nineteen patients were male, and the mean age was 63.5 years (±11.5). The mean Karnofsky status was 62.9 (±10). The mean dose of oral morphine equivalents before switching to TP was 112 mg (±57) and the initial mean dose of TP was 343 mg (±150). Pain intensity significantly decreased. Tapentadol escalation index in percentage was 1.26 (TPEI% ± 2.6) and Tapentadol escalation index in mg was 2.76 (TPEImg ± 4.96). No significant relationships were found with primary tumor (TPEI%, p = 0.204; TPEImg, p = 0.180), pain mechanism (TPEI%, p = 0.863; TPEImg, p = 0.846), age (TPEI%, p = 0.882; TPEImg, p = 0.884), or gender (TPEI%, p = 0.287; TPEImg, p = 0.325). DS decreased, but non-significantly (p = 0.1). Ten patients did not complete the study period: five patients discontinued TP for uncontrolled pain, despite increasing doses of TP over 600 mg/day. Two patients discontinued TP for adverse effects and three patients dropped out, one patient for poor compliance and two patients for unrecorded reasons. In our sample, TP used in doses of 350-450 mg/day was well tolerated and effective in opioid tolerant patients with cancer pain and could be considered as a flexible drug to be used for the management of moderate to severe cancer pain. Like most studies in patients with cancer pain, it was limited by its open-label, uncontrolled design, the number of patients lost in follow-up, and discontinuation of the treatment for several reasons. Further studies in a large number of patients should confirm these preliminary results.


Prima facie reasons to question enclosed intellectual property regimes and favor open-source regimes for germplasm.
In principle, intellectual property protections (IPPs) promote and protect important but costly investment in research and development. However, the empirical reality of IPPs has often gone without critical evaluation, and the potential of alternative approaches to lend equal or greater support for useful innovation is rarely considered. In this paper, we review the mounting evidence that the global intellectual property regime (IPR) for germplasm has been neither necessary nor sufficient to generate socially beneficial improvements in crop plants and maintain agrobiodiversity. Instead, based on our analysis, the dominant global IPR appears to have contributed to consolidation in the seed industry while failing to genuinely engage with the potential of alternatives to support social goods such as food security, adaptability, and resilience. The dominant IPR also constrains collaborative and cumulative plant breeding processes that are built upon the work of countless farmers past and present. Given the likely limits of current IPR, we propose that social goods in agriculture may be better supported by alternative approaches, warranting a rapid move away from the dominant single-dimensional focus on encouraging innovation through ensuring monopoly profits to IPP holders.


Effects of obesity on breast cancer stage at diagnosis in Korean women.
This study was carried out to test the hypothesis that palpation for lumps may be more difficult in large breasts than in small breasts, resulting in a delay in the detection and diagnosis of breast cancer, and to determine whether this hypothesis is confirmed in Asian women. Of 833 new breast cancer patients registered in the Daegu Cancer Registry in 1997-1999, 579 were used in the final data analysis, after excluding patient records containing many missing data on study variables related with cancer staging. There was no difference in means of body mass index (BMI) according to tumour, either in all cases or in those under 49 years of age. In the 50+ age group, the means+/-standard deviations of BMI of T1, T2 and T3 were 23.7+/-2.8, 24.2+/-3.0, and 26.2+/-4.3, respectively (P=0.01). In univariate logistic regression of tumour characteristics with BMI, no statistically significant odds ratios were found either by continuous or quartiles of BMI. In conclusion, these results suggest that the hypothesis is partially confirmed in Korean breast cancer patients and further studies are needed to clarify the relationship between BMI and tumour stage at diagnosis.


Substituted 2-hydroxy-1,2-dihydropyrrol-3-ones: fluorescent markers pertaining to oxidative stress and aging.
Previous observations that the aging process correlates with occurrence of certain fluorescent biological pigments have led to numerous efforts in elucidating the chemical nature of the fluorophores generated through reactions of primary amines and various products of lipid peroxidation. In this study, model reactions of saturated aldehydes with aliphatic amines in the presence of peroxides were found to generate structurally unusual fluorescent compounds. Substitution of a lysine-containing peptide for simpler amines has also yielded similar fluorescence. The spectral excitation and emission maxima (around 360 and 430 nm, respectively) of these fluorophores match those widely reported in peroxidized biological objects. The fluorescent compounds in our model studies have been chromatographically isolated and their structures determined through mass spectrometry, NMR spectrometry, and Fourier-transform infrared spectroscopy. The spectrometric data indicate the fluorescent products to be alkylated 2-hydroxy-1,2-dihydropyrrol-3-ones, obtained by the action of 1,2,4-triketone intermediates upon the primary amines. Independent syntheses of several 1,2,4-triketones were carried out. One such triketone reacted with hexylamine to form a fluorescent compound spectroscopically identical to the fluorescent reaction product of hexanal, hydrogen peroxide, and hexylamine.


Evidence for the adaptive evolution of the carbon fixation gene rbcL during diversification in temperature tolerance of a clade of hot spring cyanobacteria.
Determining the molecular basis of enzyme adaptation is central to understanding the evolution of environmental tolerance but is complicated by the fact that not all amino acid differences between ecologically divergent taxa are adaptive. Analysing patterns of nucleotide sequence evolution can potentially guide the investigation of protein adaptation by identifying candidate codon sites on which diversifying selection has been operating. Here, I test whether there is evidence for molecular adaptation of the carbon fixation gene rbcL for a clade of hot spring cyanobacteria in the genus Synechococcus that has diverged in thermotolerance. Amino acid replacements during Synechococcus radiation have resulted in an increase in the number of hydrophobic residues in the RbcLs of more thermotolerant strains. A similar increase in hydrophobicity has been observed for many thermostable proteins. Maximum likelihood models which allow for heterogeneity among codon sites in the ratio of nonsynonymous to synonymous nucleotide substitutions estimated a class of amino acid sites as a target of positive selection. Depending on the model, a single amino acid site that interacts with a flexible element involved in the opening and closing of the active site was estimated with either low or moderate support to be a member of this class. Site-directed mutagenesis approaches are being explored in order to directly test its adaptive significance.


Eating habits of patients with cleft lip and palate terated with fixed appliances.
Health education, built on the basis of various models as a lifelong process, has a considerable impact on eating habits. Correct nutritional patterns are particularly important during the period of intense growth and adolescence. The need to observe dietary recommendations concerns healthy, as well as sick persons, especially those with chronic diseases. To-date the data on the dietary habits of patients with cleft lip and palate during orthodontic treatment have been scarce. The objective of the study was to determine the eating habits of patients with cleft lip and palate before and during orthodontic treatment with a fixed appliance. The study covered 125 patients with cleft lip and palate, aged 14 to 31. The research tool was an own questionnaire assessing the dietary behaviour and oral hygiene habits during the treatment with a fixed orthodontic appliance. In the course of the orthodontic treatment with a fixed appliance, 79 patients (57.6%) did not change their eating patterns and 32 patients (24%) changed them to a moderate degree. The mean of 53 patients (42.7%) changed their hygienic habits considerably. The number of meals remained the same, however in the period when patients suffered pain after orthodontic adjustment appointments, the number of persons having 4-5 meals a day decreased by 32%. It is worth considering that no statistically significant changes were recorded as regards the habit of having sweet snacks and the insufficient consumption of fruit and vegetables. Difficulties with correct oral hygiene were reported after the consumption of e.g. spinach (59.8%), cucumber (57.6%), berries (54.4%), meat (58.2%). Eating habits of a considerable percentage of patients with a cleft defect, before or during the treatment with a fixed appliance, do not comply with healthy nutrition recommendations. The dietary education of patients undergoing orthodontic treatment is necessary to ensure proper oral health and prevent diet-related illnesses.


Vortex Polymer Optical Fiber with 64 Stable OAM States.
This research introduces a numerical design of an air-core vortex polymer optical fiber in cyclic transparent optical polymer (CYTOP) that propagates 32 orbital angular momentum (OAM) modes, i.e., it may support up to 64 stable OAM-states considering left- and right-handed circular polarizations. This fiber seeks to be an alternative to increase the capacity of short-range optical communication systems multiplexed by modes, in agreement with the high demand of low-cost, insensitive-to-bending and easy-to-handle fibers similar to others optical fibers fabricated in polymers. This novel fiber possesses unique characteristics: a diameter of 50 µm that would allow a high mechanical compatibility with commercially available polymer optical fibers, a difference of effective index between neighbor OAM modes of around 10-4 over a bandwidth from 1 to 1.6 µm, propagation losses of approximately 15 × 10-3 dB/m for all OAM modes, and a very low dispersion for OAM higher order modes (±l = 16) of up to +2.5 ps/km-nm compared with OAM lower order modes at a telecom wavelength of 1.3 µm, in which the CYTOP exhibits a minimal attenuation. The spectra of mutual coupling coefficients between modes are computed considering small bends of up to 3 cm of radius and slight ellipticity in the ring of up to 5%. Results show lower-charge weights for higher order OAM modes.


A Reduced Tryptophan Diet in Patients with Diarrhoea-Predominant Irritable Bowel Syndrome Improves Their Abdominal Symptoms and Their Quality of Life through Reduction of Serotonin Levels and Its Urinary Metabolites.
(1). An essential component of any treatment for patients with irritable bowel syndrome (IBS) is an adequate diet. Currently, a low FODMAP diet is recommended as a first-line therapy, but it does not relieve abdominal discomfort in all patients, and alternative nutritional treatment is required. The purpose of this study was to evaluate the effect of a tryptophan-lowering diet (TRP) on abdominal and mental symptoms in patients with irritable bowel syndrome with predominant diarrhea (IBS-D). (2). The study included 40 patients with IBS-D, and 40 healthy subjects served as a baseline for IBS-D patients, after excluding comorbidities. The TRP intake was calculated using the nutritional calculator. The severity of abdominal symptoms was assessed using the gastrointestinal symptom rating scale (GSRS-IBS). Mental state was assessed using the Hamilton anxiety rating scale (HAM-A), the Hamilton depression rating scale (HAM-D), and the insomnia severity index (ISI). The serum levels of serotonin and melatonin and the urinary excretion of their metabolites 5-hydroxyindoleacetic acid (5-HIAA) and 6-sulfatoxymelatonin (aMT6) were determined by the ELISA method. The severity of symptoms and laboratory data were analyzed before and after a 12 week diet with tryptophan restricted to a daily dose 10 mg per kilogram body weight. (3). Compared to the control group, patients with IBS-D had a higher serum level of serotonin (198.2 ± 38.1 vs. 142.3 ± 36.4 ng/mL; p < 0.001) but a similar level of melatonin (8.6 ± 1.1 vs. 9.4 ± 3.0 pg/mL; p > 0.05). The urinary excretion of 5-HIAA was also higher in patients with IBS-D patients (7.7 ± 1.5 vs. 6.0 ± 1.7 mg/24 h; p < 0.001). After nutritional treatment, both the serum serotonin level and the urinary 5-HIAA excretion significantly decreased (p < 0.001). The severity of the abdominal symptoms and anxiety also decreased, while the HAM-D score and the ISI score remained unchanged (4). Lowering the dietary intake of tryptophan may reduce abdominal complaints and does not alter the mental state of IBS-D patients.


Comparing the Health of Populations: Methods to Evaluate and Tailor Population Management Initiatives in the Netherlands.
Health care no longer focuses solely on patients and increasingly emphasizes regions and their populations. Strategies, such as population management (PM) initiatives, aim to improve population health and well-being by redesigning health care and community services. Hence, insight into population health is needed to tailor interventions and evaluate their effects. This study aims to assess whether population health differs between initiatives and to what extent demographic, personal, and lifestyle factors affect these differences. A population health survey that included the Short Form 12 version 2 (SF12, physical and mental health status), Patient Activation Measure 13 (PAM13), and demographic, personal, and lifestyle factors was administered in 9 Dutch PM initiatives. Potential confounders were determined by comparing these factors between PM initiatives using analyses of variance and chi-square tests. The influence of these potential confounders on the health outcomes was studied using multivariate linear regression. Age, education, origin, employment, body mass index, and smoking were identified as potential confounders for differences found between the 9 PM initiatives. Each had a noteworthy influence on all of the instruments' scores. Not all health differences between PM initiatives were explained, as the SF12 outcomes still differed between PM initiatives once corrected. For the PAM13, the differences were no longer significant. Demographic and lifestyle factors should be included in the evaluation of PM initiatives and population health differences found can be used to tailor initiatives. Other factors beyond health care (eg, air quality) should be considered to further refine the tailoring and evaluation of PM initiatives.


Change in Circulating Undercarboxylated Osteocalcin (ucOCN) Is Associated With Fat Accumulation in HIV-Seropositive Women.
Bone mineral density loss and fat accumulation are common in people living with HIV. The bone-derived hormone, undercarboxylated osteocalcin (ucOCN) regulates fat metabolism. We investigated the relationship between ucOCN change and body fat change among perimenopausal/postmenopausal HIV-seronegative and HIV-seropositive women on long-term antiretrovirals. Perimenopausal and postmenopausal women enrolled in the Women's Interagency HIV Study MSK substudy underwent trunk and total fat assessment by dual energy x-ray absorptiometry (DXA) at study enrollment (index visit) and again 2 years later. Circulating ucOCN and cOCN were also measured at the index and 2-year visits. The correlation between the 2-year change in ucOCN and cOCN and change in trunk and total fat was assessed as a function of HIV serostatus using linear regression modeling. Multivariate linear regression assessed the association between ucOCN and cOCN change and total and trunk fat change after adjusting for sociodemographic variables. Linear regression models restricted to HIV-seropositive women were performed to examine the contributions of HIV-specific factors (index CD4 count, viral load, and combined antiretroviral therapy use) on the associations. Increased ucOCN over the 2-year follow-up was associated with less trunk and total fat accumulation in models adjusting for HIV serostatus and participants sociodemographics, whereas there was no association with cOCN and the fat parameters. None of the HIV-specific factors evaluated influenced the association between ucOCN and fat parameters. The current study suggests that increases in ucOCN are associated with decreased fat accumulation in HIV-seronegative and HIV-seropositive postmenopausal women on long-term antiretroviral therapy.