Heterobi- and -trimetallic Ion Pairs of Zirconocene-Based Isoselective Olefin Polymerization Catalysts with AlMe₃.
The reactivity towards AlMe3 of discrete cationic ansa-zirconocenes 2 a,b that are ubiquitously used in isoselective propylene polymerization and based on [{Ph(H)C(3,6-tBu2-Flu)(3-tBu-5-Et-Cp)}ZrMe2)] {Cp-Flu} and rac-[{Me2Si-(2-Me-4-Ph-Ind)2}ZrMe2] {SBI} was scrutinized. The first example of a structurally characterized Group 4 metallocene AlMe3 adduct (3 b) is reported. In the presence of excess AlMe3, the {SBI}-based AlMe3 adduct 3 b undergoes a slow decomposition via C-H activation in a bridging methyl unit to yield a new species (4 b) with a trimetallic {Zr(μ-CH2)(μ-Me)AlMe(μ-Me)AlMe2} core. EXSY NMR data for the process 2 b⇄3 b→4 b suggest very rapid and reversible binding of an additional AlMe3 molecule onto AlMe3 adduct 3 b. The resulting heterotrimetallic species intermediates exchange of methyl groups between different metal centers and slowly undergoes the C-H activation reaction towards 4 b.


Incidental synovial myxoma with extensive intermuscular infiltration in a dog.
A 16-year-old male mixed-breed dog was euthanized due to progression of renal failure caused by renal adenocarcinoma in the left kidney. Apart from main symptomatic lesion, accumulation of transparent jelly-like fluid was observed between the right femoral muscles. Gross examination of the right hindlimb revealed multiple nodules in the articular surface and capsule of the stifle joints, which extended into the crural muscles. Histopathologically, the joint and intermuscular masses were characterized by variously-sized hypocellular nodules consisting of spindle to stellate cells suspended in an abundant myxoid matrix. There were cystic structures within the intermuscular masses, lined by synoviocyte-like cells. Based on the gross and histopathologic findings, the case was diagnosed as synovial myxoma with extensive intermuscular infiltration. Synovial myxoma should be considered in the differential diagnosis of dogs with myxomatous tumor between skeletal muscles, even in absence of joint or muscle symptoms.


Multiple dispersal vectors drive range expansion in an invasive marine species.
The establishment and subsequent spread of invasive species is widely recognized as one of the most threatening processes contributing to global biodiversity loss. This is especially true for marine and estuarine ecosystems, which have experienced significant increases in the number of invasive species with the increase in global maritime trade. Understanding the rate and mechanisms of range expansion is therefore of significant interest to ecologists and conservation managers alike. Using a combination of population genetic surveys, environmental DNA (eDNA) plankton sampling and hydrodynamic modelling, we examined the patterns of introduction of the predatory Northern Pacific seastar (Asterias amurensis) and pathways of secondary spread within southeast Australia. Genetic surveys across the invasive range reveal some genetic divergence between the two main invasive regions and no evidence of ongoing gene flow, a pattern that is consistent with the establishment of the second invasive region via a human-mediated translocation event. In contrast, hydrodynamic modelling combined with eDNA plankton sampling demonstrated that the establishment of range expansion populations within a region is consistent with natural larval dispersal and recruitment. Our results suggest that both anthropogenic and natural dispersal vectors have played an important role in the range expansion of this species in Australia. The multiple modes of spread combined with high levels of fecundity and a long larval duration in A. amurensis suggests it is likely to continue its range expansion and significantly impact Australian marine ecosystems.


Role of calcineurin in calcium-mediated hypoxic injury to white matter.
Calcium influx into cells is responsible for initiating the "final pathway" to cell death in neuronal tissue after traumatic or hypoxic injury. The specific pathways in this cascade are myriad and the importance each one plays is controversial. It is clear, though, that blocking individual pathways confers protection to these tissues. In the present study we examined the role of Cyclosporin A (CsA), FK-506 and rapamycin in modulating the effects of Ca(2+) influx through their interactions with immunophilins and specifically the end result of calcineurin modulation. Dorsal columns were isolated from the spinal cord of adult rats and injured by exposure to hypoxic conditions for 60 minutes. The samples were monitored electrophysiologically in an in vitro recording chamber (maintained at 37 C degrees ) during injury, and the compound action potential (CAP) was monitored with glass microelectrodes. The dorsal column was exposed to hypoxic Ringers solution alone or with the different immunosuppressants and compared with baseline readings. Functional recovery of the dorsal column was then assessed by recovery of the CAP. The mean CAP decreased to about 20% of baseline control levels during hypoxia and returned 53.8+/-7.6% of baseline (p<.05) after reoxygenation. CsA, an immunosuppressant known to inhibit calcineurin, promoted a significantly greater recovery of CAP amplitude to 76.8+/-5.2% and 72.1+/-13.2% of control (p<.05) after hypoxic injury and reoxygenation of dorsal column white matter when applied at concentrations of 1 microM and 10 microM, respectively. FK-506, which also inhibits calcineurin, was applied at a concentration of 0.1 microM, and promoted CAP amplitude recovery to 82.6+/-5.0% of control after hypoxic injury and reoxygenation of dorsal column white matter. The addition of rapamycin (1 microM), which binds to the same immunophilin as FK-506, to the FK-506 (0.1 microM) solution during hypoxic injury showed recovery of CAP amplitudes to only 56.9+/-6.7% of control. Electron microscopy revealed remarkable protection of axons and prevention of organelle disruption in segments treated with CsA and FK-506 during hypoxia when compared with hypoxic controls. In conclusion, both CsA and FK-506 confer in vitro protection to dorsal columns during hypoxic injury at physiological temperatures, and rapamycin blocks the protective effect of FK-506. Thus, calcineurin may play an important role in the physiology of neuronal injury.


Cationic Chalcogenoviologen Derivatives for Photodynamic Antimicrobial Therapy and Skin Regeneration.
A series of water-soluble cationic chalcogenoviologen-based photosensitizers for photodynamic antimicrobial therapy (PDAT) is reported. The Se-containing derivatives (SeMV2+ ) 5 b and 6 b showed good antimicrobial activities due to the presence of chalcogen atoms and a cationic scaffold. The former efficiently enhanced the generation of reactive oxygen species (ROS), and the latter facilitated the ROS delivery to bacteria, resulting in their death. Interestingly, alkyl-modified photosensitizers showed higher antimicrobial activities than commonly reported photosensitizers with quaternary ammonium (QA) groups. In particular, the SeMV2+ (6 b) with excellent antibacterial activities efficiently promoted the healing of infected wounds in mice. Simple yet novel, nontoxic and biocompatible chalcogenoviologens provided a promising strategy to develop new efficient photosensitizers for photodynamic antimicrobial therapy and skin regeneration.


The steroid receptor antagonists RU40555 and RU486 activate glucocorticoid receptor translocation and are not excreted by the steroid hormones transporter in L929 cells.
RU40555 is a recently available glucocorticoid receptor (GR) antagonist that differs from RU486 by a methyl radical. We have used the mouse fibroblast cell line L929 to study the in vitro effects of RU40555 on GR translocation and function and on the membrane steroid hormones transporter. The results showed that: 1) RU40555 competed for the binding of labelled dexamethasone (Dex) with a K(i) of 2.4 nM; 2) both RU40555 and RU486 were equally potent inhibitors of Dex-induced GR-mediated gene transcription; 3) maximum GR translocation induced by micromolar concentrations of Dex and the GR antagonists was approximately 30-55% loss in the cytoplasmic GR and approximately 40-90% increase in the nuclear GR (assessed by GR immunostaining in cytoplasm and nucleus and western blots of immunoprecipitated GR protein in cytosolic and nuclear fractions) and was similar for the two antagonists; 4) at nanomolar concentrations, RU40555 and RU486 induced more GR translocation than Dex (assessed by [(3)H]Dex binding and western blot of immunoreactive GR in the same cytosolic homogenates); 5) blocking the steroids membrane transporter with verapamil (100 microM) in the presence of Dex (10 nM) increased GR translocation to levels similar to those induced by RU40555 (10 nM) and RU486 (10 nM) alone; 6) verapamil did not affect GR translocation in the presence of RU40555 or RU486. These data demonstrate similar quantitative effects on GR translocation by RU486 and the new GR antagonist, RU40555. Moreover, RU40555, like RU486, is an effective GR antagonist. Finally, there is no evidence that the intracellular concentrations of RU40555 or RU486 are regulated by the steroids membrane transporter in L929 cells.


Control of the citric acid cycle by glyoxylate. Mechanism of the inhibition by oxalomalate and gamma-hydroxy-alpha-oxoglutarate.
1. Hydroxyoxoglutarate was obtained by three methods: decarboxylation of oxalomalic acid, and synthesis from glyoxylate and pyruvate by using either Mg(2+) or an enzyme from rat liver as catalysts. 2. The inhibitory effects of oxalomalate and hydroxyoxoglutarate upon aconitate hydratase, isocitrate dehydrogenase (NADP) and oxoglutarate dehydrogenase were investigated. 3. Oxalomalate at low concentrations (1mm) inhibited almost completely both aconitate hydratase and isocitrate dehydrogenase. Hydroxyoxoglutarate also inhibited these enzymes, but at concentrations approximately tenfold that of oxalomalate. 4. Oxalomalate and hydroxyoxoglutarate, at the higher concentrations, inhibited oxoglutarate dehydrogenase to approximately the same extent. 5. It is suggested that the ability of glyoxylate to control reaction rates in the tricarboxylic acid cycle must in some degree be due to its condensation with oxaloacetate and pyruvate to form enzyme inhibitors.


The changing epidemiology of esophageal cancer.
The patterns of esophageal cancer are dramatically changing in the United States. Three decades ago the large majority of these cancers were squamous cell carcinomas, but the incidence of esophageal adenocarcinoma has been steadily increasing. By the early 1990s, adenocarcinoma had become the most common cell type of esophageal cancer among white patients, although squamous cell cancers still predominated among black patients. The trends are not simply due to gastric cardia cancers now being called esophageal adenocarcinomas, because the rates of tumors appearing just below the esophageal-gastric junction are also increasing. Tobacco and alcohol consumption are the primary causes of squamous cell carcinomas of the esophagus. The causes of esophageal adenocarcinoma are not well known; thus, reasons for the increasing incidence are not clear. Tobacco smoking has now been established as a risk factor, but there appears to be little link to alcohol consumption. One of the strongest emerging risk factors, however, is obesity. Increases in the prevalence of obesity and the incidence of esophageal adenocarcinoma are parallel, and several epidemiologic studies have shown upwards of threefold excess risks among overweight individuals. Further research into the causes of these usually fatal cancers may help identify other potential determinants and provide needed information to help stem their increase.


Malolactic fermentation as a technique for the deacidification of hard apple cider.
Malolactic fermentation (MLF), the conversion of malate to lactate, is an important process leading to the deacidification of hard apple cider. MLF is dependent on the levels of inhibitory factors such as sulfur dioxide and ethanol. To assess the effect of these 2 factors on MLF, hard apple cider was produced from pasteurized, unfiltered apple cider (Malus domestica cvs Red Delicious, Golden Delicious, Braeburn, and Fuji). Apple cider was treated with 2 levels of sulfur dioxide (50 and 80 ppm) and then fermented using Saccharomyces cerevisiae montrachet. After the primary fermentation, 1 set of the samples remained unadjusted and 100% ethyl alcohol was used to adjust other sets of samples to 7%, 9%, or 11% (v/v) ethanol. Following the ethanol adjustment, Oenococcus oeni MCW was used to initiate the MLF in half of the samples. Cider parameters monitored throughout the fermentations included organic acid content, titratable acidity, pH, ethanol production, and sugar content. Since samples containing either sulfur dioxide level had similar sugar utilization rates and ethanol production it was concluded that sulfur dioxide had no effect on the primary fermentation. Sulfur dioxide content was shown to have an impact on MLF. There was no difference in the rate of malic acid consumption, but lactic acid production was faster in the 50-ppm sulfur dioxide samples. MLF was not inhibited by ethanol content.


Direct mass spectrometric measurement of gases in soil monoliths.
An integrated approach to gas analysis in soil cores was conducted to provide a novel method for observing the gas dynamics associated with upland soil ecosystems. Depth profiles of the O(2), Ar, CO(2), CH(4), N(2) and NO(x) concentrations in intact soil monoliths were obtained simultaneously using membrane inlet mass spectrometry (MIMS). This technique enables the direct measurement of multiple gas species throughout the soil core with minimal disturbance. Depth profiles provided data on the vertical heterogeneity of gas concentrations, while horizontal heterogeneity was monitored by comparison between profiles. Detailed descriptions of the modifications to current MIMS methods for in situ environmental monitoring of terrestrial soils are provided. These included a thorough examination of calibration of the MIMS probe in gas phase, stirred and unstirred H(2)O, or between glass beads immersed in H(2)O. Calibration was also carried out in sterile (autoclaved) soil. The mean concentrations of CO(2) and CH(4) in the soil monoliths increased from 27 microM and undetectable levels respectively at the surface, to maximum values of 3.6 mM and 4.3 microM at 12-cm depth. These changes corresponded with decreases in mean O(2), Ar and N(2) concentration from 300, 20 and 720 microM respectively to 0-6, 10 and 574 microM at 12-cm depth. These data indicated the presence of a gradient within the core from an aerobic environment to an O(2)-depleted, but not in all cases a completely anaerobic, one. This transition corresponded, to some extent, with that between the upper and lower soil horizons. The increased methane and CO(2) concentrations observed at depth are indicative of anaerobic environments. General trends associated with the gradually changing vertical heterogeneity of these gas profiles and the transition towards anaerobiosis did not provide evidence for the existence of localised microsites. Some evidence for microsite-specific microbial communities was however, provided by observation of broad zones of accumulation of NO(x) species, but only at concentrations close to the limit of detection of the method. The ratio of each gas, to argon was calculated at each depth. This was done to correct for physical parameters, which influence inert and biologically active gases, equally. The amount of di-nitrogen as a ratio to Ar was seen to increase with depth. This could be evidence for denitrification in the lower horizon. An example of the dynamic 'online' data collection capabilities is provided for diurnal oscillations in subsurface (5 cm) soil gas concentrations.


Livestock poisoning from oil field drilling fluids, muds and additives.
The use and potential toxicity of various components of oil well drilling fluids, muds and additives are presented. Many components are extremely caustic resulting in rumenitis. Solvent and petroleum hydrocarbon components may cause aspiration pneumonia and rumen dysfunction. Some additives cause methemoglobinemia. The most frequently encountered heavy metals are lead, chromium, arsenic, lithium and copper. Considerations for investigating livestock poisoning cases and several typical cases are reviewed.


Perforator-based anterolateral thigh adipofascial or dermal fat flaps for facial contour augmentation.
We describe our experience with perforator-based anterolateral thigh (ALT) flaps for facial contour augmentations in a standardized two-step procedure. In a series of eight consecutive patients (two men, six women) suffering from contour deformities due to different reasons (scleroderma: three, Parry-Romberg syndrome: three, trauma: one, tumor: one), soft tissue augmentations were performed via a preauricular approach. Flaps were harvested from the ALT as perforator-based dermofat (two) or adipofascial flaps (six) with only a small sheet of fascia and a minimal cuff of muscle around the perforators. All flaps were anastomosed to the superficial temporal vessels. For refinement of the primary result, excess volume was removed and minor contour irregularities were smoothed out after 6 months. Despite the small-vessel caliber, anastomoses caused no problems, and all flaps healed well. Because defects were located close to the temporal vessels, the length of the perforator pedicle was always sufficient. Facial contour could further be improved after secondary reshaping of the healed flaps. This led to nearly perfect long-term facial symmetry in all cases. The ALT proved to be a reliable donor site, providing enough well-vascularized fatty tissue for facial contour augmentation in normal-weight patients. No submandibular incision is necessary if the perforators are anastomosed to the superficial temporal vessels. The preauricular incision gives an excellent view to the operating field.


Treatment of soft-tissue injuries by pulsed electrical energy.
Twenty pairs of patients matched for sex, age, weight, and degree of trauma were treated either with an active Diapulse machine emitting pulsed, high-frequency electrical energy or with a non-active placebo machine. They were examined for swelling, pain, and disability before treatment and after three days under double-blind conditions. The results show that the pulsed, high-frequency electrical treatment has a definite biological effect on recently injured soft tissues, especially in the reduction of pain and disability.


Neuroprotective effect and mechanism of baicalin on Parkinson's disease model induced by 6-OHDA.
This research was aimed to investigate the effects of baicalin on 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease (PD) and the main mechanism of baicalin based on metabolomics. The rat model of PD was induced by 6-OHDA. The protective effects of baicalin on rat model of PD were evaluated by open field test and rotarod test. The anti-PD efficacy of baicalin was evaluated by examining the morphologic changes of neurons and the level of monoamine neurotransmitters in the striatum, the number and morphology of tyrosine hydroxylase (TH)-positive neurons, and oxidative stress. Combined with metabolomics methods, the pharmacodynamic mechanism of baicalin on PD pathogenesis was also explored. Baicalin treatment improved the rod time and voluntary movement in rat model of PD (P<0.05) by the open field test and rotarod test. In addition, baicalin also protected from oxidative stress injury (P<0.05), and regulated the content of monoamine neurotransmitters dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid (P<0.05) and the number and morphology of TH-positive cells in 6-OHDA-induced PD model rats. By metabolomics, multivariate statistical analysis, and receiver operating characteristic curve analysis, we found that two metabolites N-acetyl aspartic acid and glutamic acid had a good diagnostic value. Quantitative analysis of metabolites showed a regulatory function of baicalin. Baicalin has significant protective effect on 6-OHDA-induced PD rats, which may play a protective role through an antioxidant, promoting the release of neurotransmitters and regulating the metabolism of N-acetyl aspartate and glutamate.


[Influenza A (H1N1) and antibiotic resistance in constant progress].
The epidemics of Influenza A(H1N1) started at the end of march 2009. Since then there was an exponential growth of knowledge in this area. This review deals with information of this disease in November 2009 (epidemiology, prophylaxis, vaccination and therapy) in our region. Highlights of ICAAC 2009 dealing with antibiotic resistance are also reviewed.


Notch4 Signaling Confers Susceptibility to TRAIL-Induced Apoptosis in Breast Cancer Cells.
Notch signaling has been established as a key regulator of cell fate in development, differentiation, and homeostasis. In breast cancers, increased Notch1 and Notch4 activity have been implicated in tumor progression and, accumulation of the intracellular domain of Notch4 (ICN4), reported in basal breast cancer cells. While, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have demonstrated selectively in targeting tumor cells, the majority of primary tumors are resistant to TRAIL. This necessitates the identification of factors that might regulate TRAIL sensitivity. Here we investigate TRAIL sensitivity in tumor cells following the modulation of Notch (1 and 4) activity using siRNA-mediated depletions or ectopic expression of GFP-tagged constructs of the intracellular domains of Notch1 (ICN1) or Notch4 (ICN4). Our findings suggest that Notch4, but not Notch1 signaling, sensitizes breast tumor cells to TRAIL-induced apoptosis. ICN4-induced sensitization to TRAIL is characterized by CBF1-dependence. Apoptosis was mediated via caspase-8 activation and regulated by the Bcl-2 family pro-apoptotic proteins Bak and Bid. Finally, we present evidence that endogenous Notch4 activity regulates susceptibility to TRAIL in basal-like breast cancer cells but not in cell lines of luminal origin. These experiments reveal a hitherto unexplored Notch4-TRAIL signaling axis in breast cancer cells.


Glycosylation variants of mucins and CEACAMs as candidate biomarkers for the diagnosis of pancreatic cystic neoplasms.
Cystic lesions of the pancreas are increasingly being recognized due to the widespread use of high resolution abdominal imaging. Since certain cyst types are precursors to invasive cancer, this situation presents an opportunity to intervene prior to malignant progression. Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions with no malignant potential from those with malignant potential. Here we explored whether glycosylation variants on specific proteins in cyst fluid samples could serve as biomarkers to aid in this diagnosis. We used a novel antibody-lectin sandwich microarray method to measure the protein expression and glycosylation of mucin (MUC)1, MUC5AC, MUC16, carcinoembryonic antigen, and other proteins implicated in pancreatic neoplasia in cyst fluid samples. Fifty-three cyst fluid samples were obtained from patients with mucinous cystic neoplasms (n=17), intraductal papillary mucinous neoplasms (n=15), serous cystadenomas (n=12), or pseudocysts (n=9), with confirmation of histologic diagnosis at surgical resection. The detection of a glycan variant on MUC5AC using the lectin wheat-germ agglutinin discriminated mucin-producing cystic tumors (mucinous cystic neoplasms+intraductal papillary mucinous neoplasms) from benign cystic lesions (serous cystadenomas+pseudocysts) with a 78% sensitivity at 80% specificity, and when used in combination with cyst fluid CA 19-9 gave a sensitivity of 87% at 86% specificity. These biomarkers performed better than cyst fluid carcinoembryonic antigen (37%/80% sensitivity/specificity). These results demonstrate the value of glycan variants for biomarker discovery and suggest that these biomarkers could greatly enhance the accuracy of differentiating pancreatic cystic tumors. Validation studies will be required to determine the clinical value of these markers.


Long-term reliability and validity of alcoholism diagnoses and symptoms in a large national telephone interview survey.
The long-term reliability and validity of telephone lay interview assessments of alcoholism were examined in the context of a large national community-based survey of over 8,000 male Vietnam era veterans. A subsample of 146 men was interviewed twice by telephone using the same structured interview an average of 15 months apart to evaluate the long-term reliability of alcoholism symptoms and diagnoses. In addition, a search of Department of Veterans Affairs patient treatment files of inpatient hospitalizations between 1970 and 1993 yielded a subsample of 89 interviewed men with a past discharge diagnosis of alcohol dependence. The test-retest reliability of alcohol abuse and alcohol dependence diagnoses was good, with kappa coefficients of 0.74 and 0.61, respectively. The reliability of individual alcoholism symptoms was fair to good, with kappas of 0.46 to 0.67. Ninety-six percent of individuals identified by Department of Veterans Affairs patient treatment files as having an alcohol dependence diagnosis were correctly diagnosed by the telephone interview. The results of the present study provide additional evidence for the long-term reliability and validity of lifetime alcoholism diagnoses, and suggest that the reliability and validity of telephone interview assessments of alcoholism are as good as that of an in-person interview. Telephone administration of structured psychiatric interviews appears to be an attractive alternative to in-person interviewing for gathering information about alcoholism and alcohol-related problems.


[Incidence of heart rhythm and conduction disorders in chronic cor pulmonale among alpine inhabitants].
Electro- and echocardiographic studies were carried out in 708 male mountain-dwellers (at altitudes of 2800--4200 m) and 1047 male dwellers of lower altitudes (700--800 m), aged 30 to 59 years. One-hour ECG monitoring was conducted in 90 mountaineers. The latter population showed a high incidence of echocardiographically-confirmed signs of right-ventricular hypertrophy (RVH) of varying degrees. They also showed relatively high rates of heart rhythm and conductivity disorders (13.7% vs. 3.18% of low-altitude dwellers; p less than 0.001). As RVH gained in markedness, and as the recording time grew longer, the frequency of detected cardiac arrhythmias increased dramatically. RVH, arterial hypoxemia and pulmonary arterial hypertension are risk factors contributing to cardiac arrhythmias.


Toward a concept of stretch coupling in smooth muscle: a thesis by Lars Thuneberg on contractile activity in neonatal interstitial cells of Cajal.
The hypothesis was put forward by Thuneberg that rhythmically contracting interstitial cells of Cajal (ICC) were sensing stretch of the musculature and that this information was transmitted to smooth muscle cells via peg and socket contacts. The present study provides the evidence for the contractile nature of ICC as perceived by Thuneberg. The contractile activity is shown by video frame subtraction and by tracking areas of interest in sequential video frames. Thuneberg used neonatal ICC in culture maintained between two coverslips thereby allowing growth factors to quickly reach optimal concentrations. Contractions of ICC were seen to precede smooth muscle contractions. In addition, strong contractions were observed solely in branches of ICC. It is hoped that this communication will stimulate discussion about the contractile nature of ICC and that this phenomenon will eventually find its place amongst the physiological properties of the ICC networks of the gut musculature.


Lens-sparing vitreoretinal surgery in infants.
Lensectomy is routinely performed in infant eyes undergoing vitreoretinal surgery. Using a two-port system, we performed pars plicata vitrectomy and membrane peeling without removal of the crystalline lens. Surgical manipulations were done in the postequatorial region in eyes with areas of attached peripheral retina. Eight of 10 eyes showed no evidence of postoperative cataract formation. In no instance was a peripheral retinal break created. In selected cases, vitreoretinal surgery can be performed in infant eyes without the need for lens removal.


Activity problems in everyday life--patients' perspectives of hand osteoarthritis: "try imagining what it would be like having no hands".
To explore first-person perspectives on activities and participation in everyday life among people with hand osteoarthritis (OA). Semi-structured interviews were carried out with 5 men and 26 women of different ages living with hand OA. Supplemental data were collected via photo-interviews of two of the men and nine of the women. The analytical process was inspired by the interpretive phenomenological analysis and informed by the interpretive frameworks of critical psychology and social practice theory. Empirical findings indicate that persons with hand OA experience activity problems and participation limitations in the conduct of everyday life. Activity problems were related to self-care, paid work, as well as leisure activities. The participants also reported employing different strategies attempting to overcome the challenges of their everyday lives in order to keep actively performing valued activities. They reported environmental support of utmost importance for these attempts. Social participation in networks was also reported to be affected by the participants' activity problems. Arranging everyday life is complex and is carried out in structures of social practice. A supportive physical and social environment facilitates participation. The findings highlight the importance of paying attention to individual needs in rehabilitation processes.


Factors associated with influenza vaccination status of residents of a rural community in Japan.
The rate of influenza vaccination in Japan has declined over the past several decades. It is essential to identify community-specific factors that affect attitudes toward vaccination, but such parameters have not yet been fully determined in Japan. The present study used the Health Belief Model (HBM) to identify perceptions of influenza vaccination in a rural Japanese community. All subjects were residents of a rural town in the southern part of Kyoto, Japan. An anonymous self-administered questionnaire was mailed to 846 randomly chosen households (containing 2,665 subjects). The survey explored gender, age, history of influenza, and factors associated with obtaining influenza vaccination, based on the HBM. A total of 1,182 valid responses (response rate, 44.4%) were received. Sources of information that were associated with vaccination decisions were medical facilities for children (OR=4.21; 95% CI: 1.17-15.1), workplaces for adults (OR=2.40; 95% CI: 1.22-4.75), medical facilities, town office and family for elderly subjects (OR=6.18; 95% CI: 2.42-15.7, OR=5.59; 95% CI: 2.26-13.8 and OR=3.29; 95% CI: 1.01-10.6). Subjects, in all age groups, who strongly agreed that the vaccine was effective were significantly more likely to be vaccinated (OR=10.5; 95% CI: 2.68-41.7 for children; OR=8.85; 95% CI: 4.61-16.9 for adults; OR=19.9; 95% CI: 8.28-48.0 for the elderly). The vaccination rate of elderly subjects who expressed concerns regarding adverse vaccine effects (OR=0.34, 95% CI: 0.15-0.78) or who were worried about practical barriers to the vaccination process (OR=0.13; 95% CI: 0.05-0.31) was significantly lower than in other populations. Our results indicate that vaccination coverage can be increased if accurate information on personal risk, severity of influenza illness, and efficacy of vaccination are provided by responsible information sources that are easily accessible. Such sources include medical facilities and municipal offices. In addition, barriers and inconveniences associated with vaccination should be removed, especially if they impact on elderly people.


Nitrogen and fatty acid rumen metabolism in cattle offered high or low polyphenol oxidase red clover silage.
Polyphenol oxidase (PPO) in red clover (RC) has been shown to reduce both lipolysis and proteolysis in silo and implicated (in vitro) in the rumen. However, all in vivo comparisons have compared RC with other forages, typically with lower levels of PPO, which brings in other confounding factors as to the cause for the greater protection of dietary nitrogen (N) and C18 polyunsaturated fatty acids (PUFA) on RC silage. This study compared two RC silages which when ensiled had contrasting PPO activities (RC+ and RC-) against a control of perennial ryegrass silage (PRG) to ascertain the effect of PPO activity on dietary N digestibility and PUFA biohydrogenation. Two studies were performed the first to investigate rumen and duodenal flow with six Hereford×Friesian steers, prepared with rumen and duodenal cannulae, and the second investigating whole tract N balance using six Holstein-Friesian non-lactating dairy cows. All diets were offered at a restricted level based on animal live weight with each experiment consisting of two 3×3 Latin squares using big bale silages ensiled in 2010 and 2011, respectively. For the first experiment digesta flow at the duodenum was estimated using a dual-phase marker system with ytterbium acetate and chromium ethylenediaminetetraacetic acid as particulate and liquid phase markers, respectively. Total N intake was higher on the RC silages in both experiments and higher on RC- than RC+. Rumen ammonia-N reflected intake with ammonia-N per unit of N intake lower on RC+ than RC-. Microbial N duodenal flow was comparable across all silage diets with non-microbial N higher on RC than the PRG with no difference between RC+ and RC-, even when reported on a N intake basis. C18 PUFA biohydrogenation was lower on RC silage diets than PRG but with no difference between RC+ and RC-. The N balance trial showed a greater retention of N on RC+ over RC-; however, this response is likely related to the difference in N intake over any PPO driven protection. The lack of difference between RC silages, despite contrasting levels of PPO, may reflect a similar level of protein-bound-phenol complexing determined in each RC silage. Previously this complexing has been associated with PPOs protection mechanism; however, this study has shown that protection is not related to total PPO activity.


High-Deductible Health Plans and Cancer Survivorship: What Is the Association With Access to Care and Hospital Emergency Department Use?
To examine the associations among high-deductible health plan (HDHP) enrollment, cancer survivorship, and access to care and utilization. The 2010 to 2017 National Health Interview Survey was used to identify privately insured adults ages 18 to 64 years (cancer survivors, n = 4,321; individuals without a cancer history, n = 95,316). We used multivariable logistic regressions to evaluate the associations among HDHP/health savings account (HSA) status, delayed/forgone care for financial reasons, and hospital emergency department (ED) visits among cancer survivors compared with individuals without a cancer history. Among cancer survivors, HDHPs with or without HSA (8.9% and 13.9%, respectively; both P < .05) were associated with more delayed/forgone care compared with low-deductible health plans (LDHPs) (7.9%). HSA enrollment was associated with less delayed/forgone care among HDHP cancer survivors (P < .05). ED visits were similar by insurance type. Among individuals without a cancer history, HDHP with or without HSA (9.5% and 10.8%, respectively; both P < .05) were both associated with more delayed/forgone care compared with LDHPs (5.9%). HSA enrollment also was associated with less delayed/forgone care among HDHP enrollees without a cancer history. A small difference in ED visits was observed between HDHPs without HSA (15.3%) and LDHPs (14.1%; P < .05) or HDHPs with HSA (13.4%; P < .05) among individuals without a cancer history. HDHP enrollment and HSA status affect access to care and hospital ED visits similarly by cancer history. HDHP enrollment may serve as a barrier to access to care among cancer survivors, although HSA enrollment coupled with an HDHP may mitigate the impact on access. HDHPs and HSA status were not associated with ED visits among cancer survivors. Improvement to care coordination efforts may be needed to reduce ED visits among privately insured cancer survivors.


[Surgery for renal carcinoma with supradiaphragmatic tumor thrombus: avoiding sternotomy and cardiopulmonary bypass].
To describe a feasible surgical technique for patients with renal cell carcinoma associated with a supradiaphragmatic tumor thrombus that avoids cardiopulmonary bypass procedure. We retrospectively analyzed 2 cases with right kidney tumor and tumor thrombus above the diaphragm treated in April and August, 2015. The two patients were both female, aged 73 and 67 years. The tumor sizes of right kidneys were 7.0 cm×6.3 cm×5.7 cm and 8.7 cm×7.0 cm×5.2 cm, and the tumor thrombuses were 1.3 cm and 1.8 cm above the diaphragm. The second patient had synchronous metastasis in right adrenal gland , and the tumor thrombus arose from the adrenal vein but not the renal vein. Intraoperative transesophageal echocardiography (TEE) was used to assess real-time mobility of the thrombus. A modified chevron incision was used, the right kidney was mobilized laterally and posteriorly, and the renal artery was identified, ligated, and divided. The infradiaphragmatic inferior vena cava (IVC) was exposed and isolated by mobilizing the liver off the diaphragm or to the left (piggyback liver mobilization, case 2). The central diaphragm tendon was dissected or incised in the midline until the supradiaphragmatic intrapericardial IVC was identified and gently pulled beneath the diaphragm and into the abdomen. The tumor thrombus was then "milked" downward out of the intrapericardial IVC under the guidance of TEE. The distal and proximal IVC to the tumor thrombus, porta hepatis, and left renal vein were clamped. Tumor thrombus was removed from the IVC. The IVC was sutured and vascular clamps were placed below the major hepatic veins. Pringle's maneuver was then released and hepatic blood drainage was permitted during closure of the remaining IVC. Related literature was reviewed. Complete resection was successful through the transabdominal approach without CBP in both patients. Estimated blood loss was 1 500 mL and 2 000 mL, and 1 200 mL and 800 mL of blood were transfused. The postoperative courses were uneventful. Both patients subsequently underwent tyrosine-kinase inhibitor therapy. Both patients were alive without tumor recurrence or new metastasis during the follow-up of 6 months and 9 months. In selected cases, renal cell carcinoma extending into the IVC above the diaphragm can be resected without sternotomy, CBP or DHCA.


Alarmins and Related Molecules in Elective Surgery.
Surgery is associated with alterations of alarmins' and related molecules' levels. The aim of this study was to investigate which biomarkers are most involved in surgery. The studied group consisted of 58 patients with inguinal or umbilical hernia or cholecystolithiasis and 21 healthy controls for compa-rison. We also added seven acute patients with appendicitis, cholecystitis and incarcerated hernia. Serum concentrations of soluble receptor of advanced glycation end-products (sRAGE), extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE), calprotectin, high mobility group box 1 (HMGB1) and interleukin 6 (IL-6) were analysed by ELISA before and after surgery. Preoperative concentrations of calprotectin were significantly decreased while concentrations of sRAGE were significantly increased in patients compared to controls; the concentrations of EN-RAGE and HMGB1 did not differ significantly. IL-6 levels were undetectable in elective patients preoperatively and in controls. Postoperatively, there was a significant increase of EN-RAGE, calprotectin, HMGB1, and IL-6 and a significant decrease of sRAGE compared to preoperative levels. In acute patients, all tested molecules except for sRAGE were significantly increased preoperatively, and sRAGE was significantly decreased. In contrast, after surgery, we could observe a further increase in IL-6; the other biomarkers did not differ significantly. We can conclude that the concentrations of all tested biomarkers are significantly influenced by elective surgery. The postoperative levels of all tested molecules increase except for sRAGE, whose level is significantly decreased after surgery. In acute states, these molecules are already increased, and the influence of surgery is, apart from IL-6, insignificant.


Factor structure and validity of the Parental Competence Questionnaire in the Paediatric Hospital Emergency Setting (ECP-U).
To confirm the structure and examine the psychometric properties of the Parental Competence Questionnaire in the Paediatric Hospital Emergency Setting (ECP-U). An instrumental validation study of the ECP-U questionnaire and an examination of its psychometric properties were carried out. The participants were 260 mothers and fathers seeking care in the paediatric emergency department of a hospital in Valencia (Spain) with children aged 0 to 14 years old. The five-factor structure of the ECP-U was confirmed with excellent statistical fits. Second-order models and a more parsimonious four-factor structure with adequate but marginal fits are proposed. With the exception of the "parental agency" factor (in both models examined) and the "active social support" factor (in the original five-factor structure), the internal consistency of the different factors was modest (≥ 0.70). A negative correlation was found between the Parental Stress Scale and the ECP-U for most factors. Validity and reliability analyses indicate that the ECP-U is an instrument with modest psychometric properties. The ECP-U is an instrument that can be used by future researchers to identify different levels of parental competence in paediatric hospital emergency departments. This will enable help to be given to families with parenting issues and problems. The underlying concern is to reduce the number of frequent users and "Non-Urgent Presentations" to paediatric emergency departments due to low parental competence.


Combinatorial Screening of Nanoclay-Reinforced Hydrogels: A Glimpse of the "Holy Grail" in Orthopedic Stem Cell Therapy?
Despite the promise of hydrogel-based stem cell therapies in orthopedics, a significant need still exists for the development of injectable microenvironments capable of utilizing the regenerative potential of donor cells. Indeed, the quest for biomaterials that can direct stem cells into bone without the need of external factors has been the "Holy Grail" in orthopedic stem cell therapy for decades. To address this challenge, we have utilized a combinatorial approach to screen over 63 nanoengineered hydrogels made from alginate, hyaluronic acid, and two-dimensional nanoclays. Out of these combinations, we have identified a biomaterial that can promote osteogenesis in the absence of well-established differentiation factors such as bone morphogenetic protein 2 (BMP2) or dexamethasone. Notably, in our "hit" formulations we observed a 36-fold increase in alkaline phosphate (ALP) activity and a 11-fold increase in the formation of mineralized matrix, compared to the control hydrogel. This induced osteogenesis was further supported by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and energy-dispersive X-ray spectroscopy. Additionally, the Montmorillonite-reinforced hydrogels exhibited high osteointegration as evident from the relatively stronger adhesion to the bone explants as compared to the control. Overall, our results demonstrate the capability of combinatorial and nanoengineered biomaterials to induce bone regeneration through osteoinduction of stem cells in a natural and differentiation-factor-free environment.


Dietary Manganese Promotes Staphylococcal Infection of the Heart.
Diet, and specifically dietary metals, can modify the risk of infection. However, the mechanisms by which manganese (Mn), a common dietary supplement, alters infection remain unexplored. We report that dietary Mn levels dictate the outcome of systemic infections caused by Staphylococcus aureus, a leading cause of bacterial endocarditis. Mice fed a high Mn diet display alterations in Mn levels and localization within infected tissues, and S. aureus virulence and infection of the heart are enhanced. Although the canonical mammalian Mn-sequestering protein calprotectin surrounds staphylococcal heart abscesses, calprotectin is not released into the abscess nidus and does not limit Mn in this organ. Consequently, excess Mn is bioavailable to S. aureus in the heart. Bioavailable Mn is utilized by S. aureus to detoxify reactive oxygen species and protect against neutrophil killing, enhancing fitness within the heart. Therefore, a single dietary modification overwhelms vital host antimicrobial strategies, leading to fatal staphylococcal infection.


Liver findings in patients with Carney complex, germline PRKAR1A pathogenic variants, and link to cardiac myxomas.
This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype-phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55-17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.


Comorbid disorders as moderators of response to family interventions among adolescents with bipolar disorder.
While family interventions have shown efficacy in improving mood symptoms and family functioning in pediatric bipolar disorder, few studies have examined the effects of comorbid psychiatric conditions on patients' symptomatic or functional responses to treatment. 145 adolescents with bipolar I or II disorder were randomly assigned to family-focused therapy (FFT-A) or a brief psychoeducational therapy (enhanced care; EC) and followed over 2 years. Participants received pharmacotherapy for the study's duration. We examined whether comorbid anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and disruptive behavior disorders (DBDs; i.e., oppositional defiant and conduct disorder) predicted the proportion of weeks that participants experienced mood symptoms during follow-up, and whether comorbid disorders moderated the effects of treatment assignment on mood symptoms and family conflict. Comorbid anxiety was associated with a greater proportion of weeks with depressive symptoms, more severe (hypo)manic symptoms during follow-up, and greater family conflict over the 2-year study. Comorbid ADHD was associated with a greater proportion of weeks with (hypo)manic symptoms, more severe (hypo)manic symptoms, and greater family conflict. Additionally, youth with comorbid ADHD who received FFT-A had more favorable trajectories of (hypo)manic symptoms and family functioning than youth with comorbid ADHD who received EC. Comorbid DBDs were consistently associated with more severe depressive symptoms and greater family conflict throughout the study. Randomization to treatments was not stratified on comorbid disorders. The longitudinal trajectories of anxiety, attentional, and disruptive behavior symptoms were not examined. The course of bipolar disorder in adolescents is strongly affected by comorbid disorders. Future research should examine whether adolescents with more complex presentations of bipolar disorder should be treated with different or more intensive psychosocial protocols than adolescents without these presentations.


Natural selection in populations subject to a migration load.
Migration tends to oppose the effects of divergent natural selection among populations. Numerous theoretical and empirical studies have demonstrated that this migration-selection balance constrains genetic divergence among populations. In contrast, relatively few studies have examined immigration's effects on fitness and natural selection within recipient populations. By constraining local adaptation, migration can lead to reduced fitness, known as a "migration load," which in turn causes persistent natural selection. We develop a simple two-island model of migration-selection balance that, although very general, also reflects the natural history of Timema cristinae walking-stick insects that inhabit two host plant species that favor different cryptic color patterns. We derive theoretical predictions about how migration rates affect the level of maladaptation within populations (measured as the frequency of less-cryptic color-pattern morphs), which in turn determines the selection differential (the within-generation morph frequency change). Using data on color morph frequencies from 25 natural populations, we confirm previous results showing that maladaptation is higher in populations receiving more immigrants. We then present novel evidence that this increased maladaptation leads to larger selection differentials, consistent with our model. Our results provide comparative evidence that immigration elevates the variance in fitness, which in turn leads to larger selection differentials, consistent with Fisher's Theorem of Natural Selection. However, we also find evidence that recurrent adult migration between parapatric populations may tend to obscure the effects of selection.


Cardiovascular functions and arterial stiffness after JUUL use.
The rapid growth in the e-cigarette market after the launch of JUUL e-cigarettes led to much discussion on the potential benefits and risks of pods, JUUL devices, and conventional e-cigarettes compared with combustible cigarettes. Independent data are required to assess the effects of these products on cardiovascular surrogate parameters and cardiovascular risk. We conducted a single-center three-arm study comparing combustible cigarettes with JUUL e-cigarettes with the old and new technology. We recruited 32 participants who were active smokers (n=15) or vapers (n=17) and performed a total of 39 measurements before and 5, 15, and 30 minutes, after participants smoked a combustible cigarette or vaped a JUUL e-cigarette with the new or old technology. Measurements included peripheral and central blood pressures and parameters of arterial stiffness, including pulse wave velocity and augmentation index. Peripheral systolic blood pressure, central blood pressure, and peripheral pulse rate increased significantly in all three groups (each p<0.05). Heart rate (HR) changes lasted significantly longer than blood pressure changes. The augmentation index and pulse wave velocity increased in all three groups, and a multivariate analysis of variance showed that the increases were independent of systolic blood pressure, sex, age, device, and HR. Changes in blood pressure and arterial stiffness are similar after cigarette smoking and JUUL use. These changes may be associated with an increased cardiovascular risk compared with no product use. However, a long-term follow-up evaluation of JUUL use and a head-to-head comparison with conventional e-cigarettes are still needed.


Ultrafast nematic-orbital excitation in FeSe.
The electronic nematic phase is an unconventional state of matter that spontaneously breaks the rotational symmetry of electrons. In iron-pnictides/chalcogenides and cuprates, the nematic ordering and fluctuations have been suggested to have as-yet-unconfirmed roles in superconductivity. However, most studies have been conducted in thermal equilibrium, where the dynamical property and excitation can be masked by the coupling with the lattice. Here we use femtosecond optical pulse to perturb the electronic nematic order in FeSe. Through time-, energy-, momentum- and orbital-resolved photo-emission spectroscopy, we detect the ultrafast dynamics of electronic nematicity. In the strong-excitation regime, through the observation of Fermi surface anisotropy, we find a quick disappearance of the nematicity followed by a heavily-damped oscillation. This short-life nematicity oscillation is seemingly related to the imbalance of Fe 3dxz and dyz orbitals. These phenomena show critical behavior as a function of pump fluence. Our real-time observations reveal the nature of the electronic nematic excitation instantly decoupled from the underlying lattice.


The effect of cross-links on the mobility of proteins in dodecyl sulphate-polyacrylamide gels.
The effect of reduction of intramolecular disulphide bridges on the mobility of proteins in 5% (w/v) polyacrylamide gels in the presence of sodium dodecyl sulphate was investigated. A series of polypeptide polymers, containing up to 68 intramolecular disulphide bridges, was prepared by cross-linking proteins of known structure with glutaraldehyde. These model polypeptides were denatured with heat, sodium dodecyl sulphate and urea, and their mobilities in sodium dodecyl sulphate-polyacrylamide gels compared before and after reduction with dithiothreitol. The mobilities of polypeptides containing no cystine were unaffected by reduction. However, reduction generally decreased the mobilities of polypeptides containing cystine; the extent of this decrease depended on the number of cystine residues originally present in the polypeptide polymer, and on the protein from which the latter was derived. In contrast with their higher oligomers, the monomer of lysozyme and the dimer of ribonuclease increased in mobility after reduction. The reduced polypeptide oligomers formed by reaction with glutaraldehyde were generally found to migrate at a rate significantly faster than was expected from their calculated molecular weights. It was concluded that the use of unreduced proteins and protein aggregates for molecular-weight measurements by the sodium dodecyl sulphate-polyacrylamide-gel method may give erroneous estimates of the molecular weight of any protein being investigated.


Finding more constructive ways forward in the debate over vaccines with increased disability cultural competence.
The aim of this article is to study the discursive construction of disability that takes place in the vaccine-autism controversy from the 1990s to 2000s, and an attempt to develop a more holistic framework to understand vaccine decisions and their motivations. It is argued that the debate over vaccines produces knowledge and meanings about disability, and that the vaccine-autism controversy is kept alive largely because of how it reproduces stigmatising accounts of disability and autism. The suggestion is that if the stigmatising elements of disability were removed in the debate over vaccines, there would be no controversy to keep alive in the broader vaccine debate. Hence, this article is an attempt to increase disability cultural competence in the media and among health authorities and health professionals and therethrough broaden the shared understanding of what it means to be or become disabled. By investigating the driving forces for past vaccine controversies, the goal is to find more constructive ways forward in present day and future debates over vaccines.


The role of operations for distantly metastatic well-differentiated thyroid carcinoma.
The role of operations for distantly metastatic well-differentiated thyroid carcinoma (DTC) is poorly defined. We review the indications for operation for metastatic DTC. This study consists of 260 patients treated between 1941 and 2000 for metastatic DTC, of which 59 (23%) underwent operations. Median follow-up was 7 years (range, 1 to 49 years). Metastases were identified clinically in 157 (60%) and radiologically in 103 (40%) patients. The disease-specific survival was estimated with the Kaplan-Meier method. Twenty-four patients (9%) were disease-free with resection. Palliative resection was indicated for painful bone metastasis, pathologic fracture, or symptomatic spinal cord involvement (35/260, 14%). Patients who could undergo complete metastasectomy survived longer than those having incomplete/palliative resection or nonoperative treatment for metastatic DTC (5-year disease-specific survival, 78% vs 43% vs 46%, P =.03). Solitary distant metastasis of DTC amenable to complete resection is infrequent. Complete metastasectomy may be associated with improved survival for localized distant disease. Palliative resection is indicated to improve quality of life for symptomatic distant metastasis.


Auditory processing in anurans.
Anurans (frogs and toads) represent an example of peripheral specialization of the auditory systems. Their inner ear contains two distinct auditory organs: the amphibian papilla and the basilar papilla. Each organ is tuned to different species-specific frequency ranges. Because of this peripheral specialization, anurans offer an excellent opportunity to explore neural decoding of complex sounds in the central auditory system.


Diagnosis and management of chronic persistent dry cough.
Cough is one of the commonest symptoms of lung disease and is a frequent problem encountered in general practice as well as in hospital practice. A wide range of disease processes may present with cough and definitive treatment depends on making an accurate diagnosis of the cause. A diagnostic work-up for patients with persistent dry cough is presented. The most common associated conditions are post-viral cough, asthma, rhinosinusitis (post-nasal drip or 'nasal catarrh') and gastro-oesophageal reflux. Treatment with angiotensin-converting enzyme inhibitors can also lead to a persistent dry cough. Specific treatment of the cause should control the cough, but this may not occur in all cases and in a sizeable proportion of patients, no associated cause can be found. An increased sensitivity of the cough reflex can be observed in patients with persistent dry cough. Symptomatic relief must be considered when the cough interferes with the patient's health and sleep but the most effective antitussive opiates cause sedation and may be addictive. Treatment of persistent dry cough remains a challenge in some patients and there is still scope for improvement in its diagnosis and effective therapy.


Distributed lag and spline modeling for predicting energy expenditure from accelerometry in youth.
Movement sensing using accelerometers is commonly used for the measurement of physical activity (PA) and estimating energy expenditure (EE) under free-living conditions. The major limitation of this approach is lack of accuracy and precision in estimating EE, especially in low-intensity activities. Thus the objective of this study was to investigate benefits of a distributed lag spline (DLS) modeling approach for the prediction of total daily EE (TEE) and EE in sedentary (1.0-1.5 metabolic equivalents; MET), light (1.5-3.0 MET), and moderate/vigorous (> or = 3.0 MET) intensity activities in 10- to 17-year-old youth (n = 76). We also explored feasibility of the DLS modeling approach to predict physical activity EE (PAEE) and METs. Movement was measured by Actigraph accelerometers placed on the hip, wrist, and ankle. With whole-room indirect calorimeter as the reference standard, prediction models (Hip, Wrist, Ankle, Hip+Wrist, Hip+Wrist+Ankle) for TEE, PAEE, and MET were developed and validated using the fivefold cross-validation method. The TEE predictions by these DLS models were not significantly different from the room calorimeter measurements (all P > 0.05). The Hip+Wrist+Ankle predicted TEE better than other models and reduced prediction errors in moderate/vigorous PA for TEE, MET, and PAEE (all P < 0.001). The Hip+Wrist reduced prediction errors for the PAEE and MET at sedentary PA (P = 0.020 and 0.021) compared with the Hip. Models that included Wrist correctly classified time spent at light PA better than other models. The means and standard deviations of the prediction errors for the Hip+Wrist+Ankle and Hip were 0.4 +/- 144.0 and 1.5 +/- 164.7 kcal for the TEE, 0.0 +/- 84.2 and 1.3 +/- 104.7 kcal for the PAEE, and -1.1 +/- 97.6 and -0.1 +/- 108.6 MET min for the MET models. We conclude that the DLS approach for accelerometer data improves detailed EE prediction in youth.


Effects of stimulation of muscarinic and of beta-catecholamine receptors on the intracellular distribution of protein kinase C in guinea pig exocrine glands.
Stimulation of exocrine cells via muscarinic receptors is associated with an activation of protein kinase C [Padel & Söling (1985) Eur. J. Biochem. 151, 1-10]. We show here that stimulation of isolated parotid gland lobules with 8 X 10(-6) M-carbamoylcholine leads to a translocation of protein kinase C from the cytosolic to the particulate compartment within 30 s (25% and 45% of total activity recovered in the particulate fraction of controls and stimulated samples respectively). The specific enzyme activity in the particulate fraction increased to 169% of the corresponding control value. After 10 min the changes started to reverse and, after 30 min, cytosolic protein kinase C was higher in stimulated than in unstimulated lobules. Isoproterenol (2 X 10(-5) M) stimulated the release of amylase more than did carbamoylcholine, but did not significantly affect intracellular distribution of protein kinase C during the observation time of 30 min. In isolated pancreatic lobules a significant carbamoylcholine-mediated translocation of protein kinase C into the particulate fraction could be observed after 5 and 20 min, but not after 1 min. After 5 min the specific enzyme activity in the particulate fraction had increased to 153% of the corresponding controls. The corresponding decrease (-38%) in the specific enzymic activity of cytosolic protein kinase C stayed constant up to 30 min. In isolated parotid gland lobules alpha-amylase secretion proceeded at a linear rate already during the first 1 min of stimulation, whereas in pancreatic lobules a measurable rate of alpha-amylase secretion did not occur before 5 min. These differences in time course paralleled the differences in the onset of translocation of protein kinase C. The results support a direct involvement of protein kinase C in carbamoylcholine-mediated but not in isoproterenol-mediated stimulation of exocytosis in exocrine cells.


[Pattern electroretinography in routine clinical diagnosis of open angle glaucoma].
According to current opinion, the pattern electroretinogram (ERG) is generated in the retinal ganglion cells. Therefore, the amplitude is expected to be reduced in diseases of the optic nerve. This leads to the conclusion that the pattern ERG might be applied in detecting ganglion cell loss in the routine clinical diagnosis of chronic open-angle glaucoma. Pattern ERGs were recorded in 15 patients with defined chronic open-angle glaucoma and 21 control individuals using a DTL fiber electrode at two different check sizes. A Fourier analysis of the ERG results reduces the subjectivity when analysing the amplitudes on screen and implies the possibility of multicentric comparability. The reliability of coordinating a value of a future patient to the correct group was estimated to 82% for the Fourier data by the bivariate discriminant analysis, based on the amplitudes of both check sizes. In this way, the relatively high interindividual variability will be partly overcome. The ability of the ERG amplitudes to separate glaucoma patients from healthy persons was determined by the AUC value, using a combination of sensitivity and specificity extracted from the ROC curves. The AUC value has its maximum at 1.0. We found an AUC value of 0.8, which confirmed the information given by the pattern ERG amplitudes. Healthy individuals and glaucoma patients cannot be separated completely by the procedure but, combined with additional clinical parameters, further validation can be achieved.


T lymphocyte migration to lymph nodes is maintained during homeostatic proliferation.
The immune system maintains appropriate cell numbers through regulation of cell proliferation and death. Normal tissue distribution of lymphocytes is maintained through expression of specific adhesion molecules and chemokine receptors such as L-selectin and CCR7, respectively. Lymphocyte insufficiency or lymphopenia induces homeostatic proliferation of existing lymphocytes to increase cell numbers. Interestingly, homeostatic proliferation of T lymphocytes induces a phenotypic change from naïve- to memory-type cell. Naïve T cells recirculate between blood and lymphoid tissues whereas memory T cells migrate to nonlymphoid sites such as skin and gut. To assess effects of homeostatic proliferation on migratory ability of T cells, a murine model of lymphopenia-induced homeostatic proliferation was used. Carboxyfluorescein diacetate, succinimidyl ester-labeled wild-type splenocytes were adoptively transferred into recombination activation gene-1-deficient mice and analyzed by flow cytometry, in vitro chemotactic and in vivo migration assays, and immunofluorescence microscopy. Homeostatically proliferated T cells acquired a mixed memory-type CD44high L-selectinhigh CCR7low phenotype. Consistent with this, chemotaxis to secondary lymphoid tissue chemokine in vitro was reduced by 22%-34%. By contrast, no differences were found for migration or entry into lymph nodes during in vivo migration assays. Therefore, T lymphocytes that have undergone homeostatic proliferation recirculate using mechanisms similar to naïve T cells.


Sporulation of Bacillus stearothermophilus.
A broth medium containing tryptone and manganese sulfate supported heavy sporulation of Bacillus stearothermophilus ATCC 7953 (NCA 1518) and four isolates identified as B. stearothermophilus. Maximal spore yields were obtained by use of inocula grown anaerobically in a medium containing glucose with aeration of sporulation medium via bubbling. After an extended stationary period, sporulation occurred concurrently with vegetative growth between 6 and 8 hr of incubation at 60 C. Omission of glucose from the inoculum or use of a "young" (2 hr) inoculum abolished the stationary period, but decreased spore yields. A requirement of oxygen for rapid vegetative growth and sporulation was demonstrated. Manganese (15 to 30 ppm) stimulated sporulation but did not enhance cell growth.


Effects of the topically applied calcium-channel blocker flunarizine on intraocular pressure in clinically normal dogs.
To determine effects of the topically applied calcium-channel blocker flunarizine on intraocular pressure (IOP) in clinically normal dogs. 20 dogs. Baseline diurnal IOPs were determined by use of a rebound tonometer on 2 consecutive days. Subsequently, 1 randomly chosen eye of each dog was treated topically twice daily for 5 days with 0.5% flunarizine. During this treatment period, diurnal IOPs were measured. In addition, pupillary diameter and mean arterial blood pressure (MAP) were evaluated. Serum flunarizine concentrations were measured on treatment day 5. Intraday fluctuation of IOP was analyzed by use of an ANOVA for repeated measures and a trend test. Changes in IOP from baseline values were assessed and compared with IOPs for the days of treatment. Values were also compared between treated and untreated eyes. A significant intraday fluctuation in baseline IOP was detected, which was highest in the morning (mean +/- SE, 15.8 +/- 0.63 mm Hg) and lowest at night (12.9 +/- 0.61 mm Hg). After 2 days of treatment, there was a significant decrease in IOP from baseline values in treated (0.93 +/- 0.35 mm Hg) and untreated (0.95 +/- 0.34 mm Hg) eyes. There was no significant treatment effect on pupillary diameter or MAP. Flunarizine was detected in serum samples of all dogs (mean +/- SD, 3.89 +/- 6.36 microg/L). Topically applied flunarizine decreased IOP in dogs after 2 days of twice-daily application. This calcium-channel blocker could be effective in the treatment of dogs with glaucoma.


Zebrafish as a model system to study toxicology.
Monitoring and assessing the effects of contaminants in the aquatic eco-environment is critical in protecting human health and the environment. The zebrafish has been widely used as a prominent model organism in different fields because of its small size, low cost, diverse adaptability, short breeding cycle, high fecundity, and transparent embryos. Recent studies have demonstrated that zebrafish sensitivity can aid in monitoring environmental contaminants, especially with the application of transgenic technology in this area. The present review provides a brief overview of recent studies on wild-type and transgenic zebrafish as a model system to monitor toxic heavy metals, endocrine disruptors, and organic pollutants for toxicology. The authors address the new direction of developing high-throughput detection of genetically modified transparent zebrafish to open a new window for monitoring environmental pollutants.


[Alveolar-arterial oxygen gradient in cardiopulmonary patients breathing ambient air at rest and during exercise].
The alveolar to arterial difference of oxygen [(A-a)DO2] depends on variables such as ventilation, cardiac output, respiratory exchange ratio and arterial PO2. The arterial PO2 itself depends on the ventilation to perfusion ratio (V/Q) pulmonary shunt, (a-v) O2 difference, and the metabolic status of the patient. When the alveolar-ventilation is normal, the (A-a)DO2 reflects gas exchange abnormalities and when the alveolar-ventilation is increased, the (A-a)DO2 can increase because of a decrease in PaCO2. The factors capable of altering the alveolar to arterial oxygen difference were investigated in ninety patients with pulmonary disease: (pulmonary embolism, lung fibrosis and chronic obstructive lung disease), both at rest and during exercise. At rest when alveolar ventilation was increased, the (A-a)DO2 broadened due to the decrease in PaCO2. During exercise the (A-a)DO2 also increased and the PaCO2 was not significantly modified, therefore admixture it is the result of an increase in the proportion of venous. The difference between the mixed venous and arterial PO2 decreased due to alveolar hypoventilation reducing in consequence the (A-a)DO2. We conclude that in the group studied the increase in the (A-a)DO2 is mainly due to V/Q imbalance at rest and during exercise.


Expectant management of early onset, severe pre-eclampsia: maternal outcome.
To evaluate the safety and outcome of women undergoing expectant management of early onset, severe pre-eclampsia. Prospective case series extending over a five-year period. Tygerberg Hospital, a tertiary referral centre. All women (n = 340) presenting with early onset, severe pre-eclampsia, where both the mother and the fetus were otherwise stable. Frequent clinical and biochemical monitoring of maternal status, together with careful blood pressure control, in a high care obstetric ward. Major maternal complications and prolongation of gestation. Multigravid women constituted 67% of the group. Antenatal biochemistry was reassuring with some expected, but not severe, deteriorations. Twenty-seven percent of women experienced a major complication, but few had poor outcomes. No maternal deaths occurred. Most major complications resolved quickly, necessitating only three admissions (0.8%) to the intensive care unit. One woman required dialysis. Pregnancies were prolonged by a mean (median) number of 11 days (9) before delivery, with more time being gained at earlier gestations. The postpartum inpatient stay (89% < or =7 days, bearing in mind that 82% of women were delivered by caesarean section) was not extended. Careful noninvasive management of early onset, severe pre-eclampsia in a tertiary centre can diminish and limit the impact of serious maternal complications. Valuable time to prolong the pregnancy and improve neonatal outcome is thereby gained.


Nontemplate-dependent polymerization processes: polyhydroxyalkanoate synthases as a paradigm.
This review focuses on nontemplate-dependent polymerases that use water-soluble substrates and convert them into water-insoluble polymers that form granules or inclusions within the cell. The initial part of the review summarizes briefly the current knowledge of polymer formation catalyzed by starch and glycogen synthases, polyphosphate kinase (a polymerase), cyanophycin synthetases, and rubber synthases. Specifically, our current understanding of their mechanisms of initiation, elongation (including granule formation), termination, remodeling, and polymer reutilization will be presented. General underlying principles that govern these types of polymerization reactions will be enumerated as a paradigm for all nontemplate-dependent polymerizations. The bulk of the review then focuses on polyhydroxyalkanoate (PHA) synthases that generate polyoxoesters. These enzymes are of interest as they generate biodegradable polymers. Our current knowledge of PHA production and utilization in vitro and in vivo as well as the contribution of many proteins to these processes will be reviewed.


Pantothenate kinase and control of CoA synthesis in heart.
Control of coenzyme A (CoA) synthesis was studied in isolated perfused rat hearts. The data obtained support the hypothesis that phosphorylation of pantothenic acid by pantothenate kinase is the flux-generating reaction in the pathway of CoA synthesis. This reaction operated in the cell far removed from its thermodynamic equilibrium; it was saturated with substrates under all conditions studied; and the concentration of substrate changed in the opposite direction to flux when flux was altered. The reaction was subject to control by external factors associated with oxidation of glucose, pyruvate, or palmitate. CoA synthesis from 4'-phosphopantothenic acid was not inhibited by glucose and pyruvate, suggesting that pantothenate kinase is the only reaction in the pathway that is controlled in isolated hearts. Maximum rates of CoA synthesis in perfused hearts with pantothenate kinase stimulation were dependent on a supply of exogenous cysteine. Perfusate [14C]cysteine was incorporated into intermediates of this pathway and CoA. When protected from oxidation to cystine by low concentrations of dithiothreitol, 0.1 mM cysteine in the perfusate resulted in maximum rates of CoA synthesis. Evidence was obtained that indicates that addition of cysteine relieves a substrate limitation at the 4'-phosphopantothenyl cysteine synthase reaction.


Effect of Adjunctive Pimavanserin on Sleep/Wakefulness in Patients With Major Depressive Disorder: Secondary Analysis From CLARITY.
This was an analysis of the effect of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response. For this analysis of CLARITY, a phase 2 study of adjunctive pimavanserin (N = 207) conducted between December 2016 and October 2018, sleep/wakefulness disturbances were measured with the 17-item Hamilton Depression Rating Scale (HDRS₁₇) insomnia items (sum of items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline in HDRS₁₇ insomnia factor score and KSS score, correlation between the HDRS₁₇ insomnia factor score and KSS score, and change from baseline in the Sheehan Disability Scale (SDS) total score and Unproductive Days subscore in patients with a baseline KSS score ≥ 6. At baseline, HDRS₁₇ insomnia factor score ≥ 3 occurred in 76% of patients receiving placebo and 85% of patients receiving pimavanserin. The overall least squares (LS) mean weighted difference (SE) was -0.5 (0.32) with a 95% CI of -1.2 to 0.1 (P = .088) at week 5. Improvement was observed with pimavanserin versus placebo at weeks 2, 3, and 4, with effect sizes (ESs) of 0.370 to 0.524 (P < .05). For KSS score, the LS mean difference (SE) at week 5 was -1.1 (0.30) (95% CI, -1.7 to -0.5; P = .0003; ES = 0.627) for pimavanserin versus placebo. Among those with a KSS score ≥ 6 at baseline (n = 120 placebo and n = 42 pimavanserin), the LS mean difference (SE) in the mean SDS score at week 5 was -1.1 (0.46) (95% CI, -2.0 to -0.2; P = .019; ES = 0.442) for pimavanserin versus placebo. Adjunctive pimavanserin significantly improved sleep/wakefulness disturbance during treatment of MDD, an improvement that was associated with greater improvement in function. ClinicalTrials.gov identifier: NCT03018340.


[Dependence of monotrachial bacteria chemotaxis on the direction of flagella rotation].
Monotrichous bacteria V. harveyi periodically reverse their direction when moving in a liquid environment. It is reported that in a uniform surrounding the motility pattern is composed of a repeat of two sequential runs: a short and a long one separated by a reversal. The main duration of the short run was 0.4 sec and of the long one - 1.3 sec. Upon the addition of attractants or repellents the long runs became prolonged or shortened correspondingly. The duration of the short runs was independent of attractant or repellent stimuli. It is concluded that the flagellum is unresponsive to the taxis signal when rotating clockwise, which corresponds to the short run.


[Mono- and polyradicular syndromes in lumbar osteochondrosis].
The authors studied the clinical picture of lumbar osteochondritis in 1,020 patients, 151 of whom were operated on. The monoradicular syndrome was diagnosed in 68%, the biradicular (involvement of two radicles) in 27%, and the polyradicular (involvement of three and more radicles) in 7% of the patients. In the authors' opinion, the development of the mono- or polyradicular syndromes in lumbar osteochondritis depends on the character of the disc hernia (lateral, paramedian, median) and on the degree of the reactive inflammatory changes in the radicles, the epidural tissue and the spinal meninges. Of an importance in this connection is the duration of the disease, especially, of the radicular manifestations. A particular attention should be also paid to the duration of the disease relapse.


Telehealth Interventions and Outcomes Across Rural Communities in the United States: Narrative Review.
In rural communities, there are gaps in describing the design and effectiveness of technology interventions for treating diseases and addressing determinants of health. The aim of this study is to evaluate literature on current applications, therapeutic areas, and outcomes of telehealth interventions in rural communities in the United States. A narrative review of studies published on PubMed from January 2017 to December 2020 was conducted. Key search terms included telehealth, telemedicine, rural, and outcomes. Among 15 included studies, 9 studies analyzed telehealth interventions in patients, 3 in health care professionals, and 3 in both patients and health care professionals. The included studies reported positive outcomes and experiences of telehealth use in rural populations including acceptability and increased satisfaction; they also noted that technology is convenient and efficient. Other notable benefits included decreased direct and indirect costs to the patient (travel cost and time) and health care service provider (staffing), lower onsite health care resource utilization, improved physician recruitment and retention, improved access to care, and increased education and training of patients and health care professionals. Telehealth models were associated with positive outcomes for patients and health care professionals, suggesting these models are feasible and can be effective. Future telehealth interventions and studies examining these programs are warranted, especially in rural communities, and future research should evaluate the impact of increased telehealth use as a result of the COVID-19 pandemic.


Evaluation of the chronic disease management program for appropriateness of medication adherence and persistence in hypertension and type-2 diabetes patients in Korea.
The chronic disease management program (CDMP), a multilevel intervention including copayment reduction and physician incentives, was introduced in 2012 in Korea to improve blood pressure and glycemic control by strengthening the function of clinic as primary care institutions in managing hypertension and diabetes. This study, therefore, aimed to evaluate the effect of CDMP on the appropriateness of medication adherence and persistence in hypertension or type-2 diabetes patients.A pre-post retrospective study was conducted using claims cohort data from 2010 to 2013. Hypertension or type-2 diabetes patients were selected as the CDMP group, while dyslipidemia patients were the control group. Study groups were further categorized as clinic shifters or non-shifters on the basis of whether hospital use changed to clinic use during the study period. Pre-post changes in adherence and persistence were assessed. Adherence was measured by medication possession ratio (MPR) and categorized as under (<0.8), appropriate (0.8-1.1), and over-adherence (>1.1). Persistence was measured by 12-month cumulative persistence rate.The pre-post change was significantly improved for appropriate-adherence (hypertension, +6.0%p; diabetes, +6.1%p), 12-month cumulative persistence (hypertension, +6.5%p; diabetes, +10.8%p), and over-adherence (hypertension, -5.3%p; diabetes, -2.8%p) only among the shifters in the CDMP group. Among these, patients visiting the same, single clinic showed a significant increase in appropriate-adherence, whereas those who changed their clinics showed a nonsignificant increase. No significant improvement was verified among the non-shifters in the CDMP group.CDMP improved medication adherence and persistence by significantly increasing appropriate-adherence and 12-month cumulative persistence rate in hypertension and type-2 diabetes patients. Particularly, CDMP significantly improved over-adherence, which was associated with increasing healthcare costs and hospitalization risk.


The putative oligosaccharide translocase SypK connects biofilm formation with quorum signaling in Vibrio fischeri.
Quorum signaling (QS) describes how bacteria can use small signaling molecules (autoinducers) to coordinate group-level behaviors. In Vibrio fischeri, QS is achieved through a complex regulatory network that ultimately controls bioluminescence, motility, and host colonization. We conducted a genetic screen focused on qrr1, which encodes a small regulatory RNA that is necessary for the core quorum-signaling cascade to transduce autoinducer information into cellular responses. We isolated unique mutants with a transposon inserted into one of two genes within the syp locus, which is involved in biofilm formation. We found that overexpression of sypK, which encodes a putative oligosaccharide translocase, is sufficient to activate qrr1, and, in addition, this effect appears to depend on the kinase activity of the sensor LuxQ. Consistent with the established model for QS in V. fischeri, enhanced expression of qrr1 by the overexpression of sypK resulted in reduced bioluminescence and increased motility. Finally, we found that induction of the syp locus by overexpression of sypG was sufficient to activate qrr1 levels. Together, our results show how conditions that promote biofilm formation impact the quorum-signaling network in V. fischeri, and further highlight the integrated nature of the regulatory circuits involved in complex bacterial behaviors.


MicroRNA-155-3p promotes breast cancer progression through down-regulating CADM1.
Cell adhesion molecule 1 (CADM1) functions as a tumor suppressor and has been identified to be frequently inactivated in breast cancer, and closely associated with patients' poor prognosis and advanced TNM stage. However, the mechanisms underlying CADM1 in breast cancer progression remains incompletely clear. miR-155, a predicted modulator of CADM1 was reported to be overexpressed in breast cancer, and its high expression level was closely related to the malignant progression of breast cancer. The present study aimed to explore whether miR-155-3p could modulate CADM1 expression and then involved in the progression of breast cancer. The expression patterns of miR-155-3p in breast cancer tissues and cell lines were determined by RT-PCR technology. The relationship between CADM1 and miR-155-3p were determined by the luciferase gene reporter and Western Blot (WB) assays. Cell proliferation, apoptosis rates and tumorigenesis were determined by CCK-8, flow cytometry and in vivo xenotransplanation experiments, respectively. miR-155-3p was up-regulated in breast cancer tissues and cells when compared to the adjacent normal tissues and normal breast MCF 10A cells. The mRNA and protein levels of CADM1 showed opposite expression patterns to that of miR-155-3p expression detected, and miR-155-3p could negatively regulate CADM1 expression in breast cancer MCF-7 cells. Moreover, gain-of function assay showed that overexpression of miR-155-3p promoted cell proliferation, tumorigenesis and repressed cell apoptosis, but these effects were all significantly impaired when the cells were simultaneously transfected with OE-CADM1, the overexpressing vector of CADM1. This study revealed that miR-155-3p could accelerate the progression of breast cancer via down-regulation of CADM1 expression.


3D Printed Vascularized Device for Subcutaneous Transplantation of Human Islets.
Transplantation of pancreatic islets or stem cell derived insulin secreting cells is an attractive treatment strategy for diabetes. However, islet transplantation is associated with several challenges including function-loss associated with dispersion and limited vascularization as well as the need for continuous immunosuppression. To overcome these limitations, here we present a novel 3D printed and functionalized encapsulation system for subcutaneous engraftment of islets or islet like cells. The devices were 3D printed with polylactic acid and the surfaces treated and patterned to increase the hydrophilicity, cell attachment, and proliferation. Surface treated encapsulation systems were implanted with growth factor enriched platelet gel, which helped to create a vascularized environment before loading human islets. The device protected the encapsulated islets from acute hypoxia and kept them functional. The adaptability of the encapsulation system was demonstrated by refilling some of the experimental groups transcutaneously with additional islets.


Functional capacity and physical performance of community-dwelling elderly: a longitudinal study.
This study aimed to verify the occurrence of changes in the functional capacity and physical performance of community-dwelling elderly and its determining factors over a two-year period. This is a quantitative, observational and longitudinal household survey conducted in 2014 and 2016, with the participation of 380 elderly from Uberaba, Minas Gerais. The following instruments were used: The Mini-Mental State Examination and questionnaires with sociodemographic/economic, clinical and life habits data. The functional capacity was evaluated through the Katz Index and Lawton-Brody's scale. Physical performance was verified through the Short Physical Performance Battery. A descriptive, bivariate and linear multiple regression analysis was conducted, with a significance level of α < 0.05. The results showed reduced functional capacity for the instrumental activities of daily living and physical performance in a two-year period. The determining factors for both outcomes were age group, occupational activity, and physical activity. Schooling was a specific factor only for the instrumental activities of daily living, and gender and the number of medicines used, for physical performance.


[Comparison of bicycle ergometry and step-ladder exercise (author's transl)].
Repeat exercises (three hours apart) on a bicycle ergometer and a vertical step-ladder were performed in a randomised series on 79 subjects: 13 doctors, 44 patients and 22 sportsmen. Duration of exercise was on average 250% longer in the three groups on the step-ladder than the bicycle. Correspondingly, exercise-pulse sums, recovery-pulse sums and exercise indices were two-and-a-half to three times higher than on bicycle ergometry. As a sign of comparability of the exercise by the two methods there was, on average, no significant difference with regard to the final heart rate, although duration of exercise was longer on the step-ladder. 67% of subjects discontinued the exercise because of peripheral muscle fatigue on the bicycle ergometer, compared with only 8% on the step-ladder. During bicycle ergometry lactate concentration rose by 6.7 mmol/l compared with only 0.78 mmol/l during step-ladder exercise. These results indicate that the value of bicycle ergometry exercise is limited by muscle fatigue in the legs: step-ladder exercise can be extended much longer. The practical significance is that patients with coronary heart disease especially have symptoms and/or ECG changes of ischaemia only at higher levels of physical exercise.


The isoflavone genistein inhibits internalization of enteric bacteria by cultured Caco-2 and HT-29 enterocytes.
The dietary isoflavone genistein is the focus of much research involving its role as a potential therapeutic agent in a variety of diseases, including cancer and heart disease. However, there is recent evidence that dietary genistein may also have an inhibitory effect on extraintestinal invasion of enteric bacteria. To study the effects of genistein on bacterial adherence and internalization by confluent enterocytes, Caco-2 and HT-29 enterocytes (cultivated for 15-18 d and 21-24 d, respectively) were pretreated for 1 h with 0, 30, 100, or 300 micromol/L genistein, followed by 1-h incubation with pure cultures of Listeria monocytogenes, Salmonella typhimurium, Proteus mirabilis, or Escherichia coli. Pretreatment of Caco-2 and HT-29 enterocytes with genistein inhibited bacterial internalization in a dose-dependent manner (r = 0.60-0.79). Compared to untreated enterocytes, 1-h pretreatment with 300 micromol/L genistein was generally associated with decreased bacterial internalization (P < 0. 05) without a corresponding decrease in bacterial adherence. Using Caco-2 cell cultures, decreased bacterial internalization was associated with increased integrity of enterocyte tight junctions [measured by increased transepithelial electrical resistance (TEER)], with alterations in the distribution of enterocyte perijunctional actin filaments (visualized by fluorescein-labeled phalloidin), and with abrogation of the decreased TEER associated with S. typhimurium and E. coli incubation with the enterocytes (P < 0.01). Thus, genistein was associated with inhibition of enterocyte internalization of enteric bacteria by a mechanism that might be related to the integrity of the enterocyte tight junctions, suggesting that genistein might function as a barrier-sustaining agent, inhibiting extraintestinal invasion of enteric bacteria.


Chromomycosis. The association of fungal elements and wood splinters.
In two separate specimens received for histopathologic examination, pigmented fungal elements were found within or on embedded wood splinters associated with a foreign-body reaction. The fungus was found to be in direct contact with the surrounding dermis. These findings support the concept of inoculation as a pathogenetic mechanism in cutaneous chromomycosis.


Halothane and isoflurane have additive minimum alveolar concentration (MAC) effects in rats.
Studies suggest that at concentrations surrounding MAC (the minimum alveolar concentration suppressing movement in 50% of subjects in response to noxious stimulation), halothane depresses dorsal horn neurons more than does isoflurane. Similarly, these anesthetics may differ in their effects on various receptors and ion channels that might be anesthetic targets. Both findings suggest that these anesthetics may have effects on movement in response to noxious stimulation that would differ from additivity, possibly producing synergism or even antagonism. We tested this possibility in 20 rats. MAC values for halothane and (separately) for isoflurane were determined in duplicate before and after testing the combination (also in duplicate; six determinations of MAC for each rat). The sum of the isoflurane and halothane MAC fractions for individual rats that produced immobility equaled 1.037 +/- 0.082 and did not differ significantly from a value of 1.00. That is, the combination of halothane and isoflurane produced immobility in response to tail clamp at concentrations consistent with simple additivity of the effects of the anesthetics. These results suggest that the immobility produced by inhaled anesthetics need not result from their capacity to suppress transmission through dorsal horn neurons. Despite differences in their capacities to inhibit spinal dorsal horn cells, isoflurane and halothane are additive in their ability to suppress movement in response to a noxious stimulus.


Toolkit for determination of dose-response relations, validation of radiobiological parameters and treatment plan optimization based on radiobiological measures.
Accurately determined dose-response relations of the different tumors and normal tissues should be estimated and used in the clinic. The aim of this study is to demonstrate developed tools that are necessary for determining the dose-response parameters of tumors and normal tissues, for clinically verifying already published parameter sets using local patient materials and for making use of all this information in the optimization and comparison of different treatment plans and radiation techniques. One of the software modules (the Parameter Determination Module) is designed to determine the dose-response parameters of tumors and normal tissues. This is accomplished by performing a maximum likelihood fitting to calculate the best estimates and confidence intervals of the parameters used by different radiobiological models. Another module of this software (the Parameter Validation Module) concerns the validation and compatibility of external or reported dose-response parameters describing tumor control and normal tissue complications. This is accomplished by associating the expected response rates, which are calculated using different models and published parameter sets, with the clinical follow-up records of the local patient population. Finally, the last module of the software (the Radiobiological Plan Evaluation Module) is used for estimating and optimizing the effectiveness a treatment plan in terms of complication-free tumor control, P(+). The use of the Parameter Determination Module is demonstrated by deriving the dose-response relation of proximal esophagus from head and neck cancer radiotherapy. The application of the Parameter Validation Module is illustrated by verifying the clinical compatibility of those dose-response parameters with the examined treatment methodologies. The Radiobiological Plan Evaluation Module is demonstrated by evaluating and optimizing the effectiveness of head and neck cancer treatment plans. The results of the radiobiological evaluation are compared against dosimetric criteria. The presented toolkit appears to be very convenient and efficient for clinical implementation of radiobiological modeling. It can also be used for the development of a clinical data and health information database for assisting the performance of epidemiological studies and the collaboration between different institutions within research and clinical frameworks.


Using Network Theory to Understand and Predict Biological Invasions.
Understanding and predicting biological invasions is challenging because of the complexity of many interacting players. A holistic approach is needed with the potential to simultaneously consider all relevant effects and effectors. Using networks to describe the relevant anthropogenic and ecological factors, from community-level to global scales, promises advances in understanding aspects of invasion from propagule pressure, through establishment, spread, and ecological impact of invaders. These insights could lead to development of new tools for prevention and management of invasions that are based on species' network characteristics and use of networks to predict the ecological effects of invaders. Here, we review the findings from network ecology that show the most promise for invasion biology and identify pressing needs for future research.


IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity.
Group 2 innate lymphoid cells (ILC2 cells) are important for type 2 immune responses and are activated by the epithelial cytokines interleukin 33 (IL-33), IL-25 and thymic stromal lymphopoietin (TSLP). Here we demonstrated that IL-1β was a critical activator of ILC2 cells, inducing proliferation and cytokine production and regulating the expression of epithelial cytokine receptors. IL-1β also governed ILC2 plasticity by inducing low expression of the transcription factor T-bet and the cytokine receptor chain IL-12Rβ2, which enabled the conversion of these cells into an ILC1 phenotype in response to IL-12. This transition was marked by an atypical chromatin landscape characterized by the simultaneous transcriptional accessibility of the locus encoding interferon-γ (IFN-γ) and the loci encoding IL-5 and IL-13. Finally, IL-1β potentiated ILC2 activation and plasticity in vivo, and IL-12 acted as the switch that determined an ILC2-versus-ILC1 response. Thus, we have identified a previously unknown role for IL-1β in facilitating ILC2 maturation and plasticity.